Role of farnesoid X receptor and bile acids in alcoholic liver disease

Abstract

Alcoholic liver disease (ALD) is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover, ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor (FXR) and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, FoxO3a (forkhead box-containing protein class O3a) and PPARα (peroxisome proliferator-activated receptor alpha) in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure.

Keywords: 6ECDCA, 6α-ethyl-chenodeoxycholic acid; ADH, alcohol dehydrogenase; AF, activation function; AKT, protein kinase B; ALD, alcoholic liver disease; ALT, alanine aminotransferase; ASBT, apical sodium dependent bile acid transporter; Alcoholic liver disease; Atg, autophagy-related; Autophagy; BAAT, bile acid CoA:amino acid N-acyltransferase; BACS, bile acid CoA synthetase; BSEP, bile salt export pump; Bile acids; CA, cholic acid; CB1R, cannabinoid receptor type 1; CDCA, chenodeoxycholic acid; CREB, cAMP response element-binding protein; CREBH, cAMP response element-binding protein, hepatocyte specific; CRTC2, CREB regulated transcription coactivator 2; CYP, cytochrome P450; DCA, deoxycholic acid; DR1, direct repeat 1; FGF15/19, fibroblast growth factor 15/19; FGFR4, fibroblast growth factor receptor 4; FXR, farnesoid X receptor; Farnesoid X receptor; FoxO3; FoxO3a, forkhead box-containing protein class O3a; GGT, gamma-glutamyltranspeptidase; HCC, hepatocellular carcinoma; IR-1, inverted repeat-1; KO, knockout; LC3, light chain 3; LRH-1, liver receptor homolog 1; LXR, liver X receptor; MRP4, multidrug resistance protein 4; NAD+, nicotinamide adenine dinucleotide; NTCP, sodium taurocholate cotransporting polypeptide; OSTα/β, organic solute transporter α/β; PE, phosphatidylethanolamine; PPARα, peroxisome proliferator-activated receptor alpha; ROS, reactive oxygen species; RXRα, retinoid X receptor-alpha; SHP, small heterodimer partner; SQSTM, sequestome-1; SREBP1, sterol regulatory element-binding protein 1; Sirt1, sirtuin 1; TCA, taurocholic acid; TFEB, transcription factor EB; TLR4, toll-like receptor 4; TUDCA, tauro-ursodeoxycholic acid; UDCA, ursodeoxycholic acid; WAY, WAY-362450; WT, wild type.

Graphical abstract

Figure 1

Schematic diagram of the cellular and molecular events of alcohol exposure on FXR, enterohepatic circulation, gut microbiome and autophagy. Alcohol treatment inhibits FXR in the liver, which results in increased bile acid synthesis. Moreover, alcohol exposure decreases taurine conjugation of bile acids and increases efflux of bile acids out of the hepatocytes into the portal vein and bile duct. Acute alcohol exposure also induces autophagy by inhibiting AKT, which results in FoxO3a activation and FoxO3a-mediated up-regulation of Atg genes. Alcohol increases the uptake of bile acids into the enterocytes and promotes efflux of bile acids into the portal circulation from the intestines. Alcohol exposure also inhibits intestinal FXR activation, which leads to decreased FGF15/19 expression and promotes bacteria overgrowth and dysbiosis. Increased abundance of intestinal bacteria promotes taurine metabolism and bile acid deconjugation. Finally, increased levels of unconjugated bile acids including DCA exacerbate alcohol-induced dysbiosis. FXR may negatively regulate autophagy and cholestasis, and autophagy protects against ALD.