| Nonalcoholic fatty liver disease (Nonalcoholic fatty liver disease, NAFLD) is one of the most common metabolic diseases. The incidence rate is about 10-24%, so prevention and treatment of fatty liver attract great attention.Hepatocyte nuclear factor 4a (Hepatocyte nuclear factor 4-alpha, HNF4a) is a transcription factor that plays an important role in the regulation of hepatic lipid and gluconeogenesis in all aspects. HNF4a increases fatty acid oxidation, promotes the secretion of bile acids, increases VLDL triglyceride as well as facilitates the transport of plasma, but in the NAFLD, HNF4a often appears low expression and promotes nonalcoholic fatty liver lipid aggregation. Many reports confirm that deletion HNF4a functional caused liver steatosis, for example, in NAFLD patients, about half of the patients showed HNF4a mutation or deletion. However, the mechanism of HNF4a adjustment in high energy intake induced NAFLD need further study.In this study, we use high-fat diet fed mice to establish models of fatty liver. We found that high-fat diet-induced the retention of HNF4a in cytoplasm and inhibited the expression levels of liver apolipoprotein B (ApolipoproteinB, ApoB). So it can explain the reason of high-fat diet hinder VLDL secretion. We isolate mice primary hepatocytes in vitro simulation of NAFLD in the environment, from a series of stimulus screening found that LPS (Lipopolysaccharide, LPS), palmitic acid (Palmitate, PA) and tumor necrosis factor-a (Tumor necrosis factor-a, TNF-a) is capable of inducing HNF4a cytoplasmic retention, thus proving the high fat, inflammation of the function of the HNF4a. Further study found that high-fat, liver inflammation activated protein kinase C (Protein kinase C, PKC). PKC by phosphorylated HNF4a, then induced its cytoplasmic retention. Thus, HNF4a regulated ApoB transcription regulation was suppressed. We reveal inflammation, high fat/PKC/HNF4α lipid metabolism pathways, thus providing new ideas for the treatment of NAFLD. |
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