The Lipid Droplet Protein Hypoxia-inducible Gene 2 Promotes Hepatic Triglyceride Deposition by Inhibiting Lipolysis
Authors
DiStefano, Marina T.Danai, Laura V.
Roth Flach, Rachel J.
Chawla, Anil K.
Pedersen, David J.
Guilherme, Adilson L.
Czech, Michael P.
Student Authors
Laura V. DanaiUMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2015-06-12
Metadata
Show full item recordAbstract
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.Source
J Biol Chem. 2015 Jun 12;290(24):15175-84. doi: 10.1074/jbc.M115.650184. Epub 2015 Apr 28. Link to article on publisher's siteDOI
10.1074/jbc.M115.650184Permanent Link to this Item
http://hdl.handle.net/20.500.14038/33361PubMed ID
25922078Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M115.650184