Postprandial dyslipidemia in insulin resistance: Mechanisms and role of intestinal insulin sensitivity

Atherosclerosis Supplements 9 (2008) 7–13

Postprandial dyslipidemia in insulin resistance: Mechanisms and role of intestinal insulin sensitivity Joanne Hsieh, Amanda A. Hayashi, Jennifer Webb, Khosrow Adeli ∗ Molecular Structure & Function, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, M5G 1X8 Canada Received 1 February 2008; received in revised form 3 March 2008; accepted 13 May 2008

Abstract Insulin resistance is strongly associated with metabolic dyslipidemia, which is largely a postprandial phenomenon. Though previously regarded as a consequence of delayed triglyceride-rich lipoprotein clearance, emerging evidence present intestinal overproduction of apoB48-containing lipoproteins as a major contributor to postprandial dyslipidemia. The majority of mechanistic information is however derived from animal models, namely the fructose-fed Syrian Golden hamster, and extension to human studies to date has been limited. Work in our laboratory has established that aberrant insulin signalling exists in the enterocyte, and that inflammation appears to induce intestinal insulin resistance. The intestine is a major site of lipid synthesis in the body, and upregulated intestinal de novo lipogenesis and cholesterogenesis have been noted in insulin resistant and diabetic states. There is also enhanced dietary lipid absorption attributable to changes in ABCG5/8, NPC1L1, CD36/FAT, and FATP4. Proteins that are involved in chylomicron assembly and secretion, including MTP, MGAT, DGAT, apoAI-V, and Sar1 GTPase, show evidence of increased expression and activity levels. Increased circulating free fatty acids, typically observed in insulin resistant states, may serve to deliver lipid substrates to the intestine for enhanced chylomicron assembly and secretion. To compound the dysregulation of intestinal lipid metabolism, there are changes in the secretion of gut-derived peptides, which include GLP-1, GLP-2, and GIP. Thus, accumulating evidence presents intestinal lipoprotein secretion as a highly regulated process that is sensitive to perturbations in whole body energy homeostasis, and is severely perturbed in insulin resistant states. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Diabetes; Insulin signalling; Postprandial lipemia; Triglyceride; Cholesterol; Lipoproteins; Lipid transporters; Glucagon-like peptide; Intestine

Abbreviations: ABC-transporters, ATP-binding cassette transporters; ACC, acetyl CoA carboxylase; ApoA-IV, apolipoproteinA-IV; apoB-48, apolipoprotein B-48; CD36, cluster determinant 36; CM, chylomicron; COPII, coatomer II protein; DGAT, diacylglycerol acyltransferase; ERK-1/2, extracellular signal-related kinase-1/2; FA, fatty acid; FABP, fatty acid binding protein; FAS, fatty acid synthase; FAT, fatty acid translocase; FATP, fatty acid transporter protein; GIP, gastric inhibitory peptide; GLP-1, glucagon-like peptide-1; GLUT4, glucose transporter 4; HDL, high density lipoproteins; HMG-CoA, hydroxymethylglutaryl CoA; IL-6, interleukin-6; IRS1/2, insulin receptor substrate 1/2; JNK, c-Jun NH2 -terminal kinase; LDL, low density lipoproteins; L-FABP, liver-fatty acid binding protein; LpL, lipoprotein lipase; MAPK, mitogen-activated protein kinases; MG, sn-2-monoacylglycerol; MTP, microsomal triglyceride transfer protein; NPC1L1, Niemann-Pick C1-like 1; PCTV, prechylomicron transport vesicle; PI3-K, phosphatidylinositol-3-kinase; PPAR, peroxisome proliferators activated receptor; PTP-1B, protein tyrosine phosphatase; RELM ␤, resistin-like molecule ␤; SR-BI, scavenger receptor class B type I; Shc, Src homology 2 domain containing; SREBP, sterol regulatory element binding protein; TNF-␣, tumor necrosis factor-␣; TRL, triglyceride-rich lipoproteins; TZD, thiazolidinedione; VAMP7, vesicular associated membrane protein 7; VLDL, very low density lipoproteins. ∗ Corresponding author at: Division of Clinical Biochemistry, DPLM, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario, M5G 1X8 Canada. Tel.: +1 416 813 8682; fax: +1 416 813 6257. E-mail address: [email protected] (K. Adeli). 1567-5688/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosissup.2008.05.011

