HDAC6-mediated acetylation of lipid droplet–binding protein CIDEC regulates fat-induced lipid storage
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
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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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 6

FA induces CIDEC acetylation and dynamic association among CIDEC, PCAF, and HDAC6.

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FA induces CIDEC acetylation and dynamic association among CIDEC, PCAF, ...
(A) FAs increase CIDEC protein levels. Data represent results from at least 3 independent experiments. (B) OA enhances the stability of endogenous CIDEC in 3T3-L1 adipocytes. Data represent results from at least 3 independent experiments. NC, negative control that without OA treatment. (C) OA-induced CIDEC acetylation was at the K56 residue (AcK56) in 3T3-L1 adipocytes. Data represent results from at least 3 independent experiments. (D) Knockdown of Pcaf abolished OA-induced CIDEC acetylation. Data represent results from at least 3 independent experiments. (E) OA-induced CIDEC acetylation was inhibited by the expression of HDAC6. Data represent results from at least 3 independent experiments. (F) Levels of CIDEC ubiquitination (Ub) were decreased in the presence of OA or TSA. Data represent results from at least 3 independent experiments. (G) Interaction among CIDEC, PCAF, HDAC6, and HDAC10 in differentiated 3T3-L1 adipocytes. Data represent results from at least 3 independent experiments. (H) OA inhibited the interaction between CIDEC and HDAC6 but stimulated the interaction between CIDEC and PCAF in the 3T3-L1 adipocytes. Data represent results from at least 3 independent experiments. (I) OA induced PCAF and CIDEC interaction in a dose-dependent manner. Data represent results from at least 3 independent experiments. (J) OA inhibited CIDEC and HDAC6 interaction in a dose-dependent manner. Data represent results from at least 3 independent experiments. (K) OA induced PCAF and CIDEC interaction but inhibited HDAC6 and CIDEC interaction. Data represent results from at least 3 independent experiments. (L) PCAF showed high binding affinity to the acetylation-defective form of CIDEC. Data represent results from at least 3 independent experiments. (M) HDAC6 had high affinity to the acetylation-mimicking form CIDEC. Data represent results from at least 3 independent experiments.