- Email: [email protected]
Liver sinusoidal endothelial cells (LSECs) function and NAFLD; NO-based therapy targeted to the liver
Pharmacological Reports 67 (2015) 689–694
Contents lists available at ScienceDirect
Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep
Review article
Liver sinusoidal endothelial cells (LSECs) function and NAFLD; NO-based therapy targeted to the liver Edyta Maslak a, Aleksandra Gregorius a, Stefan Chlopicki a,b,* a b
Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krako´w, Poland Department of Experimental Pharmacology, Jagiellonian University Medical College, Krako´w, Poland
A R T I C L E I N F O
Article history: Received 17 February 2015 Received in revised form 13 April 2015 Accepted 17 April 2015 Available online 2 May 2015 Keywords: Liver sinusoidal endothelial cells NAFLD Liver cells crosstalk Liver-selective therapy
A B S T R A C T
Liver sinusoidal endothelial cells (LSECs) present unique, highly specialised endothelial cells in the body. Unlike the structure and function of typical, vascular endothelial cells, LSECs are comprised of fenestrations, display high endocytic capacity and play a prominent role in maintaining overall liver homeostasis. LSEC dysfunction has been regarded as a key event in multiple liver disorders; however, its role and diagnostic, prognostic and therapeutic significance in nonalcoholic fatty liver disease (NAFLD) is still neglected. The purpose of this review is to provide an overview of the importance of LSECs in NAFLD. Attention is focused on the LSECs-mediated NO-dependent mechanisms in NAFLD development. We briefly describe the unique, highly specialised phenotype of LSECs and consequences of LSEC dysfunction on function of hepatic stellate cells (HSC) and hepatocytes. The potential efficacy of liver selective NO donors against liver steatosis and novel treatment approaches to modulate LSECs-driven liver pathology including NAFLD are also highlighted. ß 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Morphology and function of LSECs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . LSEC-derived mediators in NAFLD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fenestrated (healthy) and defenestrated (dysfunctional) liver endothelium . . . The NO-dependent crosstalk between LSECs, HSC and hepatocytes in the liver The liver-selective NO-based drug therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Nonalcoholic fatty liver disease (NAFLD) is a group of interrelated chronic liver disorders associated with increased fat deposition within hepatocytes (simple steatosis, SS), lobular and portal inflammation and fibrosis (nonalcoholic steatohepatitis,
* Corresponding author. E-mail address: [email protected] (S. Chlopicki).
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
689 690 690 690 691 692 693 693 693
NASH), that may lead to the development of cirrhosis or hepatocellular carcinoma [1,2]. NAFLD affects about 30% of the population of Western Europe and Eastern countries [3–6], and is increasingly diagnosed in children and adolescents along with the concomitant increased prevalence of obesity in this population [7]. The prevailing hypothesis of NAFLD development is still poorly understood; however, several insults (‘‘hits’’) may be jointly involved in causing progressive liver injury. A classically recognised hit comes from increased consumption of a diet rich in saturated fats and simple carbohydrates, which leads to excessive
http://dx.doi.org/10.1016/j.pharep.2015.04.010 1734-1140/ß 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.
690
E. Maslak et al. / Pharmacological Reports 67 (2015) 689–694
triglyceride accumulation in the hepatocytes. The inappropriate diet is also responsible for peripheral insulin resistance, which shifts free fatty acids metabolism to non-adipose tissues, including the liver. Recently, it was shown that apart from skeletal muscles, adipose tissue and hepatocytes, dietary fat also induced insulin resistance in liver sinusoidal endothelial cells (LSECs) [8]. Therefore, it may well be that a liver subjected to primary hit, most likely associated with the development of dysfunction of LSECs, is vulnerable to subsequent insults, which perpetuates pro-inflammatory and pro-fibrotic response of activated Kupffer cells (KC) and hepatic stellate cells (HSC). Subsequently, simple steatosis may lead to the progression of NASH, cirrhosis or hepatocellular carcinoma. Among a variety of proposed factors, oxidative stress [9], lipotoxicity [10], and gut-derived bacterial endotoxin [11] have been implicated. All of them might also aggravate LSEC dysfunction and contribute to NAFLD pathology. Furthermore, impaired microcirculation, reduced oxygen delivery and altered mitochondrial function due to increased fat deposition in hepatocytes [12] may also play a pathogenetic role. Liver steatosis is, indeed, associated with an increased portal pressure and intrahepatic resistance [13] linked to the impairment of endothelial-dependent regulation of hepatic flow. Altogether, LSEC dysfunction seems to play a prominent role in the pathogenesis of NAFLD. In the present review we focus on the role of LSECs-mediated NO-dependent mechanisms that could prevent NAFLD, and on the potential efficacy of liver selective NO donors in NAFLD. We also briefly describe the unique, highly specialised phenotype of LSECs, consequences of LSEC dysfunction on function of other cells in the liver such as HSC and hepatocytes, and finally novel treatment approaches to modulate LSEC dysfunction that contribute to the development of NAFLD. Morphology and function of LSECs The LSECs comprise about 3% of the total liver volume, which makes 20% of the total number of liver cells. Despite overall similarities, LSECs differ from other endothelial cells considerably and present the best example for remarkable heterogeneity in structure and function among endothelial cells [14]. Under physiological conditions, LSECs are very thin cells lining the liver sinusoids. Unlike typical vascular endothelial cells, LSECs are comprised of pores, called fenestrations, with diameters of about approximately 50–150 nm that are grouped together and dynamically regulated to form so-called ‘‘sieve plates’’, which determine their normal ‘‘differentiated’’ phenotype [15–17]. The sinusoidal endothelium lacks the basement membrane, which additionally constitutes its unique feature [15,16,18]. LSECs fenestrations allow for efficient transfer of lipoproteins, small chylomicron remnants and other macromolecules between blood and the space of Disse, where they are taken up by hepatocytes [19,20]. The structure and function of LSECs are closely linked, as the defenestration is the first phenotypic marker of LSEC dysfunction [21]. LSECs, unlike other endothelial cells but rather similar to phagocyting cells, have high endocytic capacity. Indeed, LSECs have been shown to represent one of the most actively endocytosing cell types in the body mediating clearance of soluble waste macromolecules and colloid material, including blood-borne adenovirus [22,23]. Unlike other endothelial cells LSECs express various scavenger receptors (SR) on their surface including SR-A (also known as macrophage SR), SR-B (SR-B1 and CD36), and the most important SR-H receptor (stabilin-1/FEEL-1 and stabilin-2/ FEEL-2/HARE) [24]. Accordingly, in the liver, not only KC but also LSECs are involved in waste clearance, and these cells seem to complement each other. LSECs represent the professional
pinocyting cells, clearing the blood from soluble macromolecules and small particles (<200 nm), while macrophages (KC) eliminate larger, insoluble particles by phagocytosis [25]. LSEC-derived mediators in NAFLD Despite the unique structural and functional features of LSECs, their repertoire of mediators include nitric oxide (NO), prostacyclin (PGI2), carbon monoxide (CO), endothelin-1 (ET-1), similarly to other endothelial cell types. Still, evidence of function and biochemical profile of LSECs is limited mainly due to technical challenges to plate and culture them [26]. Nevertheless, there is abundant evidence that NO depletion is involved in a number of liver disorders. For example, NO deficiency resulted in massive fat deposition in the liver [27] and was associated with HSC activation towards pro-fibrogenic phenotype [28]. Interestingly, diminished eNOS activity was reported in cirrhotic rats [29]. LSECs expression of eNOS and NO production is mediated by signalling events dependent on Rho GTPases and integrin linked kinase (ILK). Overexpression of ILK mediated by ET-1, vascular endothelial growth factor (VEGF) and transforming growth factor beta-1 (TGFb-1), released in response to liver injury, led to a compensatory increase in eNOS expression and NO production. On the other hand, a lack of ILK led to LSECs detachment, loss of actin fibres and defective vascular development [30,31]. LSECs also express haeme oxygenase (HO) converting protoheme IX to biliverdin–IXa, free divalent iron and CO which, next to NO, seems to serve as an important hepatoprotective mediator [32,33]. For example, CO regulated liver perfusion and HSC function [32]. PGI2, the major anti-platelet and atheroprotective agent [34] also protects against liver injury. Diminished PGI2 production contributed to the hepatotoxic effect of ethanol [35]. The balance between PGI2 and TxB2 is of key importance in vascular homeostasis. In the liver, TxA2 produced from arachidonic acid by cyclooxygenase-1 (COX-1) resulted in HSC activation [36,37]. In fact, cirrhotic livers displayed an increased expression of COX-1 in LSECs [36], and acetylcholine increased the production of TxA2 [38,39], suggesting the role of LSEC-derived TxA2. There is convincing evidence that LSECs produce ET-1, ET-2, and ET-3 affecting HSC activation by two receptors, ETA and ETB [33,40–42]. Inflammatory and oxidative stress linked with hyperresponsiveness of hepatic sinusoids to detrimental effects of ET-1 may be caused by the disruption of beneficial signalling pathways dependent on the ETB receptor and eNOS-signalling of LSECs [39,43,44]. In liver injury induced by ethanol in rats, LSECs were highly activated and showed increased expression of big ET-1 and chemokines as compared with cells isolated from control rats [41]. Altogether, alterations in LSECs homeostasis and activity of LSEC-derived mediators may play an important role in liver injury and in NAFLD in particular. Fenestrated (healthy) and defenestrated (dysfunctional) liver endothelium Under physiological conditions, unique LSECs phenotype characterised by the presence of fenestrations and high endocytic capacity of LSECs, play a prominent role in maintaining liver homeostasis and integrity. However, during liver injury, the LSECs undergo morphological and functional transition. One of the most remarkable phenotypic changes is the loss of fenestrations (‘‘defenestration’’) and formation of a basement membrane on the abluminal surface of LSECs that is closely associated with reduced NO bioavailability. Defenestration has been shown to impair the hepatic uptake of various substances including cholesterol and lipoproteins [45,46] leading to severe hyperlipoproteinemia and liver steatosis [47]. Moreover, a loss of fenestrations has been
E. Maslak et al. / Pharmacological Reports 67 (2015) 689–694
accompanied by decreased LSECs’ endocytic capability [48]. It may contribute to NAFLD development since LSECs are the main scavenger system for oxLDL [49], and oxLDL-dependent pathway has been shown to initiate NASH progression [50]. The mechanisms leading to defenestration are not clear but may involve CD47-thrombospondin-1 dependent mechanisms [51] or plasmalemma vesicle-associated protein (PLVAP) expression [47]. Defenestrated LSECs change not only their structure but also their autocrine and paracrine activity leading to imbalance between LSECs-derived mediators, such as NO, PGI2, ET-1, TxA2. Indeed, in a healthy liver, with preserved fenestrated LSECs phenotype, the balance between LSECs-deriver vasodilators (NO, PGI2) and vasoconstrictors (ET-1, TxA2) is shifted towards vasodilatation [52]. In turn, during liver injury, LSECs become defenestrated and overproduce vasoconstrictors disrupting NO production and bioavailability [52] (Fig. 1). Moreover, balance between those mediators was shown to be crucial for maintaining not only LSECs viability and function but also to affect significantly the phenotype of other liver cells, i.e. HSC and hepatocytes (Fig. 1). The NO-dependent crosstalk between LSECs, HSC and hepatocytes in the liver NO plays a major role in maintaining LSECs fenestrations and responsiveness for pro-survival signal of VEGF that determines the LSECs phenotype and is produced by HSC or hepatocytes [21]. In fact, depletion of VEGF resulted in a loss of LSECs fenestrations, while the resupply of cell culture medium in VEGF restored a healthy LSECs phenotype [53]. In turn, dysfunctional LSECs showed loss of the ability to produce NO and to respond to VEGF [28]. NO is also a key determinant maintaining the quiescent HSC phenotype. The activation of HSC, as well as reversion of activated
691
HSC to a quiescent phenotype is mediated by fenestrated LSECs and depends on the NO [28]. The fluorescence of F-actin and expression of ASMA and TIMP-1, markers of HSC activation, was markedly reduced when co-cultured with freshly isolated, differentiated LSECs [28]. In turn, the addition of L-NAME blocked LSECsmaintained HSC quiescence, further supporting the essential role of NO for maintaining HSC quiescent phenotype [28]. However, DETANONOate, an NO donor, did not reduce the activated HSCs in culture, suggesting that reversal of HSC activation is dependent on VEGF-stimulated NO production, associated with a differentiated LSECs phenotype that promoted the reversal of activated HSC to quiescence [21]. Accordingly, LSECs’ ability for maintaining the quiescent HSC phenotype comprises not only paracrine action of NO but also some other, not yet defined, LSECs mediators, and is highly dependent on the ongoing biochemical crosstalk between LSECs, hepatocytes and HSC. VEGF-NO pathway plays a particularly important role in liver regeneration. VEGF activated LSECs for NO production and also induced hepatic growth factor (HGF) release from LSECs [54]. Moreover, HGF action is conditioned by NO availability. The hepatocytes mitogenic response to HGF was blunted when NO synthesis was inhibited, and the addition of NO donor overcame this effect [55]. This data indicates that quiescent hepatocytes in a normal liver are not able to respond to proliferative stimuli and need to be primed by LSEC-derived NO to respond to HGF signal [55]. Quite surprisingly, KC can also protect against LSECs injury. Fasmediated apoptosis was limited by KC released interleukin-6 binding to glycoprotein 130 on LSECs surface [56], while LSECderived NO limited the activation of KC [57]. Taken all together, direct cellular contact and dynamic biochemical signalling underlying crosstalk between fenestrated LSECs, HSC, KC and hepatocytes maintain liver integrity and function, and NO seems to be a major player. Since NO also
Fig. 1. The cellular crosstalk between liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSC) and hepatocytes in a healthy liver and nonalcoholic fatty liver disease (NAFLD). In a healthy liver (left panel), fenestrated LSECs without a basement membrane facilitate transport of macromolecules between blood and hepatocytes, and maintain liver homeostasis by balanced production of mediators. Hepatocytes absorption area increases by the presence of hepatocyte microvilli while quiescent HSC stores vitamin A (vit. A). Paracrine action of hepatocytes and HSC maintains fenestrated phenotype of LSECs by vascular endothelial growth factor (VEGF) production. In NAFLD liver (right panel), LSECs porosity is reduced (i.e. loss of fenestrations) with presence of basement membrane. An activated HSC loses vit. A and changes phenotype towards myofibroblasts. Fat-loaded hepatocytes lose the hepatocytes microvilli. In addition, the cellular signalling is shifted towards proinflammatory and profibrogenic pathway. Modified from [76,77].
692
E. Maslak et al. / Pharmacological Reports 67 (2015) 689–694
regulates lipid and glucose homeostasis in the liver [27,58,59], a therapeutic approach enhancing cellular NO bioavailability seems to have fundamental implications to treat liver pathology, including NAFLD. The liver-selective NO-based drug therapy V-PYRRO/NO is a stable, hepatoselective NO-releasing prodrug, of the diazeniumdiolate family of NO donors [60] that passively diffuses through the cellular membrane and is metabolised in the liver to NO by several cytochrome P450 isoforms, including mainly CYP2E1 [61], but also by CYP2C9 and CYP3A4 and CYP1A2 [62]. VPYRRO/NO showed beneficial effects in various in vivo and in vitro models of acute hepatotoxicity [63–67] and lacks systemic vasodilation effects [60]. In our recent study [68], we showed that V-PYRRO/NO therapy improved liver steatosis and postprandial glucose tolerance in a mice model of NAFLD (Fig. 2). V-PYRRO/NO inhibited de novo fatty
acid synthesis by phosphorylation of acetyl-CoA carboxylase (ACC) resulting in decreased content of total liver lipids (TAG, DAG, CER) and attenuated liver steatosis. Moreover, those effects were related to a favourable decrease in liver SFA and MUFA and a simultaneous increase in PUFA content. Since DAG and CER were shown to be involved in the insulin signalling pathways and maintaining glucose homeostasis [69], and SFA/UFA balance represents a marker of NAFLD severity [70,71], NO-mediated changes in liver fatty acid composition may bear additional therapeutic importance. Anti-steatotic effects of V-PYRRO/NO also involved the activation of Akt, an important signalling molecule in the insulin signalling pathway, and improvement in hepatic microcirculation perfusion. A comprehensive profile of antiNAFLD activity of V-PYRRO/NO suggests that NO-therapy targeted to the liver may represent a promising and novel approach to treat NAFLD that could be perhaps reinforced by pharmacology of other LSEC-derived mediators. CO was shown to ameliorate liver steatosis induced by a high-fructose, methionine-deficient and
Fig. 2. The therapy with liver-selective nitric oxide (NO) donor, V-PYRRO/NO represents an effective approach against liver steatosis induced by a high-fat (HF) diet in mice. Representative pictures of H&E (A), one step Gomorie’s trichrome (B), and Oil Red O (C) stained section of liver taken from mice fed for 15 weeks standard AIN-93G diet or HF diet with or without treatment. Semi-automatic quantitative analysis of liver fat content from Oil Red O pictures using Image J software (Carl Zeiss, Oberkochen, Germany) (D) and GC/FID chromatography results of liver triglyceride (TG) content are presented (E). Values are means SEM (n = 6). Values with different superscript letters within each animal group are significantly different (p 0.05). AIN-93G: control group; HF: high fat group; HF + metformin: high fat group treated with metformin; HF+V-PYRRO/NO: high fat group treated with V-PYRRO/NO. Figure is reproduced with permission from [68].
