FXR deficiency alters bile acid pool composition and exacerbates chronic alcohol induced liver injury

Abstract

Recent studies have investigated the roles of FXR deficiency in the pathogenesis of alcoholic liver disease (ALD). However, the underlined molecular mechanisms remain unclear. In this study, FXR knockout (FXR −/−) and wild-type (WT) mice were subjected to chronic-plus-binge alcohol feeding to study the effect of FXR deficiency on ALD development. The degree of liver injury was greater in FXR −/− mice compared to WT mice. Ethanol feeding enhanced hepatic steatosis in FXR −/− mice, accompanied by decreased mRNA levels of Pparα and Srebp-1c. The expression of Lcn2 was increased by ethanol treatment, despite unchanged expression of pro-inflammatory cytokines Tnfα, II6 and II-1 β. Furthermore, ethanol treatment altered bile acid (BA) homeostasis to a greater extent in FXR −/− mice, as well as serum and hepatic BA pool composition. The mRNA levels of hepatic Cyp7a1 and Shp, as well as intestinal Fgf15, were decreased in WT mice with ethanol feeding, which were further reduced in FXR −/− mice. Levels of both primary and

Bile Acid pool composition and Gallbladder function are controlled by TGR5 to protect the liver against Bile Acid overload

“…BA signaling and BA pool composition are increasingly considered as crucial for intestine and liver pathophysiology [14,15,16,24,25], and therapeutic strategies targeting BA and their receptors begin to emerge [26]. This is particularly true in the field of metabolic diseases such as obesity and diabetes [17], as well as for cholestatic liver diseases [27].…”

“…Importantly, the BA pool composition, in particular its hydrophobicity and the balance between primary and secondary BA, is more and more recognized as crucial for liver pathophysiology [14,15,16].…”

A perspective of intestinal immune-microbiome interactions in alcohol-associated Liver Disease

“…In mice fed Lieber DeCarli ethanol diet, farnesoid X receptor (FXR), a regulator of bile acids, lipids, and glucose metabolism, is downregulated, leading to a higher amount of bile acids being produced and secreted by the liver [209]. Mice with whole-body depletion of FXR treated with a chronic plus binge ethanol feeding model were susceptible to hepatic steatosis and ethanol-induced liver disease [209][210][211]. Experimental treatment of isoalloLCA and 3-oxoLCA to naïve CD4+ T cells isolated from FXR deficient mice, did not change FOXP3 expression when compared to the controls [208].…”

Hepatoprotective impact of the bile acid receptor TGR5

“…Importantly, hepatocyte cell cycle progression is also boosted through FXR‐dependent mechanisms, 15 allowing the functional hepatocyte mass to replenish and thereby progressively restoring a full BA handling capacity. Also, in the ileum enterocyte, BA‐induced FXR‐dependent FGF15 induction has been identified as an important regulator of liver homeostasis, 44 regeneration after PH 45,46 and alcohol‐related liver injury 47 . Direct positive impact on hepatocyte (and cholangiocyte) cell cycle progression, 45,48 and indirect regulation through BA synthesis suppression 45 by FGF15 have been reported, although more complex effects of FGF15 appear to be involved in relation to NASH and fibrosis 49 .…”

“…These BA pool features are now viewed as protective against cholestatic liver injury not only in mice, 106 but also in children with progressive intrahepatic cholestasis 108 . Recent data also pointed out that BA pool composition had impact on alcoholic and non‐alcoholic liver diseases 47,55 . `Recently, the BA metabolizing enzyme CYP2c70, which converts CDCA, the hydrophobic primary BA, in the more hydrophilic MCA has been identified as a master regulator of the BA pool composition in mice 109 .…”