Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Center for Metabolic Regulation of Healthy Aging (CMHA), Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
J Diabetes Investig. 2021 Oct;12(10):1765-1774. doi: 10.1111/jdi.13567. Epub 2021 May 31.
AIMS/INTRODUCTION: Peroxisome proliferator-activated receptor (PPAR)-γ2 is a transcription factor crucial for regulating adipogenesis and glucose/lipid metabolism, and synthetic PPARγ ligands, such as thiazolidinediones, are effective oral medication for type 2 diabetes. Sirtuin 7 (SIRT7), a nicotinamide adenine dinucleotide-dependent deacetylase, also controls metabolism. However, it is not known whether SIRT7 regulates the function of PPARγ2 by its deacetylation.
Physical interaction between SIRT7 and PPARγ2, the effect of SIRT7 on PPARγ2 acetylation, and the deacetylation residue targeted by SIRT7 were investigated. The effects of PPARγ2 K382 acetylation on lipid accumulation, gene expression in C3H10T1/2 cell-derived adipocytes, and ligand-dependent transactivation activity were also evaluated.
We demonstrated that SIRT7 binds to PPARγ2 and deacetylates PPARγ2 at K382. C3H10T1/2-derived adipocytes expressing PPARγ2 (a mimic of acetylated K) accumulated much less fat than adipocytes expressing wild-type PPARγ2 or PPARγ2 (a mimic of nonacetylated K). Global gene expression analysis of adipocytes expressing PPARγ2 revealed that K382Q caused the dysregulation of a set of genes involved in lipogenesis, including Srebp1c, Acaca, Fasn, and Scd1. The rosiglitazone-dependent transcriptional activity of PPARγ2 was reduced compared with that of PPARγ2 .
Our findings indicate that SIRT7-dependent PPARγ2 deacetylation at K382 controls lipogenesis in adipocytes.
目的/引言：过氧化物酶体增殖物激活受体（PPAR）-γ2 是一种转录因子，对调节脂肪生成和葡萄糖/脂质代谢至关重要，合成的 PPARγ 配体，如噻唑烷二酮类，是治疗 2 型糖尿病的有效口服药物。Sirtuin 7（SIRT7）是一种烟酰胺腺嘌呤二核苷酸依赖性去乙酰化酶，也控制着新陈代谢。然而，目前尚不清楚 SIRT7 是否通过去乙酰化作用来调节 PPARγ2 的功能。
研究了 SIRT7 与 PPARγ2 之间的物理相互作用、SIRT7 对 PPARγ2 乙酰化的影响以及 SIRT7 靶向的去乙酰化残基。还评估了 PPARγ2 K382 乙酰化对脂质积累、C3H10T1/2 细胞衍生的脂肪细胞中基因表达以及配体依赖性转录激活活性的影响。
我们证明了 SIRT7 与 PPARγ2 结合，并使 PPARγ2 在 K382 处去乙酰化。表达 PPARγ2（模拟乙酰化 K）的 C3H10T1/2 衍生脂肪细胞比表达野生型 PPARγ2 或 PPARγ2（模拟非乙酰化 K）的脂肪细胞积累的脂肪少得多。表达 PPARγ2 的脂肪细胞的全基因组基因表达分析表明，K382Q 导致参与脂肪生成的一组基因的失调，包括 Srebp1c、Acaca、Fasn 和 Scd1。与 PPARγ2 相比，rosiglitazone 依赖性 PPARγ2 转录活性降低。
我们的研究结果表明，SIRT7 依赖性 PPARγ2 在 K382 处的去乙酰化作用控制脂肪细胞中的脂肪生成。