8

J. Hsieh et al. / Atherosclerosis Supplements 9 (2008) 7–13

1. Postprandial dyslipidemia in insulin resistant states

2. Aberrant insulin signalling occurs in the enterocyte

The rise in incidence of type 2 diabetes is so astonishing that it has been deemed a worldwide “epidemic” [1]. Given current trends in obesity, it is projected that 37.7 million individuals in the United States of America will be afflicted by diabetes in 2031 [2], with the majority of the cases being attributed to type 2 diabetes. Central to type 2 diabetes is insulin resistance, which is commonly associated with metabolic dyslipidemia, as characterized by hypertriglyceridemia, elevated plasma very low density lipoproteins (VLDLs) [3], depressed high density lipoproteins (HDLs) cholesterol levels [4], and small dense low density lipoproteins (LDLs) [5]. Although hepatic contributions to plasma lipoprotein levels play a major role in these observations, the metabolic dyslipidemia in insulin resistance has been recognized as a postprandial phenomenon [6]. Indeed, numerous studies have shown excessive postprandial lipemia in diabetic patients regardless of fasting hypertriglyceridemia (one such study is Ref. [7]). The impetus to understand mechanisms leading to elevated circulating intestinally derived apolipoprotein B48 (apoB-48)-containing lipoproteins is given by clinical and experimental evidence that triglyceride-rich lipoproteins (TRLs) and particularly chylomicron (CM) remnants pose as risk factors for atherosclerosis [8]. Additionally, apoB-48 can be detected in atherosclerotic plaques [9]. The increased accumulation of CM remnants in insulin resistance has long been regarded as a function of impaired clearance. Recent evidence supports this view showing that apolipoprotein E-deficient chylomicrons are produced in the diabetic state, contributing to delayed clearance [10]. If anything, this study points to the importance of focusing on intestinally secreted lipoproteins rather than peripheral factors in understanding aberrant postprandial lipemia in insulin resistance. It has become apparent that the intestine, long regarded as merely an absorptive organ, plays a dynamic role in lipid homeostasis in fed and fasting states. The intestine is sensitive to metabolic signals, as insulin reduces CM and apoB-48 secretion from cultured fetal jejunal explants in a posttranscriptional mechanism [11]. There is evidence for an increased basal rate of apoB48-containing lipoprotein secretion in insulin resistant [12] and type 2 diabetic [13] intestines, a process that is sensitive to the increased free fatty acid flux from adipose and non-adipose tissue. In addition, a growing body of evidence from both human studies [14] and various animal models [15–17] presents intestinal lipoprotein overproduction as having a causative role in the postprandial dyslipidemia observed in insulin resistant states. Whereas Gary Lewis’s review in this issue addresses the clinical observations, this review will outline the mechanistic information on intestinal chylomicron overproduction gathered from experimental models.

Insulin signalling involves a complex cascade downstream the insulin receptor through a series of tyrosine residue phosphorylations that engage the insulin-receptor substrates1/2 (IRS-1/2) to activate two divergent signalling arms: the phosphatidylinositol-3-kinase (PI3-K)/Akt pathway and the mitogen-activated protein kinases (MAPK) pathway. Numerous studies have documented perturbed insulin signalling in various tissues, including adipose, liver, and muscle in insulin resistant states, but there remains a paucity of information regarding the intestine and its insulin signalling status. Work in our laboratory suggests that insulin resistance can occur at the level of the enterocyte in the fructose-fed hamster model of insulin resistance, as summarized in Fig. 1. Reduced tyrosine phosphorylation on the insulin receptor and IRS-1, and increased protein tyrosine phosphatase (PTP)-1B protein abundance were observed, indicating that enterocytes from the intestine of fructose-fed hamster were refractory to insulin stimulation [18]. Interestingly, there was an increase in the basal levels of phosphorylated extracellular signal-related kinase-1/2 (ERK-1/2) (member of the MAPK signalling). The MEK/ERK proved to be essential to intestinal apoB-48 oversecretion as inhibition of this cascade reduced intestinal lipoprotein production.

