Basal PPARα inhibits bile acid metabolism adaptation in chronic cholestatic model induced by α-naphthylisothiocyanate. (January 2019)

• Record Type: Journal Article
• Authors: Hua, Huiying; Dai, Manyun; Luo, Yishuang; Lin, Hante; Xu, Gangming; Hu, Xiaowei; Xu, Liping; Zhang, Haoyue; Tang, Zhiyuan; Chang, Liming; Liu, Aiming; Yang, Julin
• Is Part Of: Toxicology letters. Volume 300(2019)
• Page Start: 31
• Page End: 39
• Publication Date: 2019-01
• Subjects: ANIT alpha-naphthylisothiocyanate -- ALP alkaline phosphatase -- ALT alanine aminotransferase -- AST aspartate aminotransferase -- Bsep bile salt export pump -- Cyp7a1 cholesterol 7α-hydroxylase -- Cyp8b1 sterol 12α-hydroxylase -- c-Jun transcription factor AP-1-like -- Fga fibrinogen alpha chain -- Socs3 suppressor of cytokine signaling 3 -- DDC 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine -- LCA lithocholic acid -- Fgb fibrinogen alpha chain -- Fgg fibrinogen alpha chain -- Mdr2 multidrug resistance protein 2 -- Mdr3 multidrug resistance-related protein 3 -- Mrp4 multidrug resistance-related protein 4 -- Mrp2 multidrug resistance-related protein 2 -- Oatp1 organic anion transporting polypeptide 1 -- Ostb organic solute-transporter-β -- TBA total bile acid -- FXR Farnesoid X receptor -- SHP small heterodimer partner -- STAT3 signal transducer and activator of transcription 3 -- GAPDH glyceraldehyde-3-phosphate dehydrogenase; PPARα -- FXR pathway -- Alpha-naphthylisothiocyanate -- Chronic cholestasis; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2018.10.015
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: In chronic cholestsis, bile acid metabolism adaptation is inhibited in wild-type mice but not in Ppara -null mice. FXR pathway is activated in Ppara -null mice, not in wild-type mice. Cross-talk between basal PPARα and FXR inhibit bile acid metabolism adaptation in chronic cholestasis. Abstract: Cholestasis is one of the most challenging diseases to be treated in current hepatology. However little is known about the adaptation difference and the underlying mechanism between acute and chronic cholestasis. In this study, wild-type and Pparα -null mice were orally administered diet containing 0.05% ANIT to induce chronic cholestasis. Biochemistry, histopathology and serum metabolome analysis exhibited the similar toxic phenotype between wild-type and Pparα -null mice. Bile acid metabolism was strongly adapted in Pparα -null mice but not in wild-type mice. The Shp and Fxr mRNA was found to be doubled in cholestatic Pparα -null mice compared with the control group. Western blot confirmed the up-regulated expression of FXR in Pparα -null mice treated with ANIT. Inflammation was found to be stronger in Pparα -null mice than those in wild-type mice in chronic cholestasis. These data chain indicated that bile acid metabolism and inflammation signaling were different between wild-type and Pparα -null mice developing chronic cholestasis, although their toxic phenotypes could not be discriminated. So basal PPARα cross-talked with FXR and inhibited bile acid metabolism adaptation in chronic cholestasis.