E. Maslak et al. / Pharmacological Reports 67 (2015) 689–694
choline-deficient diets [72]. The beraprost, a stable PGI2 analogue, attenuated HFD-induced hepatic steatosis, reduced expression of inflammatory cytokines, adipocyte size and macrophage infiltration in white adipose tissue of diet-induced obesity in mice and rats [73,74]. On the other hand, ET-1 receptor antagonist, bosentan, possessed a hepatoprotective effect against diabetesinduced liver damage [75]. In conclusion, LSECs represent a structurally and functionally unique type of endothelium, which plays a fundamental role in maintaining liver homeostasis. Similarly to systemic endothelium maintaining cardiovascular health and endothelial dysfunction promoting cardiovascular diseases, LSEC dysfunction seems to have diagnostic, prognostic and therapeutic significance in NAFLD and other liver diseases. Conflict of interest The authors declare that there are no conflicts of interests. Funding This study was supported by the European Union from the resources of the European Regional Development Fund under the Innovative Economy Programme (grant coordinated by JCET-UJ, No. POIG.01.01.02-00-069/09). References [1] McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis & clinical management. J Hepatol 2014;62:1148–55. [2] Yatsuji S, Hashimoto E, Tobari M, Taniai M, Tokushige K, Shiratori K. Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C. J Gastroenterol Hepatol 2009;24:248–54. [3] Bedogni G, Miglioli L, Masutti F, Castiglione A, Croce` LS, Tiribelli C, et al. Incidence and natural course of fatty liver in the general population: the dionysos study. Hepatology 2007;46:1387–91. [4] Haring R, Wallaschofski H, Nauck M, Do¨rr M, Baumeister SE, Vo¨lzke H. Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels. Hepatology 2009;50:1403–11. [5] Caballeria L, Pera G, Auladell MA, Toran P, Munoz L, Miranda D, et al. Prevalence and factors associated with the presence of nonalcoholic fatty liver disease in an adult population in Spain. Eur J Gastroenterol Hepatol 2010;22:24–32. [6] Yan J, Xie W, Ou W-N, Zhao H, Cheng J. 1281 epidemiological survey of prevalence of fatty liver and its risk factors in permanent residents of Beijing. J Hepatol 2012;56:S506. [7] Imhof A, Kratzer W, Boehm B, Meitinger K, Trischler G, Steinbach G, et al. Prevalence of non-alcoholic fatty liver and characteristics in overweight adolescents in the general population. Eur J Epidemiol 2007;22:889–97. [8] Pasarı´n M, Abraldes JG, Rodrı´guez-Vilarrupla A, La Mura V, Garcı´a-Paga´n JC, Bosch J. Insulin resistance and liver microcirculation in a rat model of early NAFLD. J Hepatol 2011;55:1095–102. [9] Sumida Y, Niki E, Naito Y, Yoshikawa T. Involvement of free radicals and oxidative stress in NAFLD/NASH. Free Radic Res 2013;47:869–80. [10] Malhi H, Gores GJ. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis 2008;28:360–9. [11] Compare D, Coccoli P, Rocco A, Nardone OM, De Maria S, Cartenı` M, et al. Gutliver axis: the impact of gut microbiota on non alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2012;22:471–6. [12] Mantena SK, Vaughn DP, Andringa KK, Eccleston HB, King AL, Abrams GA, et al. High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo. Biochem J 2009;417:183–93. [13] Francque S, Laleman W, Verbeke L, Van Steenkiste C, Casteleyn C, Kwanten W, et al. Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture. Lab Investig 2012;92:1428–39. [14] Regan ER, Aird WC. Dynamical systems approach to endothelial heterogeneity. Circ Res 2012;111:110–30. [15] Wisse E. An electron microscopic study of the fenestrated endothelial lining of rat liver sinusoids. J Ultrastruct Res 1970;31:125–50. [16] Wisse E. An ultrastructural characterization of the endothelial cell in the rat liver sinusoid under normal and various experimental conditions, as a contribution to the distinction between endothelial and Kupffer cells. J Ultrastruct Res 1972;38:528–62.
693
[17] Svistounov D, Warren A, McNerney GP, Owen DM, Zencak D, Zykova SN, et al. The Relationship between fenestrations, sieve plates and rafts in liver sinusoidal endothelial cells. PLoS ONE 2012;7:e46134. [18] Le Couteur DG, Fraser R, Cogger VC, McLean AJ. Hepatic pseudocapillarisation and atherosclerosis in ageing. Lancet 2002;359:1612–5. [19] Fraser R, Bosanquet AG, Day WA. Filtration of chylomicrons by the liver may influence cholesterol metabolism and atherosclerosis. Atherosclerosis 1978;29:113–23. [20] Cogger VC, Hilmer SN, Sullivan D, Muller M, Fraser R, Le Couteur DG. Hyperlipidemia and surfactants: the liver sieve is a link. Atherosclerosis 2006;189:273–81. [21] Xie G, Wang X, Wang L, Wang L, Atkinson RD, Kanel GC, et al. Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats. Gastroenterology 2012;142:918–927.e6. [22] Ganesan LP, Mohanty S, Kim J, Clark KR, Robinson JM, Anderson CL. Rapid and efficient clearance of blood-borne virus by liver sinusoidal endothelium. PLoS Pathog 2011;7:e1002281. [23] Simon-Santamaria J, Rinaldo CH, Kardas P, Li R, Malovic I, Elvevold K, et al. Efficient uptake of blood-borne BK and JC polyomavirus-like particles in endothelial cells of liver sinusoids and renal vasa recta. PLOS ONE 2014;9:e111762. [24] Sørensen KK, McCourt P, Berg T, Crossley C, Le Couteur D, Wake K, et al. The scavenger endothelial cell: a new player in homeostasis and immunity. Am J Physiol Regul Integr Comp Physiol 2012;303:R1217–30. [25] Seternes T, Sørensen K, Smedsrød B. Scavenger endothelial cells of vertebrates: a nonperipheral leukocyte system for high-capacity elimination of waste macromolecules. Proc Natl Acad Sci U S A 2002;99:7594–7. [26] Elvevold K, Smedsrød B, Martinez I. The liver sinusoidal endothelial cell: a cell type of controversial and confusing identity. Am J Physiol Gastrointest Liver Physiol 2008;294:G391–400. [27] Schild L, Dombrowski F, Lendeckel U, Schulz C, Gardemann A, Keilhoff G. Impairment of endothelial nitric oxide synthase causes abnormal fat and glycogen deposition in liver. Biochim Biophys Acta 2008;1782:180–7. [28] DeLeve LD, Wang X, Guo Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 2008;48:920–30. [29] Rockey DC, Chung JJ. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology 1998;114:344–51. [30] Yokomori H, Yoshimura K, Ohshima S, Nagai T, Fujimaki K, Nomura M, et al. The endothelin-1 receptor-mediated pathway is not involved in the endothelin-1-induced defenestration of liver sinusoidal endothelial cells. Liver Int 2006;26:1268–76. [31] Shafiei MS, Lui S, Rockey DC. Integrin-linked kinase regulates endothelial cell nitric oxide synthase expression in hepatic sinusoidal endothelial cells. Liver Int 2014;35:1213–21. [32] Suematsu M, Ishimura Y. The heme oxygenase-carbon monoxide system: a regulator of hepatobiliary function. Hepatology 2000;31:3–6. [33] Iwakiri Y. Endothelial dysfunction in the regulation of cirrhosis and portal hypertension. Liver Int 2012;32:199–213. [34] Gryglewski RJ. Prostaglandins, platelets, and atherosclerosis. CRC Crit Rev Biochem 1980;7:291–338. [35] Nanji AA, Khwaja S, Sadrzadeh SM. Decreased prostacyclin production by liver non-parenchymal cells precedes liver injury in experimental alcoholic liver disease. Life Sci 1994;54:455–61. [36] Iwakiri Y, Groszmann RJ. Vascular endothelial dysfunction in cirrhosis. J Hepatol 2007;46:927–34. [37] Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006;43:121–31. [38] Yokoyama Y, Xu H, Kresge N, Keller S, Sarmadi AH, Baveja R, et al. Role of thromboxane A2 in early BDL-induced portal hypertension. Am J Physiol Gastrointest Liver Physiol 2003;284:G453–60. [39] Graupera M, March S, Engel P, Rode´s J, Bosch J, Garcı´a-Paga´n J-C. Sinusoidal endothelial COX-1-derived prostanoids modulate the hepatic vascular tone of cirrhotic rat livers. Am J Physiol Gastrointest Liver Physiol 2005;288: G763–70. [40] Rockey D. The cellular pathogenesis of portal hypertension: stellate cell contractility, endothelin, and nitric oxide. Hepatology 1997;25:2–5. [41] Yeligar S, Tsukamoto H, Kalra VK. Ethanol-induced expression of ET-1 and ETBR in liver sinusoidal endothelial cells and human endothelial cells involves hypoxia-inducible factor-1alpha and microrNA-199. J Immunol 2009;183:5232–43. [42] Liu S, Premont RT, Rockey DC. Endothelial nitric-oxide synthase (eNOS) is activated through G-protein-coupled receptor kinase-interacting protein 1 (GIT1) tyrosine phosphorylation and Src protein. J Biol Chem 2014;289:18163–74. [43] Kwok W, Lee SH, Culberson C, Korneszczuk K, Clemens MG. Caveolin-1 mediates endotoxin inhibition of endothelin-1-induced endothelial nitric oxide synthase activity in liver sinusoidal endothelial cells. Am J Physiol Gastrointest Liver Physiol 2009;297:G930–9. ˜ a B, Rodrı´guez-Vilarrupla A, Garcı´a-Caldero´ H, Bosch J, [44] Gracia-Sancho J, Lavin Garcı´a-Paga´n JC. Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat livers. J Hepatol 2007;47:220–7. [45] Fraser R, Dobbs BR, Rogers GW. Lipoproteins and the liver sieve: the role of the fenestrated sinusoidal endothelium in lipoprotein metabolism, atherosclerosis, and cirrhosis. Hepatology 1995;21:863–74.
694
E. Maslak et al. / Pharmacological Reports 67 (2015) 689–694
[46] Clark SA, Angus HB, Cook HB, George PM, Oxner RB, Fraser R. Defenestration of hepatic sinusoids as a cause of hyperlipoproteinaemia in alcoholics. Lancet 1988;2:1225–7. [47] Herrnberger L, Hennig R, Kremer W, Hellerbrand C, Goepferich A, Kalbitzer HR, et al. Formation of fenestrae in murine liver sinusoids depends on plasmalemma vesicle-associated protein and is required for lipoprotein passage. PLOS ONE 2014;9:e115005. [48] Enomoto K, Nishikawa Y, Omori Y, Tokairin T, Yoshida M, Ohi N, et al. Cell biology and pathology of liver sinusoidal endothelial cells. Med Electron Microsc 2004;37:208–15. [49] Li R, Oteiza A, Sørensen KK, McCourt P, Olsen R, Smedsrød B, et al. Role of liver sinusoidal endothelial cells and stabilins in elimination of oxidized lowdensity lipoproteins. Am J Physiol Gastrointest Liver Physiol 2011;300: G71–81. [50] Bieghs V, Walenbergh SMA, Hendrikx T, van Gorp PJ, Verheyen F, Olde Damink SW, et al. Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation. Liver Int 2013;33:1056–61. [51] Venkatraman L, Tucker-Kellogg L. The CD47-binding peptide of thrombospondin-1 induces defenestration of liver sinusoidal endothelial cells. Liver Int 2013;33:1386–97. [52] Rosado E, Rodrı´guez-Vilarrupla A, Gracia-Sancho J, Monclu´s M, Bosch J, Garcı´aPaga´n JC. Interaction between NO and COX pathways modulating hepatic endothelial cells from control and cirrhotic rats. J Cell Mol Med 2012;16: 2461–70. [53] Funyu J, Mochida S, Inao M, Matsui A, Fujiwara K. VEGF can act as vascular permeability factor in the hepatic sinusoids through upregulation of porosity of endothelial cells. Biochem Biophys Res Commun 2001;280:481–5. [54] Ding B-S, Nolan DJ, Butler JM, James D, Babazadeh AO, Rosenwaks Z, et al. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 2010;468:310–5. [55] Garcı´a-Trevijano ER, Martı´nez-Chantar ML, Latasa MU, Mato JM, Avila MA. NO sensitizes rat hepatocytes to proliferation by modifying S-adenosylmethionine levels. Gastroenterology 2002;122:1355–63. [56] Hutchins NA, Chung C-S, Borgerding JN, Ayala CA, Ayala A. Kupffer cells protect liver sinusoidal endothelial cells from Fas-dependent apoptosis in sepsis by down-regulating gp130. Am J Pathol 2013;182:742–54. [57] Tateya S, Rizzo NO, Handa P, Cheng AM, Morgan-Stevenson V, Daum G, et al. Endothelial NO/cGMP/VASP signaling attenuates Kupffer cell activation and hepatic insulin resistance induced by high-fat feeding. Diabetes 2011;60: 2792–801. [58] Tirosh O, Ilan E, Budick-Harmelin N, Ramadori G, Madar Z. Downregulation of eNOS in a nutritional model of fatty liver. E SPEN Eur E J Clin Nutr Metab 2009;4:e101–4. [59] Duplain H, Burcelin R, Sartori C, Cook S, Egli M, Lepori M, et al. Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation 2001;104:342–5. [60] Saavedra JE, Billiar TR, Williams DL, Kim Y, Watkins SC, Keefer LK. Targeting nitric oxide (NO) delivery in vivo. Design of a liver-selective NO donor prodrug that blocks tumor necrosis factor-r-induced apoptosis and toxicity in the liver. J Med Chem 1997;2623:1947–54. [61] Inami K, Nims RW, Srinivasan A, Citro ML, Saavedra JE, Cederbaum AI, et al. Metabolism of a liver-selective nitric oxide-releasing agent, VPYRRO/NO, by human microsomal cytochromes P450. Nitric Oxide 2006;14:309–15.
[62] Kus K, Walczak M, Maslak E, Zakrzewska A, Gonciarz-Dytman A, Zabielski P, et al. Hepatoselective NO-donors, V-PYRRO/NO and V-PROLI/NO in nonalcoholic fatty liver disease: a comparison of anti-steatotic effects with the biotransformation and pharmacokinetics. Drug Metab Dispos 2015;43(7): 1028–36. [63] Ricciardi R, Foley DP, Quarfordt SH, Saavedra JE, Keefer LK, Wheeler SM, et al. V-PYRRO/NO: an hepato-selective nitric oxide donor improves porcine liver hemodynamics and function after ischemia reperfusion. Transplantation 2001;71:193–8. [64] Moal F, Veal N, Vuillemin E, Barrie`re E, Wang J, Fizanne L, et al. Hemodynamic and anti fi brotic effects of a selective liver nitric oxide donor V-PYRRO/NO in bile duct ligated rats. World J Gastroenterol 2006;12:6639–45. [65] Kim YM, Kim TH, Chung HT, Talanian RV, Yin XM, Billiar TR. Nitric oxide prevents tumor necrosis factor alpha-induced rat hepatocyte apoptosis by the interruption of mitochondrial apoptotic signaling through S-nitrosylation of caspase-8. Hepatology 2000;32:770–8. [66] Liu J, Qu W, Saavedra JE, Waalkes MP. The nitric oxide donor, O2-vinyl 1(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), protects against cadmium-induced hepatotoxicity in mice. J Pharmacol Exp Ther 2004;310:18–24. [67] Liu J, Li C, Waalkes MP, Clark J, Myers P, Saavedra JE, et al. The nitric oxide donor, V-PYRRO/NO, protects against acetaminophen-induced hepatotoxicity in mice. Hepatology 2003;37:324–33. [68] Maslak E, Zabielski P, Kochan K, Kus K, Jasztal A, Sitek B, et al. The liverselective NO donor, V-PYRRO/NO, protects against liver steatosis and improves postprandial glucose tolerance in mice fed high fat diet. Biochem Pharmacol 2015;93:389–400. [69] Konstantynowicz K, Mikłosz A, Stepek T, Chabowski A. The role of hepatic lipid accumulation in the development of insulin resistance in the liver. Postepy Hig Med Dosw 2011;65:236–43. [70] Araya J, Rodrigo R, Videla LA, Thielemann L, Orellana M, Pettinelli P, et al. Increase in long-chain polyunsaturated fatty acid n 6/n 3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. Clin Sci (Lond) 2004;106:635–43. [71] Videla LA, Rodrigo R, Araya J, Poniachik J. Oxidative stress and depletion of hepatic long-chain polyunsaturated fatty acids may contribute to nonalcoholic fatty liver disease. Free Radic Biol Med 2004;37:1499–507. [72] Joe Y, Zheng M, Kim S-K, Kim S, Uddin JMD, Min TS, et al. The role of carbon monoxide in metabolic disease. Ann N Y Acad Sci 2011;1229:156–61. [73] Inoue E, Ichiki T, Takeda K, Matsuura H, Hashimoto T, Ikeda J, et al. Beraprost sodium, a stable prostacyclin analogue, improves insulin resistance in high-fat diet-induced obese mice. J Endocrinol 2012;213:285–91. [74] Sato N, Kaneko M, Tamura M, Kurumatani H. The prostacyclin analog beraprost sodium ameliorates characteristics of metabolic syndrome in obese Zucker (fatty) rats. Diabetes 2010;59:1092–100. [75] Demirci E, Ferah I, Gundogdu C, Ozkanlar S, Baygutalp NK, Bayir Y, et al. Endothelin receptor inhibition with bosentan delays onset of liver injury in streptozotocin-induced diabetic condition. Drug Res (Stuttg) 2015;65(5): 272–80. [76] Friedman SL. Mechanisms of disease: mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol 2004;1(2):98– 105. [77] Iredale JP. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest 2007;117(3):539–48.
