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

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    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. Danai
    UMass Chan Affiliations
    Program in Molecular Medicine
    Document Type
    Journal Article
    Publication Date
    2015-06-12
    Keywords
    Biochemistry
    Cellular and Molecular Physiology
    Lipids
    
    Metadata
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    Link to Full Text
    http://dx.doi.org/10.1074/jbc.M115.650184
    Abstract
    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 site
    DOI
    10.1074/jbc.M115.650184
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/33361
    PubMed ID
    25922078
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.M115.650184
    Scopus Count
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    Morningside GSBS Scholarly Publications

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