3. Importance of inflammation to development of insulin resistance in the intestine It is now widely accepted that obesity and the concomitant development of inflammation are the major components of insulin resistance. Recently, the resistin-like molecule (RELM) ␤, a cytokine produced by goblet cells in the intestine, has been implicated in insulin resistance by antagonizing insulin action and by regulating the insulin signalling cascade [19]. Few studies have explored the link between the inflammation and insulin resistance at the level of the intestine. Our laboratory has recently investigated the role of TNF-␣ on intestinal insulin signalling and on lipoprotein production [20]. Using the fructose-fed Syrian Golden hamster model, we have shown that TNF-␣ treatment interferes with normal intestinal insulin signalling (Fig. 1). In intestines of TNF-␣ treated animals, tyrosine phosphorylation of insulin receptor␤ and IRS-1, Akt activation, and phosphorylated Shc were significantly reduced compared to saline infused control animals, to signify attenuated insulin signalling. On the other hand, TNF-␣ elicited an increase in p38, ERK-1/2 and cJun NH2 -terminal kinase (JNK) activation, but only in the postprandial condition. JNK is suggested to mitigate insulin signalling by phosphorylating IRS-1 on serine residues [21]. Furthermore, the induced intestinal insulin resistance by TNF-␣ was associated with a marked overproduction of intestinally produced lipoproteins in a manner mediated by the p38 MAPK pathway. Interestingly, it has been previously

J. Hsieh et al. / Atherosclerosis Supplements 9 (2008) 7–13

reported that low dose TNF-␣ actually inhibits lipoprotein secretion from Caco-2 cells [22]. Although model differences may be attributed to the incongruence, it suggests that in the postprandial milieu, TNF-␣ can interact with other signals to yield specific effects on intestinal lipoprotein metabolism. It should be noted that in contrast to the findings of Dube et al. TNF-␣ in Caco-2 cells have been shown to increase expression of fatty acid binding proteins (FABPs) [23], which are important for chylomicron secretion (as discussed below). Altogether, these data provide evidence that intestinal inflammation may be, in part, responsible for the induction of intestinal insulin resistance and the associated postprandial dyslipidemia observed in the insulin resistant state.

4. Importance of de novo lipogenesis and cholesterogenesis in the intestine Though often ignored, the intestine is a significant site of TG production in the body. Both the fructose-fed hamster [15] and the sand rat [17] model of insulin resistance exhibit upregulated de novo lipogenesis and cholesterogenesis in the intestine. Fructose-feeding in hamsters induces activation of the key transcription factor in lipogenesis, SREBP-1c, in a mechanism possibly involving increased ERK-1/2 activity

9

[18]. SREBP-1c is the major isoform of SREBP-1 found in hamster intestines, of which mRNA expression levels correlate with fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC) and ATP citrate lyase expression [24]. Insulin action is also imperative in intestinal cholesterol metabolism, as the hormone has been implicated in reducing hydroxymethylglutaryl CoA (HMG-CoA) reductase activity through studies in diabetic models [25], and been shown to decrease rates of cholesterol esterification [26]. Interestingly, treatment with a thiazolidinedione (TZD), used as an insulin sensitizer, is associated with lower intestinal levels of mature SREBP-2, the transcriptional activator of cholesterol biosynthetic pathways [27]. Though further studies are needed, this implicates peroxisome proliferator activated receptor ␥ (PPAR␥) as a critical regulator of intestinal cholesterogenesis in states of insulin resistance.

5. Enhanced intestinal lipid absorption During the lipid assimilation, the active absorption of dietary fat and cholesterol occurs at the enterocyte brush border membrane in a protein-mediated process facilitated by intestinal lipid transporters. Different transporters for intestinal uptake of these lipids have recently been pro-

