Hypoxia-inducible lipid droplet-associated induces DGAT1 and promotes lipid storage in hepatocytes.

Abstract The storage of lipids in cells is determined by the balance between triglyceride synthesis and degradation. The rate-limiting step in triglyceride synthesis is catalyzed by diacylglycerol acyltransferases (DGAT). Here we find that the lipid droplet-associated protein HILPDA physically interacts with DGAT1 and increases DGAT activity. Deficiency of HILPDA in liver cells significantly reduced lipid storage in vitro and in vivo. 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 further revealed that HILPDA preferentially localizes to LD that are being remodelled. Overexpression of HILPDA in liver cells increased DGAT activity and DGAT1 protein levels, concurrent with increased lipid storage. Confocal microscopy coupled to Forster resonance energy transfer-fluorescence lifetime imaging microscopy analysis demonstrated that HILPDA physically interacts with DGAT1 in living liver cells. The stimulatory effect of HILPDA on lipid storage via DGAT1 was corroborated in adipocytes. Our findings suggest a novel regulatory mechanism by which fatty acids promote triglyceride synthesis and storage.