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High fat diet‐induced oxidative stress blocks hepatocyte nuclear factor 4α and leads to hepatic steatosis in mice
Author(s) -
Yu Dongsheng,
Chen Gang,
Pan Minglin,
Zhang Jia,
He Wenping,
Liu Yang,
Nian Xue,
Sheng Liang,
Xu Bin
Publication year - 2018
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.26270
Subject(s) - endocrinology , medicine , hepatocyte nuclear factor 4 , apolipoprotein b , fatty liver , very low density lipoprotein , oxidative stress , steatosis , hepatocyte , hepatocyte nuclear factors , lipoprotein , biology , chemistry , cholesterol , biochemistry , gene expression , nuclear receptor , transcription factor , gene , disease , in vitro
Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease with manifestation of over‐accumulation of fat in liver. Increasing evidences indicate that NAFLD may be in part caused by malfunction of very low density lipoprotein (VLDL) secretion. Hepatocyte nuclear factor 4α (HNF4α), a nuclear receptor protein, plays an important role in sustain hepatic lipid homeostasis via transcriptional regulation of genes involved in secretion of VLDL, such as apolipoprotein B (ApoB). However, the exact functional change of HNF4α in NAFLD remains to be elucidated. In the present study, we found that high fat diet (HFD) induced cytoplasmic retention of HNF4α in hepatocytes, which led to down‐regulation of hepatic ApoB expression and its protein level in serum, as well as reduced secretion of VLDL. We further revealed that oxidative stress, elevated in fatty liver, was the key factor inducing the cytoplasmic retention of HNF4α in hepatocytes by activating protein kinase C (PKC)‐mediated phosphorylation in HNF4α. Thus, our findings reveal a novel mechanism underlying HFD‐induced fatty liver that oxidative stress impairs function of HNF4α on ApoB expression and VLDL secretion via PKC activation, eventually promoting fat accumulation in the liver. Therefore, oxidative stress/PKC/HNF4α pathway may be a novel target to treat diet‐induced fatty liver.