Abstract
Cholesterol 7α-hydroxylase (CYP7A1) plays a critical role in control of bile acid and cholesterol homeostasis. Bile acids activate farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) to regulate lipid, glucose, and energy metabolism. However, the role of bile acids in hepatic inflammation and fibrosis remains unclear. In this study, we showed that adenovirus-mediated overexpression of Cyp7a1 ameliorated lipopolysaccharide (LPS)-induced inflammatory cell infiltration and pro-inflammatory cytokine production in WT and TGR5-deficient (Tgr5-/-) mice, but not in FXR-deficient (Fxr-/-) mice, suggesting that bile acid signaling through FXR protects against hepatic inflammation. Nuclear factor κ light-chain enhancer of activated B cells (NF-κB)-luciferase reporter assay showed that FXR agonists significantly inhibited TNF-α-induced NF-κB activity. Furthermore, chromatin immunoprecipitation and mammalian two-hybrid assays showed that ligand-activated FXR interacted with NF-κB and blocked recruitment of steroid receptor coactivator-1 to cytokine promoter and resulted in inhibition of NF-κB activity. Methionine/choline-deficient (MCD) diet increased hepatic inflammation, free cholesterol, oxidative stress, apoptosis, and fibrosis in CYP7A1-deficient (Cyp7a1-/-) mice compared with WT mice. Remarkably, adenovirus-mediated overexpression of Cyp7a1 effectively reduced hepatic free cholesterol and oxidative stress and reversed hepatic inflammation and fibrosis in MCD diet-fed Cyp7a1-/- mice. Current studies suggest that increased Cyp7a1 expression and bile acid synthesis ameliorate hepatic inflammation through activation of FXR, whereas reduced bile acid synthesis aggravates MCD diet-induced hepatic inflammation and fibrosis. Maintaining bile acid and cholesterol homeostasis is important for protecting against liver injury and nonalcoholic fatty liver disease.
Highlights
Cholesterol 7 -hydroxylase (CYP7A1) plays a critical role in control of bile acid and cholesterol homeostasis
Our study suggests that cholesterol 7 -hydroxylase (CYP7A1) plays a critical role in control of hepatic inflammation and fibrosis by maintaining bile acid and cholesterol homeostasis
The mRNA levels of a farnesoid X receptor (FXR) target gene in the liver, small heterodimer partner (SHP), and intestine FXR target genes, SHP and fibroblast growth factor 15 (FGF15), were increased in Ad-Cyp7a1 mice compared with Ad-null mice (Fig. 1A)
Summary
Cholesterol 7 -hydroxylase (CYP7A1) plays a critical role in control of bile acid and cholesterol homeostasis. Bile acids activate farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) to regulate lipid, glucose, and energy metabolism. We showed that adenovirus-mediated overexpression of Cyp7a1 ameliorated lipopolysaccharide (LPS)-induced inflammatory cell infiltration and pro-inflammatory cytokine production in WT and TGR5-deficient (Tgr5 / ) mice, but not in FXR-deficient (Fxr / ) mice, suggesting that bile acid signaling through FXR protects against hepatic inflammation. Current studies suggest that increased Cyp7a1 expression and bile acid synthesis ameliorate hepatic inflammation through activation of FXR, whereas reduced bile acid synthesis aggravates MCD diet-induced hepatic inflammation and fibrosis. Bile acids are recognized as signaling molecules that activate nuclear farnesoid X receptor (FXR) and membrane Takeda G proteincoupled receptor 5 [TGR5; known as G protein-coupled bile acid receptor-1 (Gpbar1)] and cellular signaling pathways to regulate lipid, glucose, drug, and energy metabolism [2]. Alteration of bile acid homeostasis may contribute to inflammatory cholestatic liver diseases, diabetes, and obesity [1, 3]
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