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Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by ectopic lipid accumulation in the liver, usually combined with hepatic insulin resistance. Fc-gamma receptor-IIb (FcγRIIb) and its ligand are reported to be associated with obesity and type 2 diabetes mellitus (T2DM). As knowledge about FcγRIIb in the literature is mostly generated from studies on skeletal muscle tissue, the expression and function of FcγRIIb in the liver and hepatocytes are largely unknown. In this study, we identified the expression of FcγRIIb in primary cultured mouse hepatocytes: FcγRIIb was upregulated in response to oleic acid (OA) in a dose dependent manner. FcγRIIb knockdown using shRNA suppressed the lipid and triglyceride accumulation, and mRNA expression of ACC1, FASn, CD36, MTTP, and ApoB in OA-treated HepG2 cells. FcγRIIb deficiency mice fed with high fat diet (HFD) had significantly lower liver weight and liver to body weight ratio, as well as less triglyceride accumulation in the livers. In glycometabolism, FcγRIIb hindered insulin-induced phosphorylation of AKT and FOXO1, and in turn upregulated G6Pase and PEPCK mRNA expression, suggesting that FcγRIIb promotes gluconeogenesis by suppressing the AKT/FOXO1/G6Pase/PEPCK pathway in hepatocytes. This study reveals a novel role for FcγRIIb in regulating lipid metabolism and glycometabolism, and provides a new therapeutic target to improve NAFLD.
Highlights
IntroductionPatients with Non-alcoholic fatty liver disease (NAFLD) have ectopic lipid accumulation in liver, and are in a high risk of developing into non-alcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma (HCC), and hepatic insulin resistance [1]
Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease
Quantitative RT-PCR analysis showed that FcγRIIb mRNA was expressed in hepatocytes compared with the FcγRIIb positive cell, RAW264.7, and that the mRNA level of FcγRIIb was markedly higher in primary cultured hepatocytes from wildtype(FcγRIIb+/+) mice than that in hepatocyte from FcγRIIb knockout(FcγRIIb−/−) mice (Figure 1A,B)
Summary
Patients with NAFLD have ectopic lipid accumulation in liver, and are in a high risk of developing into non-alcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma (HCC), and hepatic insulin resistance [1]. Under insulin resistance, accumulation of free fatty acid (FFA) in the liver, and high concentration of glucose in blood will occur [6]. Liver de novo lipogenesis and fatty acid esterification are the two main sources that promote lipid synthesis in hepatocyte [2,3,7]. Lipolysis controls lipid accumulation in hepatocytes through fatty acid β-oxidation in mitochondria [8]. Suppression of PPARα makes fatty acid fail to import into the mitochondria, which results in low lipolysis and lipid accumulation in the hepatocyte [8]
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