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Activation of PPARγ inhibits hepatic cholestasis with involvement of Nogo‐B expression
Author(s) -
Zhang Shuang
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.539.5
Subject(s) - cholestasis , farnesoid x receptor , rosiglitazone , obeticholic acid , ursodeoxycholic acid , cholesterol 7 alpha hydroxylase , medicine , peroxisome proliferator activated receptor , endocrinology , primary biliary cirrhosis , bile acid , chemistry , biology , nuclear receptor , transcription factor , receptor , biochemistry , gene , agonist
Hepatic cholestasis can develop to fibrosis, cirrhosis and liver failure. Currently, the therapeutic effect of ursodeoxycholic acid (UDCA) on primary biliary cirrhosis (PBC) is limited to early stages of the disease. Recently, obeticholic acid (OCA) has been approved by FDA for the treatment of PBC. However, the safety, efficacy and tolerance of OCA may need further investigation in clinics. Herein, we report the effect of peroxisome proliferator activated receptor γ (PPARγ), a ligand‐activated transcription factor, on hepatic cholestasis. Pre‐treatment of mice with a PPARγ ligand, rosiglitazone, substantially inhibited α‐naphthylisothiocyanate (ANIT)‐induced hepatic cholestasis in a PPARγ expression‐dependent manner. Rosiglitazone substantially reduced ANIT‐induced hepatic necrosis, restored muddy and dark colored bile and serum to normal. It also ameliorated serum biochemical parameters including ALT, AST, ALP, γ‐GT, total bilirubin and lipid profiles. In both mouse liver and HepG2 cells, activation of PPARγ induced expression of bile synthesis and secretion genes (CYP7A1, ABCB4, BSEP, ABCG5 and FXR) and Nogo‐B suggesting PPARγ enhances bile homeostasis and functions which might be involved with Nogo‐B expression. Surprisingly, we observed that deficiency of Nogo‐B expression in HepG2 cells greatly boosted expression of CYP7A1, ABCB4, ABCG5 and FXR while abolished PPARγ‐induced expression of these genes indicating the dual regulatory role of Nogo‐B in bile synthesis/secretion. In vivo , deficiency of Nogo‐B expression also increased expression of hepatic bile synthesis/secretion genes, and protected mice against ANIT‐induced hepatic cholestasis. Taken together, we identified that Nogo‐B is a target of PPARγ which might be involved in PPARγ‐inhibited cholestasis by its dual regulatory functions. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .