Cytochrome P450-derived eicosanoids and inflammation in liver diseases

Journal Pre-proof Cytochrome P450-Derived Eicosanoids and Inflammation in Liver Diseases Sherif M. Shoieb, Mahmoud A. El-Ghiaty, Mohammed A. Alqahtani, Ayman O.S. El-Kadi

PII:

S1098-8823(19)30151-0

DOI:

https://doi.org/10.1016/j.prostaglandins.2019.106400

Reference:

PRO 106400

To appear in:

Prostaglandins and Other Lipid Mediators

Received Date:

3 May 2019

Revised Date:

8 October 2019

Accepted Date:

12 November 2019

Please cite this article as: Shoieb SM, El-Ghiaty MA, Alqahtani MA, El-Kadi AOS, Cytochrome P450-Derived Eicosanoids and Inflammation in Liver Diseases, Prostaglandins and Other Lipid Mediators (2019), doi: https://doi.org/10.1016/j.prostaglandins.2019.106400

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Cytochrome P450-Derived Eicosanoids and Inflammation in Liver Diseases Sherif M. Shoieb, Mahmoud A. El-Ghiaty, Mohammed A. Alqahtani, Ayman O.S. El-Kadi* Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta,

of Correspondence:

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*Address

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Canada

Ayman O.S. El-Kadi, PhD,

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Faculty of Pharmacy & Pharmaceutical Sciences,

University of Alberta,

Phone: 780-492-3071.

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Fax: 780-492-1217.

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Edmonton, Alberta, Canada T6G 2E1.

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2142J Katz Group-Rexall Centre for Pharmacy and Health Research,

E-mail: [email protected]

Highlights

Hepatitis is a key pathologic feature in both acute and chronic liver diseases

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 

Balanced intake of n-6 and n-3 PUFAs is necessary to maintain good health



Linoleic and α-linolenic acid are the major source of polyunsaturated fatty acids



CYP-derived eicosanoids can alter the pathogenesis of inflammatory liver diseases



Therapeutic strategies to boost the salutary effects of PUFAs should be considered

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Abstract

Hepatic inflammation is a key pathologic mediator in a wide array of acute and chronic liver

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diseases. Hepatitis is a crucial driver of liver tissue damage provoking the progression to severe fibrosis, cirrhosis and hepatocellular carcinoma, irrespective of the etiologic cause. Inflammatory

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liver diseases are collectively considered one of the most critical public health risks. Cytochrome

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P450 (CYP) enzymes are superfamily of monooxygenases which possess the greater diversity of substrate structures amidst all other enzyme families. Members of omega-3 as well as omega-6

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polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid and arachidonic acid, respectively, can be metabolized by CYP isoforms leading to the production of biologically active lipid mediators called eicosanoids. CYP-derived eicosanoids have been shown to play significant roles in the pathophysiology and protection of multiple inflammatory liver diseases. In this review,

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we elucidate the intricate role of CYP-derived eicosanoids in inflammation in liver diseases paving the way for better therapeutic approaches. Keywords:

inflammation;

liver

diseases;

Cytochrome

polyunsaturated fatty acids (PUFAs)

2

P450s

(CYPs);

eicosanoids;

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1. Introduction

Inflammation is recognized as a central event in both acute and chronic liver diseases. The hepatic

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injury could occur due to a variety of stimuli, including those that are primary to the organ (e.g., viral hepatitis) or secondary to other diseases such as right-sided cardiac failure or metastatic

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hepatocellular carcinoma. Irrespective of the etiology, hepatitis and accompanying cellular

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consequences such as recruitment of inflammatory cells and stimulation of inflammatory response are typically observed [1,2]. Acute liver failure frequently exists in individuals who do not have a

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previous history of hepatic diseases [3]. It could occur due to a variety of insults to hepatic cells, the most recurring are due to infection with viruses or the exposure to toxic effects of medications such as paracetamol and chemicals like tetrahydrochloride [4]. Acute liver failure causes a high mortality rate that could reach 80% of the cases in some reports [5].

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On the other hand, chronic liver diseases are a result of variable causes that lead to necrosis in addition to inflammatory response that eventually progress to liver fibrosis and nodular regeneration. These events consequently damage the hepatic histo-architecture and cause significant deformation to the hepatic vasculature [6]. This end-stage structural modification is called cirrhosis. The most common causes of cirrhosis in western countries are alcohol, virus C

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infection (HCV) and nonalcoholic fatty liver disease (NAFLD). On the contrary, hepatitis B virus (HBV) is the predominant cause in considerable number of developing countries [7]. NAFLD represents wide spectrum of liver injury that affects people who drink little to no alcohol. The underlying pathophysiological features range from simple deposition of macrovesicular fats to the most severe, non-alcoholic steatohepatitis (NASH) with or without cirrhosis [8]. NAFLD is

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considered to be the most prevalent chronic hepatic disease in the western countries where it is reported to affect approximately 30% of the general population [9]. It affects around 60% of type-

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2 diabetes mellitus patients, 30 to 37% of obese patients and 50 to 60% of hyperlipidemic

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patients[10–12]. One prominent feature of the histological picture of NAFLD is accumulation of more than 5% of liver fat composed of hepatic triglycerides leading to hepatic inflammation [13].

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Inflammation is an evident hallmark in case of alcoholic steatohepatitis, a chronic hepatic condition that affects up to 40% of people with heavy alcohol drinking [14]. Alcohol and its

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metabolites have been shown to be involved in activation of nuclear factor-κB (NF-κB) signaling pathway and release of tumor necrosis factor-α (TNF-α) initiating the hepatic inflammatory

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response [15].

