The Lipid Droplet Protein Hypoxia-inducible Gene 2 Promotes Hepatic Triglyceride Deposition by Inhibiting Lipolysis

• Published in: The Journal of biological chemistry 2015-06, Vol.290 (24), p.15175-15184
• Main Authors: DiStefano, Marina T., Danai, Laura V., Roth Flach, Rachel J., Chawla, Anil, Pedersen, David J., Guilherme, Adilson, Czech, Michael P.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Cells, Cultured; fatty acid oxidation; hepatocyte; hypoxia-inducible gene 2 (Hig2); lipid droplet; lipolysis; Lipolysis - physiology; liver; Liver - metabolism; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Neoplasm Proteins - chemistry; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; non-alcoholic fatty liver disease (NAFLD); Triglycerides - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.650184

The liver is a major site of glucose, fatty acid, and triglyceride (TG) synthesis and serves as a major regulator of whole body nutrient homeostasis. Chronic exposure of humans or rodents to high-calorie diets promotes non-alcoholic fatty liver disease, characterized by neutral lipid accumulation in lipid droplets (LD) of hepatocytes. Here we show that the LD protein hypoxia-inducible gene 2 (Hig2/Hilpda) functions to enhance lipid accumulation in hepatocytes by attenuating TG hydrolysis. Hig2 expression increased in livers of mice on a high-fat diet and during fasting, two states associated with enhanced hepatic TG content. Hig2 expressed in primary mouse hepatocytes localized to LDs and promoted LD TG deposition in the presence of oleate. Conversely, tamoxifen-inducible Hig2 deletion reduced both TG content and LD size in primary hepatocytes from mice harboring floxed alleles of Hig2 and a cre/ERT2 transgene controlled by the ubiquitin C promoter. Hepatic TG was also decreased by liver-specific deletion of Hig2 in mice with floxed Hig2 expressing cre controlled by the albumin promoter. Importantly, we demonstrate that Hig2-deficient hepatocytes exhibit increased TG lipolysis, TG turnover, and fatty acid oxidation as compared with controls. Interestingly, mice with liver-specific Hig2 deletion also display improved glucose tolerance. Taken together, these data indicate that Hig2 plays a major role in promoting lipid sequestration within LDs in mouse hepatocytes through a mechanism that impairs TG degradation. Background: Excess hepatic triglyceride accumulation is associated with metabolic disease. Results: Hig2 localizes to hepatic lipid droplets, enhancing their lipid content, and its deficiency increases triglyceride lipolysis. Conclusion: Hig2 is a lipid droplet protein in hepatocytes that promotes liver triglyceride deposition by reducing its rate of degradation. Significance: Hig2 is revealed as a critical lipid droplet protein controlling liver fat.