Download This Paper
Hypoxia-Inducible Lipid Droplet-Associated Interacts with DGAT1 to Promote Lipid Storage in Hepatocytes
48 Pages Posted: 15 Apr 2020 Publication Status: Review Complete
More...Abstract
Lipid droplets (LD) are dynamic organelles that can expand and shrink, driven by fluctuations in the rate of triglyceride synthesis and degradation. Triglyceride synthesis, storage in LD, and degradation are governed by a complex set of LD-associated proteins. One of these LD-associated proteins, hypoxia-inducible lipid droplet-associated (HILPDA), was found to impair LD breakdown by inhibiting adipose triglyceride lipase. Here we characterized the physiological role and mechanism of action of HILPDA in hepatocytes. Expression of HILPDA was induced by fatty acids in several hepatoma cell lines. Fluorescence microscopy showed that HILPDA partly colocalizes with LD and with the endoplasmic reticulum, is especially abundant in perinuclear areas, and mainly associates with newly added fatty acids. Real-time fluorescence live-cell imaging revealed that HILPDA preferentially localizes to LD that are being remodelled. Deficiency of HILPDA in mouse precision-cut liver slices and primary hepatocytes reduced lipid storage and accumulation of fluorescently-labelled fatty acids in LD, respectively, which was independent of adipose triglyceride lipase. Confocal microscopy and Förster resonance energy transfer-fluorescence lifetime imaging microscopy analysis indicated that HILPDA colocalizes and physically interacts with DGAT1. In human hepatoma HepG2 cells, HILPDA overexpression increased lipid storage concomitant with an increase in DGAT activity and DGAT1 protein levels. Finally, hepatocyte-specific deficiency of HILPDA in mice modestly but significantly reduced hepatic triglyceride and plasma alanine aminotransferase levels in mice with non-alcoholic fatty liver disease. Overall, our data indicate that HILPDA physically interacts with DGAT1 and increases DGAT activity and DGAT1 protein levels. These findings suggest a novel mechanism in hepatocytes that links elevated fatty acid levels to stimulation of triglyceride synthesis and storage.
Keywords: HILPDA, ATGL, DGAT1, LIPID DROPLET-ASSOCIATED PROTEIN, lipolysis, LIPOLYSOME, nonalcoholic steatohepatitis (NASH)
Suggested Citation: Suggested Citation