In clinical settings, cirrhosis has been considered as an end-stage hepatic disease that eventually causes death. Liver transplantation is regarded as the only available death-preventing modality that

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could be done [16]. Liver fibrosis is a pathological stage in almost all chronic liver diseases that precedes the stage of liver cirrhosis. The histopathological picture of liver fibrosis is distinguished by exaggerated deposition of extracellular matrix combined with inflammatory response that interferes with the normal hepatic functionality [17]. For decades, liver fibrosis was thought to be irreversible process that could occasionally be come to a halt but would not recede. However, novel therapeutic modalities for chronic liver diseases 4

have shown that liver fibrosis could regress over time [18]. According to the type of liver disease, the treatment algorithm will vary. Suppression of the inflammatory response and its downstream signaling cascades has been proposed as one of the strategies that could effectively abrogate the hepatic injury and fibrosis [19]. For instance, controlling the inflammatory response resulting from immune-mediated devastation of HBV-inhabited hepatic cells has shown to be therapeutically successful approach in the treatment of chronic hepatitis B [20]. Therefore, research into anti-

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inflammatory drugs would be of a great benefit for discovery of an effective therapeutic option

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that is able to control inflammation without intervening with the normal physiologic processes.

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CYP enzymes are a superfamily of monooxygenases, which are widely involved in the metabolism of both xenobiotics and endogenous compounds. Polyunsaturated fatty acids (PUFAs) are highly

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important elements in human body because of their structural and functional roles in cell membranes. Moreover, some PUFAs have essential functions in regulating immune and

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inflammatory responses by acting as precursors of biologically active lipid mediators, termed eicosanoids. Arachidonic acid (AA), an omega-6 PUFA representing a predominant component of

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lipid content in cell membranes, via its derived eicosanoids is recognized as an integral mediator in the inflammatory reactions and pathogenesis of several conditions such as cardiovascular and liver diseases. AA yields ultimately bioactive eicosanoids through a variety of metabolic pathways mediated by three enzyme families; cyclooxygenases (COX), lipoxygenases (LOX), and

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cytochrome P450 (CYP) [21]. The two major groups of CYP metabolic products generated from AA

are

the

anti-inflammatory

CYP

epoxygenases-derived

epoxyeicosatrienoic

and

dihydroxyeicosatrienoic acids (EETs + DHETs) and the CYP ω-hydroxylases-derived hydroxyeicosatetraenoic acids (HETEs) which, with the exception of 15-HETE whose antiinflammatory properties have been reported, are predominantly proinflammatory [22].

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Interestingly, the two groups exhibit divergent effects in the regulation of inflammation; thus, these parallel pathways have a functional balance that, if altered, may contribute to the development and progression of several pathological conditions [23]. CYP epoxygenases and ω-hydroxylases are expressed most abundantly, and consequently EETs and HETEs are produced at the highest levels in the liver, rendering it more vulnerable to the regulatory effects of these mediators [24]. In this review, we discuss the nature, resources, and metabolism of CYP-derived eicosanoids as well as

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2. Overview of omega-6 and omega-3 polyunsaturated fatty acids

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other bioactive lipid mediators and their potential significant roles in inflammatory liver diseases.

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Fatty acids represent a substantial component of cell membranes. Membrane lipids comprise both saturated and unsaturated fatty acids [25]. Unsaturated fatty acids containing two or more double

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bonds are called PUFAs and have an important impact on the structure and physical properties of

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cell membranes. When incorporated into phospholipids, PUFAs affect cell membrane properties, such as fluidity, flexibility, permeability, and the activity of membrane-bound enzymes [26]. Moreover, the membrane metabolites of PUFAs have an essential role in intercellular biochemical

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communications [27]. There are two main groups of PUFAs namely omega-6 (n-6) and omega-3 (n-3) fatty acids. In omega-6 PUFAs, the last double bond in the molecule is located between the sixth and seventh carbon atom from the terminal methyl end of the fatty acid. On the other hand,

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omega-3 PUFAs have at least one double bond between the third and fourth carbon atom. Linoleic acid (LA, 18:2n-6) is the simplest and shortest-chained omega-6 fatty acid and is referred to as the parent fatty acid of the omega-6 series (Fig. 1) [28]. While α-linolenic acid (ALA, 18:3n-3) is the parent fatty acid of the omega-3 family (Fig. 2). 3. Sources of omega-6 and omega-3 polyunsaturated fatty acids

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In humans, because of lacking the desaturase enzymes necessary to insert a double bond at the n6 or the n-3 position of a fatty acid, LA and ALA are considered an essential dietary requirement. However, humans can synthesize longer omega-6 and omega-3 fatty acids from LA and ALA, respectively, through sequential desaturation (addition of a double bond) and elongation (addition of two carbon atoms) reactions [29]. Most crop seeds and vegetable oils, including canola, soybean, corn, cotton seed, safflower, and sunflower oils, are major sources of omega-6 fatty acids

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in the form of LA [30]. It is worth noting that cultivated (farmed) fish contain more omega-6 fatty

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acids than wild (marine) fish since they consume feed made of cereal and vegetable oils that contain more proportions of omega-6 fatty acids. For example, LA was found to be six-fold higher

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in farmed salmon than in wild salmon [31].

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Omega-3 PUFAs are also widely distributed in various food sources. For instance, seafood is mainly where most of omega-3 PUFAs come from [32]. While fish and other marine invertebrates

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feed mostly on algae that serve as a food supply, they are also rich in omega-3 active forms eicosapentaenoic (EPA) and docosahexaenoic (DHA) and their metabolites [33,34]. Wild sardine,

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herring, salmon and pollock roe are considered the top sources of these beneficial fatty acids whereas their content in plant is considerably low compared to food of marine origin [35,36]. 4. Metabolism of omega-6 and omega-3 polyunsaturated fatty acids

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4.1. Biosynthesis and activity of omega-6 and omega-3 polyunsaturated fatty acids In humans, primarily in the endoplasmic reticulum of liver cells, biosynthesis of omega-6 PUFAs starts with adding a double bond at the 6th C-C bond position from the -COOH end of LA via Δ6desaturase, thus generating γ-linolenic acid (GLA, 18:3n-6). By a specific elongase, GLA undergoes two-carbon elongation yielding dihomo-γ-linolenic acid (DGLA, 20:3n-6). One more

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desaturation is achieved by a Δ5-desaturase through adding a double bond at the 5th C-C bond to produce AA (20:4n-6). AA can either be incorporated and stored in phospholipids after esterification with hydroxyl groups of the glycerol backbone of phospholipids, or undergo further elongation/desaturation steps yielding other omega-6 PUFAs [37]. Human body can also metabolize omega-3 PUFAs into physiologically active compounds [38].

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The metabolic pathway begins with the rate-limiting step of conversion of ALA by delta-6desaturase to stearidonic acid and then elongated to eicosatetraenoic acid by adding two carbons

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in the chain, consequently, desaturated (via delta-5-desaturase) into EPA as the first active form

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of omega-3 PUFAs [38]. Further steps involving elongation and desaturation (via delta-6desaturase) followed by β-oxidation to form DHA as the second active form of this chain reaction

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(Fig. 2) [39]. The conversion of ALA into EPA and DHA is carried out in a very slow manner resulting in limited supply of bioactive omega-3 PUFAs [40,41]. For that reason, EPA and DHA

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are currently available in omega-3 supplements as active ingredients in the market [38]. Since LA and ALA are metabolized by the same set of enzymes, a natural competition exists

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between members of omega-6 and omega-3 PUFAs for the corresponding desaturase and elongase enzymes. The ratio of ingested omega-6 and omega-3 PUFAs in humans is a major determinant of LA and ALA bioconversion to their respective PUFAs and subsequently affecting the levels of

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their derived eicosanoids [42]. This will eventually result in changes in cell membrane fatty acid composition [25]. For example, Modern Western diet, with high levels of LA, tends to shift in the preference of these enzymes towards metabolizing omega-6 PUFAs, leading to increased AA synthesis. However, omega-3 PUFAs status can be corrected by increasing ALA intake with decreasing LA intake is most eff ective way to improve [43].

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Since the omega-6 and omega-3 PUFAs metabolites have almost diametrically opposing physiological and pathological activities, it has often been suggested that the deleterious consequences associated with the consumption of omega-6 PUFAs-rich diets reflect high level of AA with excessive production and activities of its derived eicosanoids. On the other hand, the beneficial effects associated with the consumption of omega-3 PUFAs-rich diets reflect the excessive production and activities of their derived eicosanoids. Accordingly, a balanced intake of

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omega-6 and omega-3 PUFAs is necessary to maintain good health and avoid chronic diseases.

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Several studies have suggested that omega-6 fatty acids should be consumed in a 1:1 or 2:1 ratio to omega-3 fatty acids, instead of 16:1 which is the average ratio observed in the diet of many

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individuals today which is resulting mainly from vegetable oils [44].

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It has been observed that omega-3 PUFAs oppose inflammatory response [45]. In particular, DHA and EPA elicited inhibitory effect on lipopolysaccharide (LPS)-induced expression in monocytes

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[46,47]. Treatment with DHA and EPA resulted in lower expression of cytokines including IL-1β, IL-6 and TNF-α in mononuclear cells while treatment of DHA alone in adipocytes showed higher

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expression of anti-inflammatory cytokines, IL-10, compared to control group [48–50]. The antiinflammatory mechanism of omega-3 PUFA is mostly attributed to the NF-κB inhibition [51]. Additionally, another inhibition of NF-κB activity is exerted through IϰB modulation when treated with DHA and its metabolites [52]. Previous study showed that inhibition of glutathione

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production mitigates omega-3 PUFA suppression on NF-κB synthesis suggesting that the aforementioned FAs could be integrated within anti-oxidative defense mechanism [45,53]. DHA and EPA are substrates for the peroxisome proliferator-activated receptors (PPAR) which is involved in the regulation of NF-κB expression [54,55]. Given that omega-3 PUFAs function as anti-inflammatory agents by suppressing LPS-induced NF-κB synthesis in HK-2 cells, antagonism 9

of PPAR-γ receptor reversed that anti-inflammatory action [56]. Accordingly, cells that lack PPAR-γ showed no NF-κB suppression when omega-3 PUFAs are used, indicating their crucial involvement in regulating inflammatory responses [57]. NF-κB activity and activator protein 1 (AP-1) were observed to be hindered by PPAR through protein-protein interaction and proinflammatory genes inhibition [58]. To sum up, omega-3 PUFAs can be considered as one of the anti-inflammatory candidates that enrolled within various lipid regulatory mechanisms and being

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a novel target that needs further investigation [45].

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Interestingly, several studies have shown that omega-3 supplementation induces macrophages to

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secrete IL-6 and TNF-α while the latter is observed in higher concentration during inflammatory stimuli [59,60]. For that reason, omega-3 PUFAs are involved in pro-inflammatory pathway where

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in adipocytes and other cells, they elevate the expression of IL-1, IL-6 and TNF-α whereas the level of TNF-α inhibitor, PGE2, is suppressed [61–65]. As omega-3 PUFAs induce inflammatory

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cytokines, they are inversely correlated to PEG2 level and regulate the pro-inflammatory response through it [60,66]. Recently, a study revealed that DHA activates PKA to enhance

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CAAT/enhancer-binding protein beta (C/EBPβ) modulation. Hence, introducing additional mechanism of omega-3 PUFAs contributing in pro-inflammatory response [67]. Because of that wide spectrum of potential pathways in which omega-3 participating in lipid metabolism, further

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research is needed.

