n-3 Polyunsaturated fatty acids for the management of alcoholic liver disease: A critical review

Excess alcohol exposure leads to alcoholic liver disease (ALD), a predominant cause of liver-related morbidity and mortality worldwide. In the past decade, increasing attention has been paid to understand the association between n-3 polyunsaturated fatty acids (n-3 PUFAs) and ALD. In this review, we summarize the metabolism of n-3 PUFAs, animal model of ALD, and the findings from recent studies determining the role of n-3 PUFAs in ALD as a possible treatment. The animal models of acute ethanol exposure, chronic ethanol exposure and chronic-plus-single binge ethanol feeding have been widely used to explore the impact of n-3 PUFAs. Although the results of studies regarding the role of n-3 PUFAs in ALD have been inconsistent or controversial, increasing evidence has demonstrated that n-3 PUFAs may be useful in alleviating alcoholic steatosis and alcohol-induced liver injury through multiple mechanisms, including decreased de novo lipogenesis and lipid mobilization from adipose tissue, enhanced mitochondrial fatty acid β-oxidation, reduced hepatic inflammation and oxidative stress, and promoted intestinal homeostasis, positively suggesting that n-3 PUFAs might be promising for the management of ALD. The oxidation of n-3 PUFAs ex vivo in an experimental diet was rarely considered in most n-3 PUFA-related studies, likely contributing to the inconsistent results. Thus, the role of n-3 PUFAs in ALD deserves greater research efforts and remains to be evaluated in randomized, placebo-controlled clinic trial. ABBREVIATION AA arachidonic acid ACC acetyl-CoA carboxylase ACLY ATP-citrate lyase ACO acyl-CoA oxidase ALA α-linolenic acid ALD alcoholic liver disease ALP alkaline phosphatase ALT alanine aminotransferase AMPK AMP-activated protein kinase AST aspartate aminotransferase ATGL adipose triglyceride lipase cAMP cyclic adenosine 3',5'-monophosphate COX cyclooxygenases CPT1 carnitine palmitoyltransferase 1 CYP2E1 cytochrome P450 2E1 DGAT2 diacylglycerol acyltransferase 2 DGLA dihomo-γ-linolenic acid DHA docosahexaenoic acid DPA docosapentaenoic acid DTA docosatetraenoic acid EPA eicosapentaenoic acid ER endoplasmic reticulum ETA eicosatetraenoic acid FAS fatty acid synthase FATPs fatty acid transporter proteins GLA,γ linolenic acid GPR120 G protein-coupled receptor 120 GSH glutathione; H&E haematoxylin-eosin; HO-1 heme oxygenase-1; HSL hormone-sensitive lipase; IL-6 interleukin-6 iNOS nitric oxide synthase LA linoleic acid LBP lipopolysaccharide binding protein LOX lipoxygenases LXR liver X receptor LXREs LXR response elements MCP-1 monocyte chemotactic protein-1 MTP microsomal triglyceride transfer protein MUFA monounsaturated fatty acids MyD88 myeloid differentiation factor 88 n-3 PUFAs omega-3 polyunsaturated fatty acid NAFLD nonalcoholic fatty liver disease NASH nonalcoholic steatohepatitis NF-κB transcription factor nuclear factor κB PDE3B phosphodiesterase 3B PPAR peroxisome proliferator-activated receptor ROS reactive oxygen species RXR retinoid X receptor SCD-1 stearyl CoA desaturase-1 SDA stearidonic acid SFA saturated fatty acids SIRT1 sirtuin 1 SOD superoxide dismutase SREBP sterol regulatory element-binding protein TB total bilirubin TC total cholesterol TG triacylglycerol TLR4 Toll-like receptor-4 TNF-α tumor necrosis factor-α VLDLR very low-density lipoprotein receptor WT wild type; ZO-1 zonula occludens-1.