Fig. 1. Insulin signalling pathway depicted with perturbations known to occur in the enterocyte during insulin resistance. Certain components of the system are upregulated (↑) or downregulated (↓) with respect to either mass or phosphorylation, as determined in enterocytes of the fructose-fed hamster model. While a decrease in IRS-1 phosphorylation was observed, there was an increase in PI3K p110 subunit mass that was associated with reduced Akt mass. The mass PTP-IB, a phosphatase that negatively regulates IR activity, was noted to increase. On the other hand, insulin resistance in the fructose-fed hamster intestine was characterized by upregulated activity in the MAPK arm of the signalling pathway. TNF-␣ signalling plays a role in inducing intestinal insulin resistance, and appears to be mediated by both TNF-␣ receptor 1 (TNFR1) and TNF-␣ receptor 2 (TNFR2). Points at which TNF-␣ interrupts insulin action are shown. Infusion with TNF-␣ in hamsters resulted in decreased phosphorylation on the IR-␤ subunit, IRS-1, Akt S473 and T308, and the Src homology 2 domain containing (Shc) adaptor. TNF-␣ treatment was also shown to increase p38 and JNK phosphorylation, with a supposed interaction between inflammatory signalling (via JNK) and insulin signalling (on IRS-1 phosphorylation) represented by a dotted line. JNK is proposed to inhibit insulin signalling through the serine phosphorylation of IRS-1.

10

J. Hsieh et al. / Atherosclerosis Supplements 9 (2008) 7–13

posed, but the molecular regulation of their expression in the insulin resistant state is still in its infancy. Bloks et al. [28] have demonstrated that intestinal mRNA expression of ATP binding cassette transporter G5/8 (ABCG5 and ABCG8) were drastically reduced in the intestine of streptozotozin (STZ)-induced diabetic rats, suggesting decreased cholesterol efflux. Further work in the same animal model showed an increase in gene expression of Niemann-Pick C1-like 1 (NPC1L1) [29], which insinuates that increased cholesterol absorption across the enterocyte apical membrane also occurs in this model. However, it should be noted that treatment with ezetimibe, of which NPC1L1 is identified as the critical target, did not significantly reduce apoB-48 production rate in male patients during a constant fed state [30]. When taken in conjunction with high dose simvastatin, ezetimibe failed to significantly lower total TG in comparison to a similar dose of atorvastatin alone [31], which brings into question the actual importance of cholesterol absorption in regulating postprandial dyslipidemia. Other intestinal transporter proteins facilitate the absorption of different substrates. Evidence exists for the involvement of apically expressed cluster determinant 36 (CD36)/fatty acid translocase (FAT) in intestinal fatty acid and cholesterol absorption [32,33]. A high fat diet not only induced insulin resistance in mice, but also upregulated CD36 expression in liver and heart tissue [34], so it will be interesting to see how intestinal expression is affected. Scavenger receptor class B type I (SR-BI) has also been implicated in intestinal cholesterol absorption [35], but no consensus has been reached on defining its requirement in the process. Another important transporter is fatty acid transporter protein-4 (FATP-4), the only FATP expressed in the small intestine [36], and one that is clearly linked to obesity associated with insulin resistant state [37]. In a recent work by Milger et al. the authors demonstrate that FATP4 is important for the absorption of fatty acids because of its ER-localized fatty acyl CoA synthetase activity, which may serve to trap transported fatty acids inside the enterocyte [38].

6. Chylomicron assembly machinery on overdrive Since triglyceride (TG) is hydrolyzed and absorbed as fatty acid (FA) and sn-2-monoacylglycerol (MG) across the enterocyte apical membrane, its reconstitution to TG presents an important step in chylomicron secretion. We have shown that the activity and expression of diacylglycerol acyltransferase (DGAT), the enzyme catalyzing the final and committed step of TG synthesis, are elevated in the intestine of insulin resistant animals [39], showing that changes in DGAT levels may play a critical role in stimulated rapid TG synthesis to facilitate intestinal chylomicron assembly. The assembly of chylomicrons in intestinal enterocytes involves two steps; the first step is the formation of a primordial chylomicron by the concerted translation of apoB-48 and its lipidation by microsomal triglyceride transfer protein (MTP).