Contents lists available at ScienceDirect
Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep
Review article
Liver sinusoidal endothelial cells (LSECs) function and NAFLD; NO-based therapy targeted to the liver Edyta Maslak a, Aleksandra Gregorius a, Stefan Chlopicki a,b,* a b
Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krako´w, Poland Department of Experimental Pharmacology, Jagiellonian University Medical College, Krako´w, Poland
A R T I C L E I N F O
Article history: Received 17 February 2015 Received in revised form 13 April 2015 Accepted 17 April 2015 Available online 2 May 2015 Keywords: Liver sinusoidal endothelial cells NAFLD Liver cells crosstalk Liver-selective therapy
A B S T R A C T
Liver sinusoidal endothelial cells (LSECs) present unique, highly specialised endothelial cells in the body. Unlike the structure and function of typical, vascular endothelial cells, LSECs are comprised of fenestrations, display high endocytic capacity and play a prominent role in maintaining overall liver homeostasis. LSEC dysfunction has been regarded as a key event in multiple liver disorders; however, its role and diagnostic, prognostic and therapeutic significance in nonalcoholic fatty liver disease (NAFLD) is still neglected. The purpose of this review is to provide an overview of the importance of LSECs in NAFLD. Attention is focused on the LSECs-mediated NO-dependent mechanisms in NAFLD development. We briefly describe the unique, highly specialised phenotype of LSECs and consequences of LSEC dysfunction on function of hepatic stellate cells (HSC) and hepatocytes. The potential efficacy of liver selective NO donors against liver steatosis and novel treatment approaches to modulate LSECs-driven liver pathology including NAFLD are also highlighted. ß 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Morphology and function of LSECs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . LSEC-derived mediators in NAFLD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fenestrated (healthy) and defenestrated (dysfunctional) liver endothelium . . . The NO-dependent crosstalk between LSECs, HSC and hepatocytes in the liver The liver-selective NO-based drug therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Nonalcoholic fatty liver disease (NAFLD) is a group of interrelated chronic liver disorders associated with increased fat deposition within hepatocytes (simple steatosis, SS), lobular and portal inflammation and fibrosis (nonalcoholic steatohepatitis,
* Corresponding author. E-mail address: [email protected] (S. Chlopicki).
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
689 690 690 690 691 692 693 693 693
NASH), that may lead to the development of cirrhosis or hepatocellular carcinoma [1,2]. NAFLD affects about 30% of the population of Western Europe and Eastern countries [3–6], and is increasingly diagnosed in children and adolescents along with the concomitant increased prevalence of obesity in this population [7]. The prevailing hypothesis of NAFLD development is still poorly understood; however, several insults (‘‘hits’’) may be jointly involved in causing progressive liver injury. A classically recognised hit comes from increased consumption of a diet rich in saturated fats and simple carbohydrates, which leads to excessive
http://dx.doi.org/10.1016/j.pharep.2015.04.010 1734-1140/ß 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.
690
E. Maslak et al. / Pharmacological Reports 67 (2015) 689–694
triglyceride accumulation in the hepatocytes. The inappropriate diet is also responsible for peripheral insulin resistance, which shifts free fatty acids metabolism to non-adipose tissues, including the liver. Recently, it was shown that apart from skeletal muscles, adipose tissue and hepatocytes, dietary fat also induced insulin resistance in liver sinusoidal endothelial cells (LSECs) [8]. Therefore, it may well be that a liver subjected to primary hit, most likely associated with the development of dysfunction of LSECs, is vulnerable to subsequent insults, which perpetuates pro-inflammatory and pro-fibrotic response of activated Kupffer cells (KC) and hepatic stellate cells (HSC). Subsequently, simple steatosis may lead to the progression of NASH, cirrhosis or hepatocellular carcinoma. Among a variety of proposed factors, oxidative stress [9], lipotoxicity [10], and gut-derived bacterial endotoxin [11] have been implicated. All of them might also aggravate LSEC dysfunction and contribute to NAFLD pathology. Furthermore, impaired microcirculation, reduced oxygen delivery and altered mitochondrial function due to increased fat deposition in hepatocytes [12] may also play a pathogenetic role. Liver steatosis is, indeed, associated with an increased portal pressure and intrahepatic resistance [13] linked to the impairment of endothelial-dependent regulation of hepatic flow. Altogether, LSEC dysfunction seems to play a prominent role in the pathogenesis of NAFLD. In the present review we focus on the role of LSECs-mediated NO-dependent mechanisms that could prevent NAFLD, and on the potential efficacy of liver selective NO donors in NAFLD. We also briefly describe the unique, highly specialised phenotype of LSECs, consequences of LSEC dysfunction on function of other cells in the liver such as HSC and hepatocytes, and finally novel treatment approaches to modulate LSEC dysfunction that contribute to the development of NAFLD. Morphology and function of LSECs The LSECs comprise about 3% of the total liver volume, which makes 20% of the total number of liver cells. Despite overall similarities, LSECs differ from other endothelial cells considerably and present the best example for remarkable heterogeneity in structure and function among endothelial cells [14]. Under physiological conditions, LSECs are very thin cells lining the liver sinusoids. Unlike typical vascular endothelial cells, LSECs are comprised of pores, called fenestrations, with diameters of about approximately 50–150 nm that are grouped together and dynamically regulated to form so-called ‘‘sieve plates’’, which determine their normal ‘‘differentiated’’ phenotype [15–17]. The sinusoidal endothelium lacks the basement membrane, which additionally constitutes its unique feature [15,16,18]. LSECs fenestrations allow for efficient transfer of lipoproteins, small chylomicron remnants and other macromolecules between blood and the space of Disse, where they are taken up by hepatocytes [19,20]. The structure and function of LSECs are closely linked, as the defenestration is the first phenotypic marker of LSEC dysfunction [21]. LSECs, unlike other endothelial cells but rather similar to phagocyting cells, have high endocytic capacity. Indeed, LSECs have been shown to represent one of the most actively endocytosing cell types in the body mediating clearance of soluble waste macromolecules and colloid material, including blood-borne adenovirus [22,23]. Unlike other endothelial cells LSECs express various scavenger receptors (SR) on their surface including SR-A (also known as macrophage SR), SR-B (SR-B1 and CD36), and the most important SR-H receptor (stabilin-1/FEEL-1 and stabilin-2/ FEEL-2/HARE) [24]. Accordingly, in the liver, not only KC but also LSECs are involved in waste clearance, and these cells seem to complement each other. LSECs represent the professional
pinocyting cells, clearing the blood from soluble macromolecules and small particles (<200 nm), while macrophages (KC) eliminate larger, insoluble particles by phagocytosis [25]. LSEC-derived mediators in NAFLD Despite the unique structural and functional features of LSECs, their repertoire of mediators include nitric oxide (NO), prostacyclin (PGI2), carbon monoxide (CO), endothelin-1 (ET-1), similarly to other endothelial cell types. Still, evidence of function and biochemical profile of LSECs is limited mainly due to technical challenges to plate and culture them [26]. Nevertheless, there is abundant evidence that NO depletion is involved in a number of liver disorders. For example, NO deficiency resulted in massive fat deposition in the liver [27] and was associated with HSC activation towards pro-fibrogenic phenotype [28]. Interestingly, diminished eNOS activity was reported in cirrhotic rats [29]. LSECs expression of eNOS and NO production is mediated by signalling events dependent on Rho GTPases and integrin linked kinase (ILK). Overexpression of ILK mediated by ET-1, vascular endothelial growth factor (VEGF) and transforming growth factor beta-1 (TGFb-1), released in response to liver injury, led to a compensatory increase in eNOS expression and NO production. On the other hand, a lack of ILK led to LSECs detachment, loss of actin fibres and defective vascular development [30,31]. LSECs also express haeme oxygenase (HO) converting protoheme IX to biliverdin–IXa, free divalent iron and CO which, next to NO, seems to serve as an important hepatoprotective mediator [32,33]. For example, CO regulated liver perfusion and HSC function [32]. PGI2, the major anti-platelet and atheroprotective agent [34] also protects against liver injury. Diminished PGI2 production contributed to the hepatotoxic effect of ethanol [35]. The balance between PGI2 and TxB2 is of key importance in vascular homeostasis. In the liver, TxA2 produced from arachidonic acid by cyclooxygenase-1 (COX-1) resulted in HSC activation [36,37]. In fact, cirrhotic livers displayed an increased expression of COX-1 in LSECs [36], and acetylcholine increased the production of TxA2 [38,39], suggesting the role