| First Author | Liu H | Year | 2016 |
| Journal | J Lipid Res | Volume | 57 |
| Issue | 10 | Pages | 1831-1844 |
| PubMed ID | 27534992 | Mgi Jnum | J:236079 |
| Mgi Id | MGI:5804700 | Doi | 10.1194/jlr.M069807 |
| Citation | Liu H, et al. (2016) Cholesterol 7alpha-hydroxylase protects the liver from inflammation and fibrosis by maintaining cholesterol homeostasis. J Lipid Res 57(10):1831-1844 |
| abstractText | Cholesterol 7alpha-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 kappa light-chain enhancer of activated B cells (NF-kappaB)-luciferase reporter assay showed that FXR agonists significantly inhibited TNF-alpha-induced NF-kappaB activity. Furthermore, chromatin immunoprecipitation and mammalian two-hybrid assays showed that ligand-activated FXR interacted with NF-kappaB and blocked recruitment of steroid receptor coactivator-1 to cytokine promoter and resulted in inhibition of NF-kappaB 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. |