In the second step, MTP is responsible for the further lipidation of the immature chylomicron particle (reviewed in Ref. [40]). Apolipoprotein AIV (apoAIV), of which secretion appears to be susceptible to modulation by insulin [41], is added during this step in the ER. Interestingly, apoAIV levels predict the magnitude of postprandial hypertriglyceridemia in obese and type 2 diabetes patients [42]. After apoAIV addition, the chylomicron buds from the ER in a specialized vesicle called the prechylomicron vesicle (PCTV) in an L-FABP dependent process, to fuse with the cis-golgi in a coatomer II protein (COPII)-dependent manner (reviewed in Ref. [43]). PCTV formation appears to be the rate-limiting step in the transport of dietary fat across the enterocyte, and may determine the hypertriglyceridemia observed in the insulin resistant state. Our laboratory has recently isolated PCTVs from the small intestinal enterocytes of the Syrian golden hamsters and characterized its proteome in both normal and insulin resistant states. We have identified a number of proteins involved in lipoprotein assembly and vesicular transport that are differentially expressed, including apoB-48 and MTP, and Sar1-GTPase [44], the latter being vesicular transport protein critical to efficient chylomicron secretion [45]. As for MTP, it is now understood through the fructose-fed hamster model that impaired insulin signalling is responsible for the increase in MTP mass observed in the insulin resistant intestine [15]. We have also shown that the increased intestinal MTP expression in an animal model of insulin resistance can be reversed after treatment with rosiglitazone, a TZD family member, and this is associated with a reduced secretion of TG-rich lipoproteins [46]. These findings present potential cellular factors responsible for intestinal overproduction of apoB-48-containing lipoproteins.

7. The gut as an endocrine organ The intestine has come to be appreciated as an essential organ in whole body energy homeostasis due to its secretory repertoire of endocrine peptides. Two such peptides that have recently garnered a lot of attention are glucagonlike peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 and GIP are the two principal incretins: hormones secreted from the gastrointestinal tract in response to nutrient ingestion that potentiate glucose-dependent insulin secretion (reviewed in Ref. [47]). Notably, a physiologically relevant stimulus in GLP-1 secretion from ileal enteroendocrine L cells appears to be long chain fatty acids [48]. In addition to their ability to abrogate postprandial hyperglycemia [47], both GLP-1 and GIP have been shown to attenuate postprandial lipemia, but through two distinct mechanisms. A study in dogs suggests that GIP promotes chylomicron catabolism through adipose tissue LpL [49]. On the other hand, GLP-1’s effect is exerted at the level of intestinal lipoprotein secretion through decreased triolein absorption and lymphatic apoB and apoAIV output [50]. More strikingly, GLP-1 com-

J. Hsieh et al. / Atherosclerosis Supplements 9 (2008) 7–13

pletely eliminated the postprandial rise in plasma TG when continuously infused into healthy male subjects [51]. Interestingly, type 2 diabetic patients experience a blunted incretin response, with less GLP-1 secretion and a concomitant complete loss of GIP’s insulinotropic activity [52]. Treatment with a dipeptidyl peptidase IV (DPP-IV) inhibitor, which confers extended bioactivity of endogenous GLP-1 and GIP, suppressed chylomicron apoB-48, TG, and cholesterol levels irrespective of effects on gastric emptying [53]. Recent data in our laboratory have indicated that GLP-1 has the same inhibitory effect on intestinal apoB-containing lipoprotein output in the Syrian Golden hamster, but the effect is lost in fructose-fed, insulin-resistant hamsters [54], suggesting that insulin signalling is crucial for GLP-1’s action on the intestine. An example of a gut-derived peptide that can exacerbate postprandial lipemia is GLP-2, which is paradoxically cosecreted with GLP-1 [55]. Elevated levels of GLP-2 were reported in STZ-induced diabetic rat model, and it is even implicated in mediating the intestinal hyperplasia that accompanies diabetes [56]. GLP-2 action is not limited to its intestinotropic effects however, as an acute study in human found that a pharmacological dose of GLP-2 augmented the postprandial TG excursion [57]. Current studies in our laboratory also put forth GLP-2 as a stimulator of chylomicron secretion through enhanced intestinal lipid absorption in chow-fed Syrian Golden hamsters [54]. In summary, recent evidence clearly implicate gut peptides, GLP-1 and GLP2, as critical regulators of intestinal lipid and lipoprotein metabolism in normal and insulin resistant states.

8. Conclusion Insulin resistance, as manifested by perturbed insulin signalling due to crosstalk with inflammatory pathways, affects postprandial intestinal lipoprotein oversecretion at multiple levels. Increased de novo lipogenesis and cholesterogenesis in addition to higher expression of apical lipid transporters provide more substrate to be packaged into chylomicrons. The upregulated chylomicron assembly machinery is more poised to handle and efficiently secrete the greater substrate load. In addition, dyregulation of the endocrine functions of an insulin resistant intestine likely plays an important role in intestinal lipoprotein overproduction. Given the highly atherogenic nature of intestinally derived apoB-48chylomicrons, further research should be directed towards understanding the molecular mechanisms contributing to intestinal dysfunction and chylomicron overproduction in insulin resistance.

Conflict of interest statement There is no personal or financial conflict of interest to disclose for any of the authors listed.

11

Acknowledgement This work is supported by an operating grant from the Canadian Institutes of Health Research (CIHR) (MOP53093) to K.A. References [1] Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001;414:782–7. [2] Mainous III AG, Baker R, Koopman RJ, et al. Impact of the population at risk of diabetes on projections of diabetes burden in the United States: an epidemic on the way. Diabetologia 2007;50:934–40. [3] Taghibiglou C, Carpentier A, Van Iderstine SC, et al. Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model. J Biol Chem 2000;275:8416–25. [4] Taskinen MR. Insulin resistance and lipoprotein metabolism. Curr Opin Lipidol 1995;6:153–60. [5] Reaven GM, Chen YD, Jeppesen J, Maheux P, Krauss RM. Insulin resistance and hyperinsulinemia in individuals with small, dense low density lipoprotein particles. J Clin Invest 1993;92:141–6. [6] Taskinen MR. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia 2003;46:733–49. [7] Rivellese AA, De Natale C, Di Marino L, et al. Exogenous and endogenous postprandial lipid abnormalities in type 2 diabetic patients with optimal blood glucose control and optimal fasting triglyceride levels. J Clin Endocrinol Metab 2004;89:2153–9. [8] McNamara JR, Shah PK, Nakajima K, et al. Remnant-like particle (RLP) cholesterol is an independent cardiovascular disease risk factor in women: results from the Framingham Heart Study. Atherosclerosis 2001;154:229–36. [9] Pal S, Semorine K, Watts GF, Mamo J. Identification of lipoproteins of intestinal origin in human atherosclerotic plaque. Clin Chem Lab Med 2003;41:792–5. [10] Phillips C, Madigan C, Owens D, Collins P, Tomkin GH. Defective chylomicron synthesis as a cause of delayed particle clearance in diabetes? Int J Exp Diabetes Res 2002;3:171–8. [11] Levy E, Sinnett D, Thibault L, et al. Insulin modulation of newly synthesized apolipoproteins B-100 and B-48 in human fetal intestine: gene expression and mRNA editing are not involved. FEBS Lett 1996;393:253–8. [12] Guo Q, Avramoglu RK, Adeli K. Intestinal assembly and secretion of highly dense/lipid-poor apolipoprotein B48-containing lipoprotein particles in the fasting state: evidence for induction by insulin resistance and exogenous fatty acids. Metabolism 2005;54:689–97. [13] Curtin A, Deegan P, Owens D, et al. Elevated triglyceride-rich lipoproteins in diabetes. A study of apolipoprotein B-48. Acta Diabetol 1996;33:205–10. [14] Duez H, Lamarche B, Uffelman KD, et al. Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B48-containing lipoproteins in humans. Arterioscler Thromb Vasc Biol 2006;26:1357–63. [15] Haidari M, Leung N, Mahbub F, et al. Fasting and postprandial overproduction of intestinally derived lipoproteins in an animal model of insulin resistance. Evidence that chronic fructose feeding in the hamster is accompanied by enhanced intestinal de novo lipogenesis and ApoB48-containing lipoprotein overproduction. J Biol Chem 2002;277:31646–55. [16] Vine DF, Takechi R, Russell JC, Proctor SD. Impaired postprandial apolipoprotein-B48 metabolism in the obese, insulin-resistant JCR:LA-cp rat: increased atherogenicity for the metabolic syndrome. Atherosclerosis 2007;190:282–90.