of LSEC-derived TxA2. There is convincing evidence that LSECs produce ET-1, ET-2, and ET-3 affecting HSC activation by two receptors, ETA and ETB [33,40–42]. Inflammatory and oxidative stress linked with hyperresponsiveness of hepatic sinusoids to detrimental effects of ET-1 may be caused by the disruption of beneficial signalling pathways dependent on the ETB receptor and eNOS-signalling of LSECs [39,43,44]. In liver injury induced by ethanol in rats, LSECs were highly activated and showed increased expression of big ET-1 and chemokines as compared with cells isolated from control rats [41]. Altogether, alterations in LSECs homeostasis and activity of LSEC-derived mediators may play an important role in liver injury and in NAFLD in particular. Fenestrated (healthy) and defenestrated (dysfunctional) liver endothelium Under physiological conditions, unique LSECs phenotype characterised by the presence of fenestrations and high endocytic capacity of LSECs, play a prominent role in maintaining liver homeostasis and integrity. However, during liver injury, the LSECs undergo morphological and functional transition. One of the most remarkable phenotypic changes is the loss of fenestrations (‘‘defenestration’’) and formation of a basement membrane on the abluminal surface of LSECs that is closely associated with reduced NO bioavailability. Defenestration has been shown to impair the hepatic uptake of various substances including cholesterol and lipoproteins [45,46] leading to severe hyperlipoproteinemia and liver steatosis [47]. Moreover, a loss of fenestrations has been
E. Maslak et al. / Pharmacological Reports 67 (2015) 689–694
accompanied by decreased LSECs’ endocytic capability [48]. It may contribute to NAFLD development since LSECs are the main scavenger system for oxLDL [49], and oxLDL-dependent pathway has been shown to initiate NASH progression [50]. The mechanisms leading to defenestration are not clear but may involve CD47-thrombospondin-1 dependent mechanisms [51] or plasmalemma vesicle-associated protein (PLVAP) expression [47]. Defenestrated LSECs change not only their structure but also their autocrine and paracrine activity leading to imbalance between LSECs-derived mediators, such as NO, PGI2, ET-1, TxA2. Indeed, in a healthy liver, with preserved fenestrated LSECs phenotype, the balance between LSECs-deriver vasodilators (NO, PGI2) and vasoconstrictors (ET-1, TxA2) is shifted towards vasodilatation [52]. In turn, during liver injury, LSECs become defenestrated and overproduce vasoconstrictors disrupting NO production and bioavailability [52] (Fig. 1). Moreover, balance between those mediators was shown to be crucial for maintaining not only LSECs viability and function but also to affect significantly the phenotype of other liver cells, i.e. HSC and hepatocytes (Fig. 1). The NO-dependent crosstalk between LSECs, HSC and hepatocytes in the liver NO plays a major role in maintaining LSECs fenestrations and responsiveness for pro-survival signal of VEGF that determines the LSECs phenotype and is produced by HSC or hepatocytes [21]. In fact, depletion of VEGF resulted in a loss of LSECs fenestrations, while the resupply of cell culture medium in VEGF restored a healthy LSECs phenotype [53]. In turn, dysfunctional LSECs showed loss of the ability to produce NO and to respond to VEGF [28]. NO is also a key determinant maintaining the quiescent HSC phenotype. The activation of HSC, as well as reversion of activated
691
HSC to a quiescent phenotype is mediated by fenestrated LSECs and depends on the NO [28]. The fluorescence of F-actin and expression of ASMA and TIMP-1, markers of HSC activation, was markedly reduced when co-cultured with freshly isolated, differentiated LSECs [28]. In turn, the addition of L-NAME blocked LSECsmaintained HSC quiescence, further supporting the essential role of NO for maintaining HSC quiescent phenotype [28]. However, DETANONOate, an NO donor, did not reduce the activated HSCs in culture, suggesting that reversal of HSC activation is dependent on VEGF-stimulated NO production, associated with a differentiated LSECs phenotype that promoted the reversal of activated HSC to quiescence [21]. Accordingly, LSECs’ ability for maintaining the quiescent HSC phenotype comprises not only paracrine action of NO but also some other, not yet defined, LSECs mediators, and is highly dependent on the ongoing biochemical crosstalk between LSECs, hepatocytes and HSC. VEGF-NO pathway plays a particularly important role in liver regeneration. VEGF activated LSECs for NO production and also induced hepatic growth factor (HGF) release from LSECs [54]. Moreover, HGF action is conditioned by NO availability. The hepatocytes mitogenic response to HGF was blunted when NO synthesis was inhibited, and the addition of NO donor overcame this effect [55]. This data indicates that quiescent hepatocytes in a normal liver are not able to respond to proliferative stimuli and need to be primed by LSEC-derived NO to respond to HGF signal [55]. Quite surprisingly, KC can also protect against LSECs injury. Fasmediated apoptosis was limited by KC released interleukin-6 binding to glycoprotein 130 on LSECs surface [56], while LSECderived NO limited the activation of KC [57]. Taken all together, direct cellular contact and dynamic biochemical signalling underlying crosstalk between fenestrated LSECs, HSC, KC and hepatocytes maintain liver integrity and function, and NO seems to be a major player. Since NO also
Fig. 1. The cellular crosstalk between liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSC) and hepatocytes in a healthy liver and nonalcoholic fatty liver disease (NAFLD). In a healthy liver (left panel), fenestrated LSECs without a basement membrane facilitate transport of macromolecules between blood and hepatocytes, and maintain liver homeostasis by balanced production of mediators. Hepatocytes absorption area increases by the presence of hepatocyte microvilli while quiescent HSC stores vitamin A (vit. A). Paracrine action of hepatocytes and HSC maintains fenestrated phenotype of LSECs by vascular endothelial growth factor (VEGF) production. In NAFLD liver (right panel), LSECs porosity is reduced (i.e. loss of fenestrations) with presence of basement membrane. An activated HSC loses vit. A and changes phenotype towards myofibroblasts. Fat-loaded hepatocytes lose the hepatocytes microvilli. In addition, the cellular signalling is shifted towards proinflammatory and profibrogenic pathway. Modified from [76,77].
692
E. Maslak et al. / Pharmacological Reports 67 (2015) 689–694
regulates lipid and glucose homeostasis in the liver [27,58,59], a therapeutic approach enhancing cellular NO bioavailability seems to have fundamental implications to treat liver pathology, including NAFLD. The liver-selective NO-based drug therapy V-PYRRO/NO is a stable, hepatoselective NO-releasing prodrug, of the diazeniumdiolate family of NO donors [60] that passively diffuses through the cellular membrane and is metabolised in the liver to NO by several cytochrome P450 isoforms, including mainly CYP2E1 [61], but also by CYP2C9 and CYP3A4 and CYP1A2 [62]. VPYRRO/NO showed beneficial effects in various in vivo and in vitro models of acute hepatotoxicity [63–67] and lacks systemic vasodilation effects [60]. In our recent study [68], we showed that V-PYRRO/NO therapy improved liver steatosis and postprandial glucose tolerance in a mice model of NAFLD (Fig. 2). V-PYRRO/NO inhibited de novo fatty
acid synthesis by phosphorylation of acetyl-CoA carboxylase (ACC) resulting in decreased content of total liver lipids (TAG, DAG, CER) and attenuated liver steatosis. Moreover, those effects were related to a favourable decrease in liver SFA and MUFA and a simultaneous increase in PUFA content. Since DAG and CER were shown to be involved in the insulin signalling pathways and maintaining glucose homeostasis [69], and SFA/UFA balance represents a marker of NAFLD severity [70,71], NO-mediated changes in liver fatty acid composition may bear additional therapeutic importance. Anti-steatotic effects of V-PYRRO/NO also involved the activation of Akt, an important signalling molecule in the insulin signalling pathway, and improvement in hepatic microcirculation perfusion. A comprehensive profile of antiNAFLD activity of V-PYRRO/NO suggests that NO-therapy targeted to the liver may represent a promising and novel approach to treat NAFLD that could be perhaps reinforced by pharmacology of other LSEC-derived mediators. CO was shown to ameliorate liver steatosis induced by a high-fructose, methionine-deficient and
Fig. 2. The therapy with liver-selective nitric oxide (NO) donor, V-PYRRO/NO represents an effective approach against liver steatosis induced by a high-fat (HF) diet in mice. Representative pictures of H&E (A), one step Gomorie’s trichrome (B), and Oil Red O (C) stained section of liver taken from mice fed for 15 weeks standard AIN-93G diet or HF diet with or without treatment. Semi-automatic quantitative analysis of liver fat content from Oil Red O pictures using Image J software (Carl Zeiss, Oberkochen, Germany) (D) and GC/FID chromatography results of liver triglyceride (TG) content are presented (E). Values are means SEM (n = 6). Values with different superscript letters within each animal group are significantly different (p 0.05). AIN-93G: control group; HF: high fat group; HF + metformin: high fat group treated with metformin; HF+V-PYRRO/NO: high fat group treated with V-PYRRO/NO. Figure is reproduced with permission from [68].
