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

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

doi:10.1172/jci85963

Cited by 67 publications

(48 citation statements)

References 41 publications

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“…Loss of HDAC6 in white adipose tissue leads to increased acetylation of the cell death-inducing DNA fragmentation factor subunit a-like effector C (CIDEC) protein, leading to increased lipid droplet storage (73), a change in lipid metabolism that could help explain the accelerated weight gain we saw. The combination of higher free fatty acids with overexpressed CIDEC in an earlier LDP model (13) plus its stabilization by HDAC6 absence provides a mechanism for enhanced lipid droplet accumulation (73), further supported by the hepatic steatosis observed in the HDAC6 deficient mice in this work. However, we also observed that HDAC6 loss alone was sufficient to change gut microbiota composition, independent of other factors.…”

Section: Discussionsupporting

confidence: 68%

Loss of HDAC6 alters gut microbiota and worsens obesity

et al. 2018

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Alterations in gut microbiota are known to affect intestinal inflammation and obesity. Antibiotic treatment can affect weight gain by elimination of histone deacetylase (HDAC) inhibitor-producing microbes, which are anti-inflammatory by augmenting regulatory T (T) cells. We asked whether mice that lack HDAC6 and have potent suppressive T cells are protected from microbiota-induced accelerated weight gain. We crossed wild-type and HDAC6-deficient mice and subjected the offspring to perinatal penicillin, inducing weight gain via microbiota disturbance. We observed that male HDAC6-deficient mice were not protected and developed profoundly accelerated weight gain. The antibiotic-exposed HDAC6-deficient mice showed a mixed immune phenotype with increased CD4 and CD8 T-cell activation yet maintained the enhanced T cell-suppressive function phenotype characteristic of HDAC6-deficient mice. 16S rRNA sequencing of mouse fecal samples reveals that their microbiota diverged with time, with HDAC6 deletion altering microbiome composition. On a high-fat diet, HDAC6-deficient mice were depleted in representatives of the S24-7 family and Lactobacillus but enriched with Bacteroides and Parabacteroides; these changes are associated with obesity. Our findings further our understanding of the influence of HDACs on microbiome composition and are important for the development of HDAC6 inhibitors in the treatment of human diseases.-Lieber, A. D., Beier, U. H., Xiao, H., Wilkins, B. J., Jiao, J., Li, X. S., Schugar, R. C., Strauch, C. M., Wang, Z., Brown, J. M., Hazen, S. L., Bokulich, N. A., Ruggles, K. V., Akimova, T., Hancock, W. W., Blaser, M. J. Loss of HDAC6 alters gut microbiota and worsens obesity.

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Section: Discussionsupporting

confidence: 68%

Loss of HDAC6 alters gut microbiota and worsens obesity

et al. 2018

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“…Among the 10 proteins bound to Afadin preferentially in insulin‐stimulated conditions, we identified HDAC6, which was recently shown to modulate adiposity and insulin sensitivity as adipose tissue‐specific loss of HDAC6 promoted obesity and insulin resistance in mice . The interaction between HDAC6 and Afadin was confirmed by immunoprecipitation followed by Western blotting (Fig EV4B).…”

Section: Resultsmentioning

confidence: 57%

“…Further experiments are needed to dissect the mechanisms by which Afadin‐HDAC6 regulates acetylation and downregulation of the insulin receptor and the functional relevance of the Afadin/HDAC6/IR axis remains to be demonstrated. HDAC6 has recently been shown to regulate lipid droplet formation and thereby lipid storage in adipocytes affecting whole‐body metabolism , substantiating the importance of HDAC6 in adipose tissue biology.…”

Section: Discussionmentioning

confidence: 76%

“…Further experiments are needed to dissect the mechanisms by which Afadin-HDAC6 regulates acetylation and downregulation of the insulin receptor and the functional relevance of the Afadin/HDAC6/IR axis remains to be demonstrated. HDAC6 has recently been shown to regulate lipid droplet formation and thereby lipid storage in adipocytes affecting whole-body metabolism [25], substantiating the importance of HDAC6 in adipose tissue biology. In agreement with an involvement of Afadin in a regulatory feedback loop impeding insulin action in adipocytes, adipose tissuespecific loss of Afadin improves glucose and insulin tolerance in obese mice, without any changes in adiposity.…”

