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.ABBREVIATIONAAarachidonic acidACCacetyl-CoA carboxylaseACLYATP-citrate lyaseACOacyl-CoA oxidaseALAα-linolenic acidALDalcoholic liver diseaseALPalkaline phosphataseALTalanine aminotransferaseAMPKAMP-activated protein kinaseASTaspartate aminotransferaseATGLadipose triglyceride lipasecAMPcyclic adenosine 3’,5’-monophosphateCOXcyclooxygenasesCPT1carnitine palmitoyltransferase 1CYP2E1cytochrome P450 2E1DGAT2diacylglycerol acyltransferase 2DGLAdihomo-γ-linolenic acidDHAdocosahexaenoic acidDPAdocosapentaenoic acidDTAdocosatetraenoic acidEPAeicosapentaenoic acidERendoplasmic reticulumETAeicosatetraenoic acidFASfatty acid synthaseFATPsfatty acid transporter proteinsGLA,γlinolenic acidGPR120G protein-coupled receptor 120GSHglutathione; H&Ehaematoxylin-eosin; HO-1heme oxygenase-1; HSLhormone-sensitive lipase; IL-6interleukin-6iNOSnitric oxide synthaseLAlinoleic acidLBPlipopolysaccharide binding proteinLOXlipoxygenasesLXRliver X receptorLXREsLXR response elementsMCP-1monocyte chemotactic protein-1MTPmicrosomal triglyceride transfer proteinMUFAmonounsaturated fatty acidsMyD88myeloid differentiation factor 88n-3 PUFAsomega-3 polyunsaturated fatty acidNAFLDnonalcoholic fatty liver diseaseNASHnonalcoholic steatohepatitisNF-κBtranscription factor nuclear factor κBPDE3Bphosphodiesterase 3BPPARperoxisome proliferator-activated receptorROSreactive oxygen speciesRXRretinoid X receptorSCD-1stearyl CoA desaturase-1SDAstearidonic acidSFAsaturated fatty acidsSIRT1sirtuin 1SODsuperoxide dismutaseSREBPsterol regulatory element-binding proteinTBtotal bilirubinTCtotal cholesterolTGtriacylglycerolTLR4Toll-like receptor-4TNF-αtumor necrosis factor-αVLDLRvery low-density lipoprotein receptorWTwild type; ZO-1zonula occludens-1