The fatty acid makeup of cell membrane phospholipids has a strong influence on cell responses and function. This is achieved through a variety of lipid mediators which are derived from fatty acids released from membrane phospholipids upon cellular stimulation [68]. The membrane content of the omega-6 PUFA AA is highly important due to its role in the production of physiologically active metabolites. In humans consuming western-type diets, the membrane 10

phospholipids typically contain approximately 20% of total fatty acids as AA. In contrast, other 20-carbon PUFAs such as the omega-6 PUFA DGLA in addition to omega-3 PUFAs typically represent lower proportions of membrane fatty acids. Thus, as a major PUFA in the membranes of cells, AA is usually the dominant substrate for the synthesis of membrane lipid mediators [21]. In addition to its synthesis from LA, some dietary sources such as meat, fish (e.g. salmon and tuna), organ meats (e.g. liver, kidney and brain) and eggs contain AA which can be directly utilized for

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normal physiological functions [69]. Concentrations of free AA are typically very low in the

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circulation due to albumin binding and trafficking to cells [70].

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4.2. Omega-6 and omega-3 polyunsaturated fatty acids-related eicosanoids

Eicosanoids are a family of numerous potent chemical messengers involved in immune and

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inflammatory responses, that are oxygen-containing derivatives of 20 (eicosa) -carbon PUFAs.

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They are typically not stored within cells but rather synthesized as required. The metabolic pathways of omega-6 and omega-3 PUFAs in the liver encompass various enzymes that yields bioactive eicosanoids which play crucial roles in the regulation of inflammation, achieving overall

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physiological homeostasis [71,72].

4.2.1. Omega-6 polyunsaturated fatty acids-generated eicosanoids Endogenous AA is mainly generated from cell membrane phospholipids by the action of

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phospholipase A2 (PLA2) enzyme, which is induced by various cellular activation signals including many inflammatory stimuli and acts as an esterase that cleaves off AA from the sn-2 position of cell membrane phospholipids, particularly phosphatidylcholine [73]. Once released, free AA serves as a precursor that undergoes metabolism by various enzymes yielding a wide range of clinically important bioactive metabolites called eicosanoids. The concentrations of many

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AA-derived eicosanoids are found to be elevated in people with inflammatory conditions [21]. Processing of free AA for eicosanoid synthesis relies primarily on three families of enzymes: COX, LOX and CYP. There are two isozymes of cyclooxygenases; COX-1 and COX-2. COX-2 is an inducible enzyme as it is unexpressed under normal conditions in most cells, but elevated levels are found during

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inflammation in inflammatory cells such as monocytes, macrophages, neutrophils, and mast cells, while COX-1 is constitutively expressed in many tissues for homeostatic purposes.

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Cyclooxygenases catalyze the formation of prostanoids which are cyclic oxygenated products

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including prostaglandins (PGs), prostacyclin (PGI) and thromboxane (Tx). AA-derived prostanoids contain two double bonds. The catalytic process of COX enzymes consists of two

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reaction activities; a dioxygenase activity involves incorporation of two oxygen molecules into the carbon backbone of AA to yielding PGG2 as an intermediate, and a peroxidase activity involves

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reduction of the 15-hydroperoxyl group of PGG2 to PGH2 and water. PGH2 does not accumulate in cells but is rather converted quickly to bioactive downstream products including PGD2, PGE2,

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PGF2α, PGI2 and TxA2 which are involved in several physiological processes such as immune response and inflammation, mucosal cytoprotection, platelet aggregation and thrombus formation, and regulation of vascular tone [74]. 5-LOX, 8-LOX, 12-LOX and 15-LOX are lipoxygenases involved

in

AA

processing.

The

enzyme

5-lipoxygenase

metabolizes

AA

to

5-

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hydroperoxyeicosatetraenoic acid (5-HPETE), which in turn is metabolized to various 4-series leukotrienes (LTB4, LTC4, LTD4, and LTE4) as well as to 5-hydroxyeicosatetraenoic acid (5HETE) which may then be further metabolized to a more potent 5-keto analog, 5-oxoeicosatetraenoic acid (5-oxo-ETE) [75]. Leukotrienes family are produced by leukocytes such as neutrophils and macrophages to act as inflammatory mediators in regulating immune responses.

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They are involved in leukocyte chemotaxis, adhesion and degranulation, and enhancing vascular permeability [76]. One of their roles (specifically leukotriene D4) is to trigger contractions in the smooth muscles lining the bronchioles; and their overproduction is a major cause of inflammation in asthma and allergic rhinitis [77]. Both 5-HETE and 5-oxo-ETE are potent pro-inflammatory mediators. 5-Oxo-ETE possesses the highest potency and power in stimulating the human eosinophil type of leukocytes, and therefore it is considered to be an extremely important

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contributor to the formation and progression of eosinophil-based allergic reactions [78]. In addition

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to its significant role in inflammatory process, 5-oxo-ETE may be also involved in cancer progression through its proliferative effects [79,80]. In a similar way, the enzyme 15-LOX

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metabolizes AA to 15-HPETE which is an initial short-lived hydroperoxide, and is rapidly reduced

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to 15-HETE and via 5-LOX can yield lipoxins (LXs) such as LXA4. Lipoxins, which are mainly pro-resolving mediators exerting anti-inflammatory properties, can be also produced from AA via

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5-LOX and 15-LOX through sequential oxygenation which is mediated by LTA4 formation. A third pathway may be initiated by 5-LOX to produce LTA4 which in turn can generate lipoxins by

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12-LOX activity [81]. 15-HETE has anti-inflammatory activity and also mediates certain cellstimulating signals involved in growth-promoting and anti-apoptotic activities which may explain the excess fibrosis that causes the narrowing of pulmonary arteries in hypoxia-induced pulmonary hypertension, or narrowing of portal arteries in the portal hypertension accompanying liver

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cirrhosis [22,82,83].

12-LOX metabolizes AA to 12-hydroperoxyeicosatetraenoic acid (12-HPETE), which itself serves as a precursor for 12-hydroxyeicosatetraenoic acid (12-HETE) and to hepoxilins. Both 12-HETE and hepoxilins possess pro-inflammatory actions [84–86]. AA-derived eicosanoids are known to be linked to the inflammatory process as pivotal pro-inflammatory elements, as evidenced by anti-

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inflammatory agents developed to target any of the various steps in the synthesis of these lipid mediators such as COX inhibitors and LOX inhibitors. However, it is important to mention that not all AA-derived eicosanoids are pro-inflammatory and that some of them may play an important role in the resolution of inflammation. Interestingly, PGE2 is regarded as being a potent proinflammatory mediator, but it also acts as an inhibitor of the production of pro-inflammatory cytokines such as TNF-α [87]. Moreover, PGE2 inhibits 5-LOX thus decreasing the production of

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4-series LTs, and also induces the production of LXA4, through induction of 15-LOX, which by

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turn is involved in inflammation resolution following the acute inflammatory response [88–90].

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4.2.2. Omega-3 polyunsaturated fatty acids-generated eicosanoids and related compounds DHA and EPA are found to be metabolized into other bioactive molecules termed as specialized

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pro-resolving mediators (SPM) that regulate the resolution of inflammation [91,92]. EPA-derived

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lipid mediators are generated via COX-2 and 5-LOX each of which metabolizes EPA to yield 3series prostaglandins (PGs) and the 5-series leukotrienes (LTs) a precursor of 5hydroxyeicosapentaenoic acid (5-HEPE). Furthermore, CYP and COX-2 can also metabolize EPA

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into 18-HEPE in which it undergoes further metabolism via 5-LOX to yield resolvins E1 and E2 or by 15-LOX to yield resolvin E3. On the other hand, DHA-derived lipid mediators are generated via 15-LOX or COX-2 to metabolizing DHA into 17-HpDHA which is the precursor of 17-

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hydroxydocosahexaenoicacid (17-HDHA) and protectin D1 (PD1). Also, 5-LOX metabolizes 17HDHA into D-series resolvins [93]. Competition of omega-3 PUFAs (EPA and DHA) and AA as substrates for COX, LOX and CYP enzymes have been widely observed, regulating normal metabolic pathways [23]. 5. Synthesis of cytochrome P450-derived eicosanoids and biological significance

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CYPs are involved in the metabolism of both xenobiotics and endogenous compounds. In mammals, CYPs are localized in the endoplasmic reticulum with limited expression in mitochondria [94]. CYP enzymes are predominantly expressed in the liver, but there are significant levels of CYP isozymes found in some extrahepatic tissues including brain, lung, kidney, gastrointestinal tract and heart [95]. Certain CYPs are critical in generating biologically active eicosanoids. In addition to the COX and LOX pathways, the CYP enzymes represent the third

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major pathway for AA metabolism. They catalyze AA epoxidation, hydroxylation and allylic

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oxidation. AA is converted to bioactive EETs through an epoxygenase reaction (olefin epoxidation), terminal/subterminal HETEs through an ω-/ω-1 hydroxylase reaction (hydroxylation

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at or near the terminal methyl group), and cis,trans-conjugated dienol functionality mid-chain

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HETEs through a lipoxygenase-like reaction (allylic oxidation) (Fig. 3) [23]. In human body, the CYP 2B, 2C, and 2J sub-families are the main CYP epoxygenases, while the CYP 1A, 4A, and 4F

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subfamilies are the primary CYP ω-hydroxylases [96,97]. Synthesis of mid-chain HETEs depends mainly on the LOX system but may be also CYP-mediated; for example, CYP 1B1 is well known

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to be involved in their production [98]. AA epoxidation results in four regioisomers of cis-EETs (5,6-, 8,9-, 11,12-, and 14,15-EETs), each of which can be produced as either the R,S- or the S,Renantiomer. EETs are further metabolized to the less biologically active DHETs by soluble epoxide hydrolase (sEH) enzyme. AA hydroxylation forms a series of HETEs regioisomers.

