State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Key Laboratory of State General Administration of Sport, Shanghai Research Institute of Sports Science, 200030, Shanghai, China.
Cell Death Dis. 2019 Aug 14;10(8):614. doi: 10.1038/s41419-019-1834-4.
Previous study indicated that Sirtuin 3 (SIRT3) is a central regulator of adaptive thermogenesis in brown adipose tissue (BAT). Here we investigate the role of SIRT3 in the modulation of cellular phenotype in BAT under high salt intake (HS). HS downregulated SIRT3 level in BAT, accompanied by decreased oxygen consumption rate, and caused a severe loss of BAT characteristics. Mechanically, SIRT3 interacted with pyruvate dehydrogenase E1α (PDHA1) and deacetylated Lys-83 both in vitro and in vivo under HS. In parallel, HS suppressed salt-induced kinase (Sik) 2 phosphorylation. Silencing Sik2 further diminished SIRT3 activity and enhanced acetylation of PDHA1 K83 level. Reconstruction of SIRT3 restored PDH activity and thermogenic markers expression in differentiated brown adipocytes from SIRT3 knockout (KO) mice. In addition, loss of SIRT3 induced selective remodelling of phospholipids and glycerolipids in BAT exposure to HS. These data indicate that SIRT3 is an essential enzymatic switch that controls brown adipose cell phenotype.
先前的研究表明，Sirtuin 3（SIRT3）是棕色脂肪组织（BAT）中适应性产热的核心调节因子。在这里，我们研究了 SIRT3 在高盐摄入（HS）条件下调节 BAT 细胞表型中的作用。高盐使 BAT 中的 SIRT3 水平下调，伴随着耗氧量的降低，并导致 BAT 特征的严重丧失。在机制上，SIRT3 在 HS 条件下与丙酮酸盐脱氢酶 E1α（PDHA1）和赖氨酸 83 发生相互作用，无论是在体外还是体内。同时，HS 抑制盐诱导激酶（Sik）2 的磷酸化。沉默 Sik2 进一步降低了 SIRT3 的活性，并增强了 PDHA1 K83 水平的乙酰化。在 SIRT3 敲除（KO）小鼠的分化棕色脂肪细胞中，重建 SIRT3 恢复了 PDH 活性和产热标记物的表达。此外，SIRT3 的缺失导致 HS 暴露的 BAT 中磷脂和甘油酯的选择性重塑。这些数据表明，SIRT3 是控制棕色脂肪细胞表型的必需酶开关。
