Differential Roles of CIDE Proteins in Promoting Lipid Droplet Fusion and Growth in Subpopulations of Hepatocytes

Abstract

Liver plays a major regulatory role in whole-body lipid metabolism. Disruption of the hepatic lipid metabolism could lead to the initiation and progression of several metabolic disorders. The accumulation of fat in the form of lipid droplets (LDs) is an early pathophysiological feature of altered liver metabolism that is linked to insulin resistance and the potential progression of severe liver diseases, such as liver steatosis, liver cirrhosis and hepatocellular carcinoma. CIDE proteins including Cidea, Cideb and Cidec (also called Fsp27) play important roles in lipid metabolism. Cidea and Cidec are predominantly expressed in adipocytes, while Cideb is specifically expressed in the liver of wild-type mice. Cidea and Cidec are upregulated in the steatotic liver. Overexpression of Cidea/Cidec in mouse liver resulted in increased hepatic lipid accumulation and the formation of large LDs. Cidea expression in hepatocytes was specifically induced by saturated fatty acids, and such induction was reduced when SREBP1c was knocked down. Next, we find that CIDE proteins are all localized to LD-LD contact sites (LDCSs) and promote lipid transfer, LD fusion and growth in hepatocytes. We have identified two types of hepatocytes, one with small LDs (small LD-containing hepatocytes, SLHs) and one with large LDs (large LD-containing hepatocytes, LLHs) in the liver. Cideb is localized to LDCSs and promotes lipid exchange and LD fusion in both SLHs and LLHs, whereas Cidea and Cidec are specifically localized to the LDCSs and promote lipid exchange and LD fusion in LLHs. Fasting or High-fat-diet dramatically induces the expression of Cidea/Cidec and increases the percentage of LLHs in the liver. Knocking down Cidea or Cidec significantly reduced lipid storage in the livers of obese animals. Our data reveal that CIDE proteins play differential roles in promoting LD fusion and lipid storage; Cideb promotes lipid storage under normal diet conditions, while Cidea and Cidec are responsible for liver steatosis under fasting and obese conditions. Support or Funding Information This work was supported by grants from the National Basic Research Program, the National Natural Science Foundation of China and the China Postdoctoral Science Foundation. Proposed model of CIDEs mediated lipid droplets fusion in hepatocytes. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.