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Atorvastatin Induces Hepatic NgBR Expression by Regulating Geranylgeranylation of Rho Protein
Author(s) -
Zhang Wenwen,
Chen Yuanli,
Duan Yajun,
Han Jihong
Publication year - 2015
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.29.1_supplement.885.4
Subject(s) - geranylgeranylation , atorvastatin , protein expression , microbiology and biotechnology , chemistry , medicine , prenylation , biology , biochemistry , gene , enzyme
NgBR, a receptor for Nogo‐B, plays an important role in cellular cholesterol trafficking and angiogenesis in zebrafish. However, little is known the pathophysiological role of NgBR in mammalians and humans. Our recent study shows deficiency of NgBR expression results in hepatic lipid accumulation with increased free fatty acid (FFA) and triglycerides (TG) in the liver and hypertriglyceridemia. Statins are anti‐hypercholesterolemia medicine, and have non cholesterol‐lowering pleiotropic effects including reduction of lipid accumulation. Herein, we report that atorvastatin increased NgBR expression in human hepatic cell line, HepG2 cells. Associated with increased NgBR levels, phosphorylated ERK1/2 (pi‐ERK/2) and cellular TG content were decreased. In contrast, these effects were attenuated in the cells lacking NgBR expression indicating the important role of NgBR in statin‐mediated cellular lipid content. In vivo, high‐fat diet (HFD) reduced liver NgBR expression in apoe ‐/‐ mice while atorvastatin restored NgBR expression and decreased HFD‐induced liver TG levels by 36%. Both cholesterol and mevalonate blocked atorvastatin‐induced NgBR expression suggests the association of NgBR expression with cholesterol biosynthesis. Geranylgeranylpyrophosphate (GGPP) also reduced atorvastatin‐induced NgBR expression. Associated with changes of liver NgBR expression, pi‐ERK1/2 was similarly regulated. In summary, our study demonstrates the regulation of NgBR expression by atorvastatin is related to ERK1/2 activity and Rho protein geranylgeranylation, and the reduction of lipid accumulation by atorvastatin is partially through regulation of NgBR expression.