E. Maslak et al. / Pharmacological Reports 67 (2015) 689–694
choline-deficient diets [72]. The beraprost, a stable PGI2 analogue, attenuated HFD-induced hepatic steatosis, reduced expression of inflammatory cytokines, adipocyte size and macrophage infiltration in white adipose tissue of diet-induced obesity in mice and rats [73,74]. On the other hand, ET-1 receptor antagonist, bosentan, possessed a hepatoprotective effect against diabetesinduced liver damage [75]. In conclusion, LSECs represent a structurally and functionally unique type of endothelium, which plays a fundamental role in maintaining liver homeostasis. Similarly to systemic endothelium maintaining cardiovascular health and endothelial dysfunction promoting cardiovascular diseases, LSEC dysfunction seems to have diagnostic, prognostic and therapeutic significance in NAFLD and other liver diseases. Conflict of interest The authors declare that there are no conflicts of interests. Funding This study was supported by the European Union from the resources of the European Regional Development Fund under the Innovative Economy Programme (grant coordinated by JCET-UJ, No. POIG.01.01.02-00-069/09). References [1] McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis & clinical management. J Hepatol 2014;62:1148–55. [2] Yatsuji S, Hashimoto E, Tobari M, Taniai M, Tokushige K, Shiratori K. Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C. J Gastroenterol Hepatol 2009;24:248–54. [3] Bedogni G, Miglioli L, Masutti F, Castiglione A, Croce` LS, Tiribelli C, et al. Incidence and natural course of fatty liver in the general population: the dionysos study. Hepatology 2007;46:1387–91. [4] Haring R, Wallaschofski H, Nauck M, Do¨rr M, Baumeister SE, Vo¨lzke H. Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels. Hepatology 2009;50:1403–11. [5] Caballeria L, Pera G, Auladell MA, Toran P, Munoz L, Miranda D, et al. Prevalence and factors associated with the presence of nonalcoholic fatty liver disease in an adult population in Spain. Eur J Gastroenterol Hepatol 2010;22:24–32. [6] Yan J, Xie W, Ou W-N, Zhao H, Cheng J. 1281 epidemiological survey of prevalence of fatty liver and its risk factors in permanent residents of Beijing. J Hepatol 2012;56:S506. [7] Imhof A, Kratzer W, Boehm B, Meitinger K, Trischler G, Steinbach G, et al. Prevalence of non-alcoholic fatty liver and characteristics in overweight adolescents in the general population. Eur J Epidemiol 2007;22:889–97. [8] Pasarı´n M, Abraldes JG, Rodrı´guez-Vilarrupla A, La Mura V, Garcı´a-Paga´n JC, Bosch J. Insulin resistance and liver microcirculation in a rat model of early NAFLD. J Hepatol 2011;55:1095–102. [9] Sumida Y, Niki E, Naito Y, Yoshikawa T. Involvement of free radicals and oxidative stress in NAFLD/NASH. Free Radic Res 2013;47:869–80. [10] Malhi H, Gores GJ. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis 2008;28:360–9. [11] Compare D, Coccoli P, Rocco A, Nardone OM, De Maria S, Cartenı` M, et al. Gutliver axis: the impact of gut microbiota on non alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2012;22:471–6. [12] Mantena SK, Vaughn DP, Andringa KK, Eccleston HB, King AL, Abrams GA, et al. High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo. Biochem J 2009;417:183–93. [13] Francque S, Laleman W, Verbeke L, Van Steenkiste C, Casteleyn C, Kwanten W, et al. Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture. Lab Investig 2012;92:1428–39. [14] Regan ER, Aird WC. Dynamical systems approach to endothelial heterogeneity. Circ Res 2012;111:110–30. [15] Wisse E. An electron microscopic study of the fenestrated endothelial lining of rat liver sinusoids. J Ultrastruct Res 1970;31:125–50. [16] Wisse E. An ultrastructural characterization of the endothelial cell in the rat liver sinusoid under normal and various experimental conditions, as a contribution to the distinction between endothelial and Kupffer cells. J Ultrastruct Res 1972;38:528–62.
693
[17] Svistounov D, Warren A, McNerney GP, Owen DM, Zencak D, Zykova SN, et al. The Relationship between fenestrations, sieve plates and rafts in liver sinusoidal endothelial cells. PLoS ONE 2012;7:e46134. [18] Le Couteur DG, Fraser R, Cogger VC, McLean AJ. Hepatic pseudocapillarisation and atherosclerosis in ageing. Lancet 2002;359:1612–5. [19] Fraser R, Bosanquet AG, Day WA. Filtration of chylomicrons by the liver may influence cholesterol metabolism and atherosclerosis. Atherosclerosis 1978;29:113–23. [20] Cogger VC, Hilmer SN, Sullivan D, Muller M, Fraser R, Le Couteur DG. Hyperlipidemia and surfactants: the liver sieve is a link. Atherosclerosis 2006;189:273–81. [21] Xie G, Wang X, Wang L, Wang L, Atkinson RD, Kanel GC, et al. Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats. Gastroenterology 2012;142:918–927.e6. [22] Ganesan LP, Mohanty S, Kim J, Clark KR, Robinson JM, Anderson CL. Rapid and efficient clearance of blood-borne virus by liver sinusoidal endothelium. PLoS Pathog 2011;7:e1002281. [23] Simon-Santamaria J, Rinaldo CH, Kardas P, Li R, Malovic I, Elvevold K, et al. Efficient uptake of blood-borne BK and JC polyomavirus-like particles in endothelial cells of liver sinusoids and renal vasa recta. PLOS ONE 2014;9:e111762. [24] Sørensen KK, McCourt P, Berg T, Crossley C, Le Couteur D, Wake K, et al. The scavenger endothelial cell: a new player in homeostasis and immunity. Am J Physiol Regul Integr Comp Physiol 2012;303:R1217–30. [25] Seternes T, Sørensen K, Smedsrød B. Scavenger endothelial cells of vertebrates: a nonperipheral leukocyte system for high-capacity elimination of waste macromolecules. Proc Natl Acad Sci U S A 2002;99:7594–7. [26] Elvevold K, Smedsrød B, Martinez I. The liver sinusoidal endothelial cell: a cell type of controversial and confusing identity. Am J Physiol Gastrointest Liver Physiol 2008;294:G391–400. [27] Schild L, Dombrowski F, Lendeckel U, Schulz C, Gardemann A, Keilhoff G. Impairment of endothelial nitric oxide synthase causes abnormal fat and glycogen deposition in liver. Biochim Biophys Acta 2008;1782:180–7. [28] DeLeve LD, Wang X, Guo Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 2008;48:920–30. [29] Rockey DC, Chung JJ. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology 1998;114:344–51. [30] Yokomori H, Yoshimura K, Ohshima S, Nagai T, Fujimaki K, Nomura M, et al. The endothelin-1 receptor-mediated pathway is not involved in the endothelin-1-induced defenestration of liver sinusoidal endothelial cells. Liver Int 2006;26:1268–76. [31] Shafiei MS, Lui S, Rockey DC. Integrin-linked kinase regulates endothelial cell nitric oxide synthase expression in hepatic sinusoidal endothelial cells. Liver Int 2014;35:1213–21. [32] Suematsu M, Ishimura Y. The heme oxygenase-carbon monoxide system: a regulator of hepatobiliary function. Hepatology 2000;31:3–6. [33] Iwakiri Y. Endothelial dysfunction in the regulation of cirrhosis and portal hypertension. Liver Int 2012;32:199–213. [34] Gryglewski RJ. Prostaglandins, platelets, and atherosclerosis. CRC Crit Rev Biochem 1980;7:291–338. [35] Nanji AA, Khwaja S, Sadrzadeh SM. Decreased prostacyclin production by liver non-parenchymal cells precedes liver injury in experimental alcoholic liver disease. Life Sci 1994;54:455–61. [36] Iwakiri Y, Groszmann RJ. Vascular endothelial dysfunction in cirrhosis. J Hepatol 2007;46:927–34. [37] Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006;43:121–31. [38] Yokoyama Y, Xu H, Kresge N, Keller S, Sarmadi AH, Baveja R, et al. Role of thromboxane A2 in early BDL-induced portal hypertension. Am J Physiol Gastrointest Liver Physiol 2003;284:G453–60. [39] Graupera M, March S, Engel P, Rode´s J, Bosch J, Garcı´a-Paga´n J-C. Sinusoidal endothelial COX-1-derived prostanoids modulate the hepatic vascular tone of cirrhotic rat livers. Am J Physiol Gastrointest Liver Physiol 2005;288: G763–70. [40] Rockey D. The cellular pathogenesis of portal hypertension: stellate cell contractility, endothelin, and nitric oxide. Hepatology 1997;25:2–5. [41] Yeligar S, Tsukamoto H, Kalra VK. Ethanol-induced expression of ET-1 and ETBR in liver sinusoidal endothelial cells and human endothelial cells involves hypoxia-inducible factor-1alpha and microrNA-199. J Immunol 2009;183:5232–43. [42] Liu S, Premont RT, Rockey DC. Endothelial nitric-oxide synthase (eNOS) is activated through G-protein-coupled receptor kinase-interacting protein 1 (GIT1) tyrosine phosphorylation and Src protein. J Biol Chem 2014;289:18163–74. [43] Kwok W, Lee SH, Culberson C, Korneszczuk K, Clemens MG. Caveolin-1 mediates endotoxin inhibition of endothelin-1-induced endothelial nitric oxide synthase activity in liver sinusoidal endothelial cells. Am J Physiol Gastrointest Liver Physiol 2009;297:G930–9. ˜ a B, Rodrı´guez-Vilarrupla A, Garcı´a-Caldero´ H, Bosch J, [44] Gracia-Sancho J, Lavin Garcı´a-Paga´n JC. Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat livers. J Hepatol 2007;47:220–7. [45] Fraser R, Dobbs BR, Rogers GW. Lipoproteins and the liver sieve: the role of the fenestrated sinusoidal endothelium in lipoprotein metabolism, atherosclerosis, and cirrhosis. Hepatology 1995;21:863–74.
694
E. Maslak et al. / Pharmacological Reports 67 (2015) 689–694
[46] Clark SA, Angus HB, Cook HB, George PM, Oxner RB, Fraser R. Defenestration of hepatic sinusoids as a cause of hyperlipoproteinaemia in alcoholics. Lancet 1988;2:1225–7. [47] Herrnberger L, Hennig R, Kremer W, Hellerbrand C, Goepferich A, Kalbitzer HR, et al. Formation of fenestrae in murine liver sinusoids depends on plasmalemma vesicle-associated protein and is required for lipoprotein passage. PLOS ONE 2014;9:e115005. [48] Enomoto K, Nishikawa Y, Omori Y, Tokairin T, Yoshida M, Ohi N, et al. Cell biology and pathology of liver sinusoidal endothelial cells. Med Electron Microsc 2004;37:208–15. [49] Li R, Oteiza A, Sørensen KK, McCourt P, Olsen R, Smedsrød B, et al. Role of liver sinusoidal endothelial cells and stabilins in elimination of oxidized lowdensity lipoproteins. Am J Physiol Gastrointest Liver Physiol 2011;300: G71–81. [50] Bieghs V, Walenbergh SMA, Hendrikx T, van Gorp PJ, Verheyen F, Olde Damink SW, et al. Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation. Liver Int 2013;33:1056–61. [51] Venkatraman L, Tucker-Kellogg L. The CD47-binding peptide of thrombospondin-1 induces defenestration of liver sinusoidal endothelial cells. Liver Int 2013;33:1386–97. [52] Rosado E, Rodrı´guez-Vilarrupla A, Gracia-Sancho J, Monclu´s M, Bosch J, Garcı´aPaga´n JC. Interaction between NO and COX pathways modulating hepatic endothelial cells from control and cirrhotic rats. J Cell Mol Med 2012;16: 2461–70. [53] Funyu J, Mochida S, Inao M, Matsui A, Fujiwara K. VEGF can act as vascular permeability factor in the hepatic sinusoids through upregulation of porosity of endothelial cells. Biochem Biophys Res Commun 2001;280:481–5. [54] Ding B-S, Nolan DJ, Butler JM, James D, Babazadeh AO, Rosenwaks Z, et al. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 2010;468:310–5. [55] Garcı´a-Trevijano ER, Martı´nez-Chantar ML, Latasa MU, Mato JM, Avila MA. NO sensitizes rat hepatocytes to proliferation by modifying S-adenosylmethionine levels. Gastroenterology 2002;122:1355–63. [56] Hutchins NA, Chung C-S, Borgerding JN, Ayala CA, Ayala A. Kupffer cells protect liver sinusoidal endothelial cells from Fas-dependent apoptosis in sepsis by down-regulating gp130. Am J Pathol 2013;182:742–54. [57] Tateya S, Rizzo NO, Handa P, Cheng AM, Morgan-Stevenson V, Daum G, et al. Endothelial NO/cGMP/VASP signaling attenuates Kupffer cell activation and hepatic insulin resistance induced by high-fat feeding. Diabetes 2011;60: 2792–801. [58] Tirosh O, Ilan E, Budick-Harmelin N, Ramadori G, Madar Z. Downregulation of eNOS in a nutritional model of fatty liver. E SPEN Eur E J Clin Nutr Metab 2009;4:e101–4. [59] Duplain H, Burcelin R, Sartori C, Cook S, Egli M, Lepori M, et al. Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation 2001;104:342–5. [60] Saavedra JE, Billiar TR, Williams DL, Kim Y, Watkins SC, Keefer LK. Targeting nitric oxide (NO) delivery in vivo. Design of a liver-selective NO donor prodrug that blocks tumor necrosis factor-r-induced apoptosis and toxicity in the liver. J Med Chem 1997;2623:1947–54. [61] Inami K, Nims RW, Srinivasan A, Citro ML, Saavedra JE, Cederbaum AI, et al. Metabolism of a liver-selective nitric oxide-releasing agent, VPYRRO/NO, by human microsomal cytochromes P450. Nitric Oxide 2006;14:309–15.
[62] Kus K, Walczak M, Maslak E, Zakrzewska A, Gonciarz-Dytman A, Zabielski P, et al. Hepatoselective NO-donors, V-PYRRO/NO and V-PROLI/NO in nonalcoholic fatty liver disease: a comparison of anti-steatotic effects with the biotransformation and pharmacokinetics. Drug Metab Dispos 2015;43(7): 1028–36. [63] Ricciardi R, Foley DP, Quarfordt SH, Saavedra JE, Keefer LK, Wheeler SM, et al. V-PYRRO/NO: an hepato-selective nitric oxide donor improves porcine liver hemodynamics and function after ischemia reperfusion. Transplantation 2001;71:193–8. [64] Moal F, Veal N, Vuillemin E, Barrie`re E, Wang J, Fizanne L, et al. Hemodynamic and anti fi brotic effects of a selective liver nitric oxide donor V-PYRRO/NO in bile duct ligated rats. World J Gastroenterol 2006;12:6639–45. [65] Kim YM, Kim TH, Chung HT, Talanian RV, Yin XM, Billiar TR. Nitric oxide prevents tumor necrosis factor alpha-induced rat hepatocyte apoptosis by the interruption of mitochondrial apoptotic signaling through S-nitrosylation of caspase-8. Hepatology 2000;32:770–8. [66] Liu J, Qu W, Saavedra JE, Waalkes MP. The nitric oxide donor, O2-vinyl 1(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), protects against cadmium-induced hepatotoxicity in mice. J Pharmacol Exp Ther 2004;310:18–24. [67] Liu J, Li C, Waalkes MP, Clark J, Myers P, Saavedra JE, et al. The nitric oxide donor, V-PYRRO/NO, protects against acetaminophen-induced hepatotoxicity in mice. Hepatology 2003;37:324–33. [68] Maslak E, Zabielski P, Kochan K, Kus K, Jasztal A, Sitek B, et al. The liverselective NO donor, V-PYRRO/NO, protects against liver steatosis and improves postprandial glucose tolerance in mice fed high fat diet. Biochem Pharmacol 2015;93:389–400. [69] Konstantynowicz K, Mikłosz A, Stepek T, Chabowski A. The role of hepatic lipid accumulation in the development of insulin resistance in the liver. Postepy Hig Med Dosw 2011;65:236–43. [70] Araya J, Rodrigo R, Videla LA, Thielemann L, Orellana M, Pettinelli P, et al. Increase in long-chain polyunsaturated fatty acid n 6/n 3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. Clin Sci (Lond) 2004;106:635–43. [71] Videla LA, Rodrigo R, Araya J, Poniachik J. Oxidative stress and depletion of hepatic long-chain polyunsaturated fatty acids may contribute to nonalcoholic fatty liver disease. Free Radic Biol Med 2004;37:1499–507. [72] Joe Y, Zheng M, Kim S-K, Kim S, Uddin JMD, Min TS, et al. The role of carbon monoxide in metabolic disease. Ann N Y Acad Sci 2011;1229:156–61. [73] Inoue E, Ichiki T, Takeda K, Matsuura H, Hashimoto T, Ikeda J, et al. Beraprost sodium, a stable prostacyclin analogue, improves insulin resistance in high-fat diet-induced obese mice. J Endocrinol 2012;213:285–91. [74] Sato N, Kaneko M, Tamura M, Kurumatani H. The prostacyclin analog beraprost sodium ameliorates characteristics of metabolic syndrome in obese Zucker (fatty) rats. Diabetes 2010;59:1092–100. [75] Demirci E, Ferah I, Gundogdu C, Ozkanlar S, Baygutalp NK, Bayir Y, et al. Endothelin receptor inhibition with bosentan delays onset of liver injury in streptozotocin-induced diabetic condition. Drug Res (Stuttg) 2015;65(5): 272–80. [76] Friedman SL. Mechanisms of disease: mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol 2004;1(2):98– 105. [77] Iredale JP. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest 2007;117(3):539–48.