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 7

FA conversion into TAG in the ER is vital for it to induce CIDEC acetylation.

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FA conversion into TAG in the ER is vital for it to induce CIDEC acetyla...
(A) FA-induced CIDEC acetylation and the dynamic interaction among CIDEC, PCAF, and HDAC6 were disrupted by the depletion of Fabp4. Data represent results from 3 independent experiments. (B) FA-induced CIDEC acetylation and HDAC6, PCAF dynamic interaction with CIDEC was depended on DGAT activity. Data represent results from 3 independent experiments. (C) Levels of CIDEC protein and its acetylation were decreased in the GWAT of lipin 1–deficient mice (Lpin1 KO) (n = 4 mice per group). (D) HDAC6 is recruited to the ER in the presence of CIDEC and dissociated from ER in the presence of OA. Data represent results from at least 3 independent experiments. (E) The ER is the site of subcellular localization of FA-induced dynamic association among CIDEC, PCAF, and HDAC6. Data represent results from at least 3 independent experiments. (F) The ER is the site for OA-induced CIDEC acetylation and the dynamic interaction among CIDEC, PCAF, and HDAC6 in 3T3-L1 adipocytes. Data represent results from at least 3 independent experiments. (G) Representative images showing the colocalization of HDAC6 (red) and CIDEC (green) in the presence of OA. Scale bars: 5 μm and 2 μm (insets). Data represent results from at least 5 independent experiments. (H) Model depicting the role of HDAC6 in mediating FA-induced CIDEC acetylation and obesity development in adipocytes. When extracellular levels of FAs are low, CIDEC is associated with HDAC6, resulting in its lower acetylation and rapid degradation. In the presence of high levels of FAs, HDAC6 is dissociated from CIDEC, resulting in the association between CIDEC and PCAF and increased CIDEC acetylation. Acetylated CIDEC is mobilized to LD to promote fusion and lipid storage.