Section: A Body Weight Bmentioning

confidence: 76%

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Afadin is a scaffold protein repressing insulin action via HDAC 6 in adipose tissue

et al. 2019

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Insulin orchestrates metabolic homeostasis through a complex signaling network for which the precise mechanisms controlling its fine‐tuning are not completely understood. Here, we report that Afadin, a scaffold protein, is phosphorylated on S1795 (S1718 in humans) in response to insulin in adipocytes, and this phosphorylation is impaired with obesity and insulin resistance. In turn, loss of Afadin enhances the response to insulin in adipose tissues via upregulation of the insulin receptor protein levels. This happens in a cell‐autonomous and phosphorylation‐dependent manner. Insulin‐stimulated Afadin‐S1795 phosphorylation modulates Afadin binding with interaction partners in adipocytes, among which HDAC6 preferentially interacts with phosphorylated Afadin and acts as a key intermediate to suppress insulin receptor protein levels. Adipose tissue‐specific Afadin depletion protects against insulin resistance and improves glucose homeostasis in diet‐induced obese mice, independently of adiposity. Altogether, we uncover a novel insulin‐induced cellular feedback mechanism governed by the interaction of Afadin with HDAC6 to negatively control insulin action in adipocytes, which may offer new strategies to alleviate insulin resistance.

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“…Acetylation occurs on the ε-amino group of lysine residues (Lu et al, 2014). As a highly reversible protein modification process, acetylation is regulated by the action of histone acetylase and histone deacetylase (Guarente, 2011;Qian et al, 2017). The acetylation of proteins was first found in histones (Gu and Roeder, 1997); however, with the development of high-throughput mass spectrometry, many nonhistone acetylation processes and acetylated proteins have been identified in a variety of different species (Wilhelm et al, 1971;Glozak et al, 2005), including the silkworm (Nie et al, 2015;Zhou et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

The effect of acetylation on the protein stability of BmApoLp‐III in the silkworm, Bombyx mori

Yang

Zhu

Liu

et al. 2019

Insect Molecular Biology

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Acetylation is an important, reversible posttranslational modification to a protein. In a previous study, we found that there were a large number of acetylated sites in various nutrient storage proteins of the silkworm haemolymph. In this study, we confirmed that acetylation can affect the stability of nutrient storage protein Bombyx mori apolipophorin‐III (BmApoLp‐III). First, the expression of BmApoLp‐III could be upregulated when BmN cells were treated with the deacetylase inhibitor panobinostat (LBH589); similarly, the expression was downregulated when the cells were treated with the acetylase inhibitor C646. Furthermore, the increase in acetylation by LBH589 could inhibit the degradation and improve the accumulation of BmApoLp‐III in BmN cells treated with cycloheximide and MG132 respectively. Moreover, we found that an increase in acetylation could decrease the ubiquitination of BmApoLp‐III and vice versa; therefore, we predicted that acetylation could improve the stability of BmApoLp‐III by competing for ubiquitination and inhibiting the protein degradation pathway mediated by ubiquitin. Additionally, BmApoLp‐III had an antiapoptosis function that increased after LBH589 treatment, which might have been due to the improved protein stability after acetylation. These results have laid the foundation for further study on the mechanism of acetylation in regulating the storage and utilization of silkworm nutrition.

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

Cited by 67 publications

References 41 publications

Loss of HDAC6 alters gut microbiota and worsens obesity

Loss of HDAC6 alters gut microbiota and worsens obesity

Afadin is a scaffold protein repressing insulin action via HDAC 6 in adipose tissue

The effect of acetylation on the protein stability of BmApoLp‐III in the silkworm, Bombyx mori

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