Abstract
This study is aimed at evaluating the effects, functions, and mechanism of HNF1α on hepatic glycolipid metabolism. In this study, free fatty acid- (FFA-) induced steatosis of hepatocyte liver cell LO2 was used as an in vitro model. The methods of Oil Red O staining, RT-qPCR, western blot, and immunofluorescence staining were used to detect LO2-regulated HNF1α expression and its effects on FFA-induced LO2 cell steatosis, the insulin signaling and SOCS-3-STAT3 signaling pathways, the expression of lipid metabolism-related regulators, and phosphorylation. With increased FFA induction time, the expression of HNF1α in the LO2 fatty degeneration hepatic cells gradually decreased. Downregulation of HNF1α expression aggravated FFA-induced steatosis of LO2 hepatocytes. HNF1α promotes activation of the insulin pathway and oxidative breakdown of fat and inhibits lipid anabolism. Inhibitors of STAT3 can reverse the regulation of decreased HNF1α expression on the insulin signaling pathway and fat metabolism. We also confirmed this pathway using HNF1α-/- mice combining treatment with STAT3 inhibitor NSC 74859 in vivo. HNF1α regulates hepatic lipid metabolism by promoting the expression of SOCS-3 and negatively regulating the STAT3 signaling pathway.
Highlights
Nonalcoholic fatty liver disease (NAFLD) refers to a type of chronic liver disease characterized by excessive deposition of fat in hepatocytes that is not due to alcohol or other defined liver factors [1,2,3,4,5,6]
The results of biochemical indicators showed that the total cholesterol (TG), triglyceride (TC), and nonesterified fatty acid (NEFA) levels of LO2 cells showed a significant upward trend with increasing FFA treatment time (Figure 1(b))
In order to evaluate the effect of Hepatocyte nuclear factor 1α (HNF1α) on lipid metabolism, we examined the expression of HNF1α and mRNA and protein expression of SREBP-1c and PPARα by RTqPCR and western blot at 24 h and 48 h
Summary
Nonalcoholic fatty liver disease (NAFLD) refers to a type of chronic liver disease characterized by excessive deposition of fat in hepatocytes that is not due to alcohol or other defined liver factors [1,2,3,4,5,6]. In patients with NAFLD, excessive deposition of fat in liver cells affects the progression of other chronic liver diseases but may lead to serious liver diseases such as cirrhosis and hepatocellular carcinoma. This increased understanding of the harmfulness of NAFLD has led some researchers to question whether it is correctly classified as benign lesions [7, 8]. Previous results showed that NAFLD is closely related to insulin resistance, which increases the risk of type 2 diabetes [9, 10]. A meta-analysis showed that the prevalence of NAFLD is about 25% worldwide and about 27%
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