12

J. Hsieh et al. / Atherosclerosis Supplements 9 (2008) 7–13

[17] Zoltowska M, Ziv E, Delvin E, et al. Cellular aspects of intestinal lipoprotein assembly in Psammomys obesus: a model of insulin resistance and type 2 diabetes. Diabetes 2003;52:2539–45. [18] Federico LM, Naples M, Taylor D, Adeli K. Intestinal insulin resistance and aberrant production of apolipoprotein B48 lipoproteins in an animal model of insulin resistance and metabolic dyslipidemia: evidence for activation of protein tyrosine phosphatase-1B, extracellular signal-related kinase, and sterol regulatory element-binding protein-1c in the fructose-fed hamster intestine. Diabetes 2006;55: 1316–26. [19] Artis D, Wang ML, Keilbaugh SA, et al. RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc Natl Acad Sci USA 2004;101:13596–600. [20] Qin B, Qiu W, Avramoglu RK, Adeli K. Tumor necrosis factor-alpha induces intestinal insulin resistance and stimulates the overproduction of intestinal apolipoprotein B48-containing lipoproteins. Diabetes 2007;56:450–61. [21] Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun NH(2)terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem 2000;275:9047–54. [22] Murthy S, Mathur SN, Field FJ. Tumor necrosis factor-alpha and interleukin-1beta inhibit apolipoprotein B secretion in CaCo-2 cells via the epidermal growth factor receptor signaling pathway. J Biol Chem 2000;275:9222–9. [23] Dube N, Delvin E, Yotov W, et al. Modulation of intestinal and liver fatty acid-binding proteins in Caco-2 cells by lipids, hormones and cytokines. J Cell Biochem 2001;81:613–20. [24] Field FJ, Born E, Mathur SN. Fatty acid flux suppresses fatty acid synthesis in hamster intestine independently of SREBP-1 expression. J Lipid Res 2003;44:1199–208. [25] Lally S, Owens D, Tomkin GH. The different effect of pioglitazone as compared to insulin on expression of hepatic and intestinal genes regulating post-prandial lipoproteins in diabetes. Atherosclerosis 2007;193:343–51. [26] Jiao S, Moberly JB, Cole TG, Schonfeld G. Decreased activity of acylCoA:cholesterol acyltransferase by insulin in human intestinal cell line Caco-2. Diabetes 1989;38:604–9. [27] Klopotek A, Hirche F, Eder K. PPAR gamma ligand troglitazone lowers cholesterol synthesis in HepG2 and Caco-2 cells via a reduced concentration of nuclear SREBP-2. Exp Biol Med (Maywood) 2006;231:1365–72. [28] Bloks VW, Bakker-Van Waarde WM, Verkade HJ, et al. Downregulation of hepatic and intestinal Abcg5 and Abcg8 expression associated with altered sterol fluxes in rats with streptozotocin-induced diabetes. Diabetologia 2004;47:104–12. [29] Lally S, Owens D, Tomkin GH. Genes that affect cholesterol synthesis, cholesterol absorption, and chylomicron assembly: the relationship between the liver and intestine in control and streptozotosin diabetic rats. Metabolism 2007;56:430–8. [30] Tremblay AJ, Lamarche B, Cohn JS, Hogue JC, Couture P. Effect of ezetimibe on the in vivo kinetics of apoB-48 and apoB-100 in men with primary hypercholesterolemia. Arterioscler Thromb Vasc Biol 2006;26:1101–6. [31] Bays HE, Ose L, Fraser N, et al. A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clin Ther 2004;26: 1758–73. [32] Nassir F, Wilson B, Han X, Gross RW, Abumrad NA. CD36 is important for fatty acid and cholesterol uptake by the proximal but not distal intestine. J Biol Chem 2007;282:19493–501. [33] Nauli AM, Nassir F, Zheng S, et al. CD36 is important for chylomicron formation and secretion and may mediate cholesterol uptake in the proximal intestine. Gastroenterology 2006;131: 1197–207.

