HDAC6-mediated acetylation of lipid droplet–binding protein CIDEC regulates fat-induced lipid storage
Hui Qian, … , Weiping Jia, Peng Li
Hui Qian, … , Weiping Jia, Peng Li
Published March 13, 2017
Citation Information: J Clin Invest. 2017;127(4):1353-1369. https://doi.org/10.1172/JCI85963.
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Research Article Cell biology Metabolism

HDAC6-mediated acetylation of lipid droplet–binding protein CIDEC regulates fat-induced lipid storage

Abstract

Obesity is characterized by aberrant fat accumulation. However, the intracellular signaling pathway that senses dietary fat and leads to fat storage remains elusive. Here, we have observed that the levels of histone deacetylase 6 (HDAC6) and the related family member HDAC10 are markedly reduced in adipose tissues of obese animals and humans. Mice with adipocyte-specific depletion of Hdac6 exhibited increased fat accumulation and reduced insulin sensitivity. In normal adipocytes, we found that reversal of P300/CBP-associated factor–induced (PCAF-induced) acetylation at K56 on cell death-inducing DFFA-like effector C (CIDEC, also known as FSP27) critically regulated lipid droplet fusion and lipid storage. Importantly, HDAC6 deacetylates CIDEC, leading to destabilization and reduced lipid droplet fusion. Accordingly, we observed elevated levels of CIDEC and its acetylated form in HDAC-deficient adipocytes as well as the adipose tissue of obese animals and humans. Fatty acids (FAs) prevented CIDEC deacetylation by promoting the dissociation of CIDEC from HDAC6, which resulted in increased association of CIDEC with PCAF on the endoplasmic reticulum. Control of CIDEC acetylation required the conversion of FAs to triacylglycerols. Thus, we have revealed a signaling axis that is involved in the coordination of nutrient availability, protein acetylation, and cellular lipid metabolic responses.

Authors

Hui Qian, Yuanying Chen, Zongqian Nian, Lu Su, Haoyong Yu, Feng-Jung Chen, Xiuqin Zhang, Wenyi Xu, Linkang Zhou, Jiaming Liu, Jinhai Yu, Luxin Yu, Yan Gao, Hongchao Zhang, Haihong Zhang, Shimin Zhao, Li Yu, Rui-Ping Xiao, Yuqian Bao, Shaocong Hou, Pingping Li, Jiada Li, Haiteng Deng, Weiping Jia, Peng Li

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Figure 4

Acetylation of CIDEC enhances its stability.

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Acetylation of CIDEC enhances its stability. (A) Knockdown Hdac6 increas...
(A) Knockdown Hdac6 increased CIDEC stability in 3T3-L1 adipocytes. Data represent mean ± SEM. Two-way repeated-measures ANOVA was used to evaluate the data; ###P < 0.001. Knockdown efficiency for Hdac6 was determined by Western blot analysis. Data represent results from at least 3 independent experiments. (B) Acetylated CIDEC is more stable. 293T cells were transfected with Flag-tagged CIDEC and treated with CHX at different time points. CIDEC protein was immunoprecipitated using antibodies against FLAG and blotted with antibody against acetylated lysine (AcK56). Data represent results from at least 3 independent experiments. (C) Stability of CIDEC and CIDEC K56R in differentiated stromal vascular fraction (SVF) adipocytes from control and Hdac6 AKO mice. Data represent results obtained from 3 experiments. (D–F) Levels of CIDEC protein and acetylation were both increased in the adipose tissue of mice, monkeys, and humans. The GWAT of WT and leptin-deficient ob/ob mice; visceral fat of normal and obese rhesus monkeys; and intra-abdominal fat of normal and obese human patients were isolated and homogenated. CIDEC protein was immunoprecipitated and normalized using antibody against CIDEC and then blotted with CIDEC or AcK56 antibody (n = 3 mice, rhesus monkey, and human samples per group).