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Hydroxylase isozymes from the CYP 4A and 4F subfamilies mainly hydroxylate AA on the terminal methyl group producing 20-HETE, but also show some AA (ω-1)-hydroxylase activity yielding 19-HETE as a minor product. Other CYP isoforms (such as CYP 1A1, CYP 1A2, and CYP 2E1) act predominantly as AA (ω-1)-hydroxylases yielding 19-HETE, but also hydroxylate other subterminal positions producing 16-, 17- and 18-HETE. Subterminal HETEs (16-, 17-, 18-

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and 19-HETE) can exist as R- or S-enantiomers due to the presence of an asymmetric carbon atom [23]. To increase their excretion, further metabolism of HETEs can be achieved by COX-2, UDP glucuronosyltransferases (UGT), alcohol dehydrogenase (ADH) or beta-oxidation. AA allylic oxidation produces mid-chain HETEs which include six regioisomeric hydroxy-metabolites containing a cis–trans-conjugated dienol (5-, 8-, 9-, 11-, 12- and 15-HETE) resembling LOXderived AA metabolites [96]. EETs and HETEs regulate several biological processes, such as

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vascular tone, angiogenesis [99]. There is also a strong evidence that the CYP epoxygenase and

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ω-hydroxylase pathways are involved in the regulation of inflammation. The EETs possess potent anti-inflammatory effect by attenuating cytokine-induced NF-κB activation and leukocyte

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adhesion to the vascular wall [100], while HETEs, more specifically 20-HETE, activate NF-κB

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signaling and induces expression of cellular adhesion molecules and cytokines, thereby promoting inflammation [101]. Because of their opposed effects in the regulation of inflammation, any

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disruption of the balance between the CYP epoxygenase and ω-hydroxylase pathways may result in the development of inflammatory diseases [24].

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6. Hepatic inflammation and liver diseases

Inflammation is a key player in the pathophysiology of chronic liver diseases. Prolonged inflammatory response to liver injuries leads to deposition of extracellular matrix (ECM); the non-

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cellular part of the liver that is comprised of fibrous proteins, glycoproteins, and proteoglycans [102]. As a result, liver fibrosis would develop after hepatic damage due to repeatedly failing trials of healing exerted by hepatocytes. As long as the tissue injury persists, the healing process declines while deposition of ECM continues over time. The most abundant ECM component involved is collagen-α1 [103].

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Hepatic inflammatory response is always related to both necrosis and apoptosis during the hepatic cell injury. They lead to a series of events that eventually result in liver fibrosis irrespective to the etiological causes of liver diseases [104]. After hepatocyte injury, the resulting apoptotic bodies are ingested by Kupffer cells, the specialized macrophages lining the wall of liver sinusoids, leading to their activation [105]. Also, kupffer cells are activated by gut-derived endotoxins that are liberated from some types of intestinal bacteria, leak from the gut, reach the bloodstream and

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the liver. Endotoxins activate kupffer cells via Toll-like receptor-4 (TLR-4) receptors leading to

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production of NF-κB [106]. Moreover, the apoptotic bodies activate another line of cells called hepatic stellate cells, pericytes found in the hepatic perisinusoidal compartment, through

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production of reactive oxygen species and fibrogenic factors. Both activated cell types are involved

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to initiate the inflammatory response and subsequent fibrogenesis [107]. Transforming growth factor‐ β (TGF‐ β) is a crucial signalling molecule during the process of fibrogenesis. It is

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produced by Kupffer cells in response to hepatocyte injury and it, in turn, leads to proliferation of hepatic stellate cells, hepatic fibroblasts and resident epithelial cells into myofibroblasts which are

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the main dominant source of collagen during the liver injury. In addition, the activated Kupffer cells also produce reactive oxygen species and proinflammatory cytokines such as interleukin (IL)6 as well as TNF-α. All together lead to stimulation and activation of hepatic stellate cells and fostering of liver fibrosis [108].

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7. Cytochrome P450-derived eicosanoids in liver diseases Chronic liver disease is a well-known factor that alter CYP-mediated drug metabolism in patients [109]. Several studies on altered hepatic CYPs function have been reported in patients with hepatitis B[110] and C [111], cirrhosis [112], cholestasis, and alcoholic liver disease [113,114]. 7.1. Cytochrome P450-derived eicosanoids in hepatic inflammation 17

The biologically active CYP-derived eicosanoids are key regulators in the hepatic inflammatory response; the resident kupffer cells react to a variety of stimuli via production of AA and biologically active lipid mediators. Accumulating studies have shown that the CYP epoxygenase and ω-hydroxylase pathways play a significant role in hepatic inflammation [115]. EETs exerted potent anti-inflammatory effects through mitigation of the activation of cytokine-induced NF-κB [116]. Additionally, it was demonstrated that PPAR-γ could be activated in endothelial cells

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directly by EETs while EET-exerted anti-inflammatory effects showed to be negated by PPAR-γ

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blockers [117]. Furthermore, previous reports have demonstrated that hepatic CYP epoxygenase enzyme expression and EETs release are reduced due to acute LPS-induced activation of the innate

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immune system elements. On the other hand, the terminal HETE (20-HETE) stimulates NF-κB

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signaling leading to an increase in the expression of cellular adhesion molecules and proinflammatory cytokines, consequently reinforcing inflammation [116].

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Eicosanoid derivatives of AA formed by CYP epoxygenases are regarded as critical elements in hepatic inflammation. A previous study has shown suppression of hepatic CYP epoxygenases

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expression with subsequent diminished EETs biosynthesis in acute inflammation triggered by LPS activation of the innate immune response. Therefore, therapeutic restoration of these epoxygenases was suggested as a potential anti-inflammatory strategy. Moreover, a significantly higher 20HETE/EET+DHET formation rate ratio was observed, suggesting that the physiological balance

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in liver is modified in favor of the CYP ω-hydroxylase pathway as a response to systemic activation of the immune system. The alterations in CYP epoxygenases and ω-hydroxylases activities end up in the functional imbalance between the two parallel pathways of antiinflammatory EETs and proinflammatory 20-HETE which may contribute to the pathologic consequences of the inflammatory response in different tissues especially the liver which is the

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predominant source of eicosanoids synthesis with the highest concentration of most CYPs [24]. In a similar model, inhibition of sEH has resulted in a significant decrease in plasma levels of proinflammatory cytokines and nitric oxide metabolites while promoting the formation of lipoxins, thus supporting inflammatory resolution. This effect is mediated by increasing cellular EETs, and renders sEH a pharmacologic target for treating inflammation [118].

