Sirtuin 6-A Key Regulator of Hepatic Lipid Metabolism and Liver Health.
Sirtuin 6-A Key Regulator of Hepatic Lipid Metabolism and Liver Health.
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Sirtuin 6-肝脏脂质代谢和肝脏健康的关键调节因子。
作者：
Sirtuin 6 （SIRT6）是一种nadd依赖性去乙酰化酶/去乙酰化酶/单adp核糖基转移酶，是Sirtuin蛋白家族的成员。SIRT6与肝脏脂质稳态和肝脏健康有关。肝脏脂肪生成由几种主要调节因子驱动，包括肝X受体（LXR）、碳水化合物反应元件结合蛋白（ChREBP）和固醇调节元件结合蛋白1 （SREBP1）。有趣的是，这三种转录因子可通过SIRT6直接去乙酰化负调控。脂肪酸氧化是由肝脏过氧化物酶体增殖物激活受体α (PPARα)调节的。SIRT6可以通过激活PPARα或抑制miR-122促进脂肪酸氧化。SIRT6还可以直接调节酰基辅酶a合成酶长链家族成员5 （ACSL5）的脂肪酸氧化活性。SIRT6还分别通过调控SREBP2和蛋白转化酶枯草素/酮蛋白9型（PCSK9），在总胆固醇和低密度脂蛋白(LDL)-胆固醇的调节中发挥关键作用。小鼠肝脏Sirt6缺乏已被证明可引起肝脂肪变性、炎症和纤维化，这是酒精性和非酒精性脂肪性肝炎的特征。SIRT6可以通过调节巨噬细胞从M1型向M2型极化来抑制肝脏炎症。肝星状细胞是肝纤维化的关键细胞类型。SIRT6通过抑制多种纤维化途径，包括转化生长因子β (TGFβ)-SMAD家族蛋白和Hippo途径，发挥强大的抗纤维化作用。SIRT6在肝癌中的作用是非常复杂的，文献报道SIRT6具有抑制肿瘤和促进肿瘤的作用。综上所述，SIRT6对代谢稳态和肝脏健康具有多种有益作用，可能作为肝脏代谢性疾病的治疗靶点。迄今为止，许多SIRT6的激活剂和抑制剂已被开发用于转化研究。
Sirtuin 6 (SIRT6) is an NAD-dependent deacetylase/deacylase/mono-ADP ribosyltransferase, a member of the sirtuin protein family. SIRT6 has been implicated in hepatic lipid homeostasis and liver health. Hepatic lipogenesis is driven by several master regulators including liver X receptor (LXR), carbohydrate response element binding protein (ChREBP), and sterol regulatory element binding protein 1 (SREBP1). Interestingly, these three transcription factors can be negatively regulated by SIRT6 through direct deacetylation. Fatty acid oxidation is regulated by peroxisome proliferator activated receptor alpha (PPARα) in the liver. SIRT6 can promote fatty acid oxidation by the activation of PPARα or the suppression of miR-122. SIRT6 can also directly modulate acyl-CoA synthetase long chain family member 5 (ACSL5) activity for fatty acid oxidation. SIRT6 also plays a critical role in the regulation of total cholesterol and low-density lipoprotein (LDL)-cholesterol through the regulation of SREBP2 and proprotein convertase subtilisin/kexin type 9 (PCSK9), respectively. Hepatic deficiency of Sirt6 in mice has been shown to cause hepatic steatosis, inflammation, and fibrosis, hallmarks of alcoholic and nonalcoholic steatohepatitis. SIRT6 can dampen hepatic inflammation through the modulation of macrophage polarization from M1 to M2 type. Hepatic stellate cells are a key cell type in hepatic fibrogenesis. SIRT6 plays a strong anti-fibrosis role by the suppression of multiple fibrogenic pathways including the transforming growth factor beta (TGFβ)-SMAD family proteins and Hippo pathways. The role of SIRT6 in liver cancer is quite complicated, as both tumor-suppressive and tumor-promoting activities have been documented in the literature. Overall, SIRT6 has multiple salutary effects on metabolic homeostasis and liver health, and it may serve as a therapeutic target for hepatic metabolic diseases. To date, numerous activators and inhibitors of SIRT6 have been developed for translational research.
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DOI：
10.1074/jbc.ra120.014883
发表时间：
2020-12-25
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Carreño M;Bresque M;Machado MR;Santos L;Durán R;Vitturi DA;Escande C;Denicola A
通讯作者：
Denicola A
新型 SIRT6 激活剂通过 EZH2/FOXC1 轴改善神经炎症和缺血性脑损伤
DOI：
10.1016/j.apsb.2020.11.002
发表时间：
2021-03
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
He T;Shang J;Gao C;Guan X;Chen Y;Zhu L;Zhang L;Zhang C;Zhang J;Pang T
通讯作者：
Pang T
影响因子：
8.8
作者：
Elhanati, Sivan;Ben-Hamo, Rotem;Cohen, Haim Y.
通讯作者：
Cohen, Haim Y.
影响因子：
5.6
作者：
Frohlich, Jan;Raffaele, Marco;Vinciguerra, Manlio
通讯作者：
Vinciguerra, Manlio
Trp53 的单倍体不足可显着延长 Sirt6 缺陷小鼠的寿命。
影响因子：
7.7
作者：
Ghosh S;Wong SK;Jiang Z;Liu B;Wang Y;Hao Q;Gorbunova V;Liu X;Zhou Z
通讯作者：
Zhou Z