[34] Koonen DP, Jacobs RL, Febbraio M, et al. Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity. Diabetes 2007;56:2863–71. [35] van BA, Werder M, Thuahnai ST, et al. Class B scavenger receptormediated intestinal absorption of dietary beta-carotene and cholesterol. Biochemistry 2005;44:4517–25. [36] Stahl A. A current review of fatty acid transport proteins (SLC27). Pflugers Arch 2004;447:722–7. [37] Fisher RM, Gertow K. Fatty acid transport proteins and insulin resistance. Curr Opin Lipidol 2005;16:173–8. [38] Milger K, Herrmann T, Becker C, et al. Cellular uptake of fatty acids driven by the ER-localized acyl-CoA synthetase FATP4. J Cell Sci 2006;119:4678–88. [39] Casaschi A, Maiyoh GK, Adeli K, Theriault AG. Increased diacylglycerol acyltransferase activity is associated with triglyceride accumulation in tissues of diet-induced insulin-resistant hyperlipidemic hamsters. Metabolism 2005;54:403–9. [40] Black DD. Development and physiological regulation of intestinal lipid absorption. I. Development of intestinal lipid absorption: cellular events in chylomicron assembly and secretion. Am J Physiol Gastrointest Liver Physiol 2007;293:G519–24. [41] Tso P, Sun W, Liu M. Gastrointestinal satiety signals IV. Apolipoprotein A-IV. Am J Physiol Gastrointest Liver Physiol 2004;286: G885–90. [42] Verges B, Guerci B, Durlach V, et al. Increased plasma apoA-IV level is a marker of abnormal postprandial lipemia: a study in normoponderal and obese subjects. J Lipid Res 2001;42:2021–9. [43] Mansbach CM, Gorelick F. Development and physiological regulation of intestinal lipid absorption. II. Dietary lipid absorption, complex lipid synthesis, and the intracellular packaging and secretion of chylomicrons. Am J Physiol Gastrointest Liver Physiol 2007;293: G645–50. [44] Wong DM, Xu E, Naples M, Adeli K. Proteomic profiling of prechylomicron transport vesicles involved in the assembly and secretion of apob48-containing chylomicrons by the intestine. Arterioscler Thromb Vasc Biol 2007;27:e115– 15 (Abstract P446). [45] Jones B, Jones EL, Bonney SA, et al. Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nat Genet 2003;34:29–31. [46] Lewis GF, Naples M, Uffelman K, et al. Intestinal lipoprotein production is stimulated by an acute elevation of plasma free fatty acids in the fasting state: studies in insulin-resistant and insulinsensitized Syrian golden hamsters. Endocrinology 2004;145:5006– 12. [47] Drucker DJ. The biology of incretin hormones. Cell Metab 2006;3:153–65. [48] Beysen C, Karpe F, Fielding BA, et al. Interaction between specific fatty acids, GLP-1 and insulin secretion in humans. Diabetologia 2002;45:1533–41. [49] Wasada T, McCorkle K, Harris V, et al. Effect of gastric inhibitory polypeptide on plasma levels of chylomicron triglycerides in dogs. J Clin Invest 1981;68:1106–7. [50] Qin X, Shen H, Liu M, et al. GLP-1 reduces intestinal lymph flow, triglyceride absorption, and apolipoprotein production in rats. Am J Physiol Gastrointest Liver Physiol 2005;288:G943– 9. [51] Meier JJ, Gethmann A, Gotze O, et al. Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans. Diabetologia 2006;49:452–8. [52] Meier JJ, Nauck MA. Incretins and the development of type 2 diabetes. Curr Diab Rep 2006;6:194–201. [53] Matikainen N, Manttari S, Schweizer A, et al. Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes. Diabetologia 2006;49:2049– 57.

J. Hsieh et al. / Atherosclerosis Supplements 9 (2008) 7–13 [54] Hsieh J, Qin B, Longuet C, et al. Glucagon-like peptides (GLP-1 and GLP-2) regulate intestinal production of apob48-containing lipoproteins: evidence for differential regulation and implications for intestinal fat absorption. Diabetes 2007;56:A376 (Abstract 1469-P). [55] Estall JL, Drucker DJ. Glucagon-like peptide-2. Annu Rev Nutr 2006;26:391–411.

13

[56] Hartmann B, Thulesen J, Hare KJ, et al. Immunoneutralization of endogenous glucagon-like peptide-2 reduces adaptive intestinal growth in diabetic rats. Regul Pept 2002;105:173–9. [57] Meier JJ, Nauck MA, Pott A, et al. Glucagon-like peptide 2 stimulates glucagon secretion, enhances lipid absorption, and inhibits gastric acid secretion in humans. Gastroenterology 2006;130:44–54.