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7.2. Cytochrome P450-derived eicosanoids in non-alcoholic fatty liver disease

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NAFLD represents a chronic non-cancerous condition that may evolve to be more detrimental affecting major hepatic functions and eventually leading to hepatocellular carcinoma (HCC) [119].

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The pathology of the disease has become more evident by conducting several studies and examinations but unfortunately no therapeutic guideline has been established for its treatment yet.

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However, in the meantime, there are some medications and other approaches used in clinical

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settings to ameliorate hepatic steatosis such as the administration of anti-diabetics, supplementation of vitamin E and changing way of living [120,121]. The severity of disease can vary considerably from steatosis, a mild inflammation with fatty infiltration of the liver, to more

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pronounced hepatic damage known as NASH [122]. Hepatic inflammation is believed to be a key pathological mediator in the progression of NAFLD to NASH [123]. NAFLD originates from imbalanced uptake and export of lipids by hepatocytes

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resulting in lipid accumulation in the liver. High hepatic lipid content activates toll-like receptors (TLRs) that drive activation of NF-κB-mediated inflammatory responses. Persistent active inflammatory response eventually leads to macrophage infiltration into the liver and ultimately ends up in fibrosis [124].

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In a NAFLD rat model developed by high saturated fat diet (HFD), increased hepatic lipid accumulation and inflammation are accompanied by stimulation of AA-derived leukotrienes production related to 5-LOX. Activation of AA/5-LOX metabolism pathway with subsequent increase generation of its potent pro-inflammatory mediators, leukotrienes, in the progression of NAFLD indicates a strong connection to the disease. This was confirmed by zileuton, a 5-LOX inhibitor, which showed a significantly delayed progression to NASH, thus suggesting inhibition

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of 5-LOX as an effective NAFLD therapeutic intervention [125]. The role of other LOXs and their

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derived lipid mediators in the pathogenesis of NAFLD has been also investigated. For instance, HFD-fed wild-type mice have shown a significant increase in 12-HETE in addition to 15-HETE

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and 5-HETE [126].

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Schuck et al, have demonstrated that significant decrease of EET levels in atherogenic diet model of NAFLD is most likely mediated by downregulation of CYP epoxygenases expression through

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TLR4, NF-κB, TNF-α. Also, mice with disrupted sEH-encoding gene (Ephx2−/−) exhibited increase in both hepatic and circulating EETs levels, as well as significant attenuation of

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inflammatory mediators expression and hepatic injury. In addition, acute hepatic inflammation and injury was exacerbated by restoring hepatic sEH production in Ephx2−/− mice through Ephx2 transgene expression [127]. The role epoxygenases-derived EETs in lipotoxicity-related inflammation and oxidative stress was investigated for the protection against high-fat diet-induced

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NAFLD in transgenic mice with endothelial-specific CYP2J2 overexpression (Tie2-CYP2J2-Tr). NAFLD attenuation in Tie2-CYP2J2-Tr mice was evident, after 24 weeks, compared with controls. Compared to wild-type control mice, Tie2-CYP2J2-Tr mice had significant decrease in plasma triglyceride levels and liver lipid accumulation, in addition to reduced inflammatory responses with less hepatic oxidative stress, and overall improvement in liver function. The

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protective mechanism is based on CYP2J2-derived EETs and has involved anti-inflammatory and antioxidant effects through inhibition of macrophage infiltration and release of proinflammatory cytokines, as well as preventing upregulation of prooxidant NADPH oxidase subunits and the loss of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX). The anti-inflammatory activity was found to be mediated by inhibition of NFκB/JNK signaling pathway activation as confirmed by the treatment of HepG2 cells with 14,15-

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EET. In, vitro, 14,15-EET-treated HepG2 cells showed reduced inflammation and enhanced

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antioxidant defense system [128].

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Recently, the role of omega-3 PUFAs in NAFLD, NASH and other liver injuries has been reported and drawn much attention. Previous study of how mice behave on HFD in the presence of

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endogenously synthesized DHA and EPA plus with cholesterol transporter blocking agent (NIgY), showed a promising improvements in the prevention of HFD-induced liver diseases [119].

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Several mechanisms including cholesterol uptake inhibition, FAs secretion and catabolism are aided by omega-3 and N-IgY combination to ameliorate fat accumulation in hepatic cells.

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Transgenic mice (Fat-1), which are able to convert endogenous omega-6 to omega-3 PUFAs, displayed significant decrease in serum cholesterol and TG. Assessment of fibrosis improved in WT mice treated with N-IgY, while the recovery of scar tissue is mainly attributed to the addition of omega-3 PUFAs that enhanced the protective effect. Further improvement of fibrosis

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assessment is found in Fat-1 mice receiving N-IgY alone. These findings elucidated the prominent role of omega-3 that are endogenously synthesized in Fat-1 mice. A cholesterol-absorption inhibitor Ezetimibe and N-IgY are found to be promoting the catabolic pathway of cholesterol to bile acids via upregulating LDL receptor. In response to HFD, both Fat1 and WT mice expressed more LDL receptor with apparently higher levels in the former type, 21

suggesting that the de novo production of PUFAs in Fat-1 has shown a remarkable improvement in lipid panel. The study concluded that N-IgY and EZM synergistically gave rise to the expression of cholesterol transporter mRNA, including ATP-binding cassette sub-family G members 5 and 8, mediating hepatic fat elimination. The principle pathway of hepatic lipid excretion is carried out by the conversion of free cholesterol to bile acid and this process is regulated by CYP7A1, a rate limiting enzyme involved in bile acid biosynthesis. This enzyme was measured in both types of

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the production of the enzyme when treated with N-IgY and EZM [119].

