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 3

CIDEC is deacetylated by HDAC6 and acetylated by PCAF at K56.

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CIDEC is deacetylated by HDAC6 and acetylated by PCAF at K56. (A) Levels...
(A) Levels of CIDEC acetylation were increased in the GWAT of Hdac6 AKO mice. Levels of α-tubulin were used as a positive control. IgG was used as a loading control. To detect CIDEC acetylation in vivo, the GWAT tissue sample was incubated with A/G beads conjugated to antibodies against acetylated lysine, and the immunoprecipitates were blotted with antibodies against CIDEC and other LD-associated proteins (PLIN1, ADRP, TIP47). Data represent results from at least 3 independent experiments. (B) Ectopically expressed CIDEC was acetylated in the presence of TSA or when Hdac6 was knocked down. Data represent results from at least 3 independent experiments. (C) PCAF acetylates CIDEC. Flag-CIDEC was coexpressed in 293T cells with different acetyltransferases. Upper panel shows levels of CIDEC acetylation; lower panel shows levels of P53 acetylation when Flag-CIDEC and Flag-P53 were coexpressed with various acetyltransferases. Data represent results from at least 3 independent experiments. (D) HDAC6 deacetylates CIDEC. Data represent results from at least 3 independent experiments. (E) PCAF acetylates CIDEC in vitro. Bacterially isolated CIDEC-MBP was incubated with GST-PCAF containing the enzymatic domain (active) in vitro. Data represent results from at least 3 independent experiments. (F) Identification of the conserved K56 residue in difference species. (G) Ratio of acetylated CIDEC at K56 in the adipose tissue of control and Hdac6 AKO mice. (H) Characterization of anti–acetyl-K56 (AcK56) antibody. Data represent results from at least 3 independent experiments. (I) Increased levels of CIDEC protein and its acetylated form in the GWAT and the BAT of Hdac6 AKO mice. The immunoprecipitated CIDEC was normalized (n = 3 mice per group).