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mice mentioned earlier on HFD and found that Fat-1 group expressed more cyp7a1, also enhanced

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7.3. Cytochrome P450-derived eicosanoids in hepatocellular carcinoma

Several pieces of evidence support the role of inflammatory lipid mediators as key players in the

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development of hepatic carcinogenesis. Both COX and LOX enzymes have been reported to be

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involved in the pathogenesis of HCC [129–132]. CYP-derived eicosanoids are also implicated in liver cancer. For example, 20-HETE concentration was proved to be elevated in the serum of HCC patients compared to normal subjects [133]. Another study investigated the role of endogenously

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elevated tissue omega-3 PUFAs in chemically-induced HCC Fat-1 mice. The main findings of this study revealed a significant decline in hepatic tumorigenesis, inflammatory and fibrosis markers. This improvement is attributed to the reduction of COX-2, IL-1β, TNF-α, hepatic macrophages,

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hepatic growth factor (HGF) in addition to suppression of myofibroblast and hepatic stellate cells. This study showed that decreasing TNF-α level by omega-3 PUFAs is a possible important pathway to inhibit the hepatic tumorigenesis [134]. Interestingly, these outcomes are in agreement with previous study showing that mice fed with DHA-enriched diet resulted in a remarkable reduction of hepatic COX-2 mRNA expression and inflammatory markers [135].

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Another example of the anti-inflammatory effect mediated by omega-3 PUFAs is the previously reported action of their hydroxy metabolites, 18-HEPE and 17-HDHA, in retarding the inflammatory signaling and impairing tumor formation in Fat-1 mice. Interestingly, their effect might be sustained by enhancing the conversion of 18-HEPE/17-HDHA to specialized proresolving mediators protectins and resolvins, respectively [136]. Furthermore, sEH inhibitors, such as t-TUCB, have been previously used to confirm the anti-inflammatory effect of omega-3 PUFAs

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in Fat-1 mice. The use of t-TUCB enhanced the stabilization of CYP-derived epoxides

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epoxyeicosatetraenoic and epoxydocosapentaenoic acids (17,18-EEQ and 19,20-EDP) and

highlighting their hepatoprotective role in HCC [79].

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8. Concluding remarks

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reinforced the omega-3 PUFA-related reduction of liver inflammation and lipid deposition

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Fatty acids not only serve as a fuel used for generating energy, but also act as essential structural and functional components in biological systems involved in physiological and pathological

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processes. In humans on a Western diet, PUFAs make a significant contribution to the fatty acids present in the membrane phospholipids of cells. AA is a precursor to a several potent proinflammatory mediators including well described PGs and LTs, which eventually has led to the development of anti-inflammatory pharmaceuticals that target their synthetic pathway to

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successfully control inflammation. AA acts also as a substrate for a number of CYP enzymes to produce several bioactive eicosanoids. CYP-derived eicosanoids are strongly involved in the pathophysiological development and progression of several inflammatory disease states such as liver and cardiovascular diseases.

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In inflammatory liver diseases, the anti-inflammatory EETs generated by CYP epoxygenases were found to be suppressed, while the pro-inflammatory HETEs (especially 20-HETE) generated by CYP hydroxylases were augmented (Fig. 4). Future studies are needed to improve our understanding of the mechanisms underlying the contribution of sEH, EETs, and HETEs to the regulation of the hepatic impairment and associated chronic inflammation, and also to evaluate the therapeutic utility of potential strategies that promote the effects of CYP-derived EETs in liver

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diseases.

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Acknowledgments This work was supported by a grant from the Canadian Institutes of Health Research [Grant

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106665] to A.O.S.E. S.M.S. is the recipient of Alberta Innovates Graduate Student Scholarship

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and Antoine Noujaim Graduate Scholarship in Pharmaceutical Sciences.

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Figure legends

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elongases metabolic enzymes, respectively.

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acids. Linoleic acid undergoes chain desaturation and elongation by the action of desaturases and

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Figure 2. Schematic representation of α-linolenic acid and its derived omega-3 polyunsaturated fatty acids. The precursor (ALA) undergoes chain desaturation and elongation by the action of desaturases and elongases metabolic enzymes, respectively.

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of ro -p re lP ur na Jo Figure 3. Metabolic pathways of arachidonic acid. Activation of phospholipase A2 (PLA2) liberates arachidonic acid and subsequent metabolism by three major enzyme families namely cycloogenases (COXs), lipooxygenases (LOXs) and cytochrome P450s (CYPs). The sequential

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oxygenation of AA by 5-LOX and then by 15-LOX yields LTA4 and eventually LXA4 and LXB4. Alternatively, AA can be first utilized by 15-LOX producing 15-HETE, which gives both LXA4 and LXB4 by 5-LOX. Another route of LXA4 and LXB4 biosynthesis involves 5- and 12-LOX. EETs, epoxyeicosatrienoic acids; HETEs, hydroxyeicosatetraenoic acids; PG, prostaglandin,

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TxA2, thromboxane A2; HPETE, hydroperoxyeicosatetraenoic acid; LT, leukotriene; LX, lipoxin.

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Figure 4. Cytochrome P450-mediated arachidonic acid metabolism. Arachidonic acid is being metabolized by various CYP families into mid-chain, terminal, subterminal HETEs and EETs. Mid-chain HETEs (except for 15-HETE) and terminal HETEs are recognized to have a pro-

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inflammatory effect while subterminal HETEs and EETs exert an anti-inflammatory action in

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inflammatory liver diseases.

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