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Feeding induces cholesterol biosynthesis via the mTORC1–USP20–HMGCR axis
Nature ( IF 50.5 ) Pub Date : 2020-11-11 , DOI: 10.1038/s41586-020-2928-y
Xiao-Yi Lu , Xiong-Jie Shi , Ao Hu , Ju-Qiong Wang , Yi Ding , Wei Jiang , Ming Sun , Xiaolu Zhao , Jie Luo , Wei Qi , Bao-Liang Song

Cholesterol is an essential lipid and its synthesis is nutritionally and energetically costly 1 , 2 . In mammals, cholesterol biosynthesis increases after feeding and is inhibited under fasting conditions 3 . However, the regulatory mechanisms of cholesterol biosynthesis at the fasting–feeding transition remain poorly understood. Here we show that the deubiquitylase ubiquitin-specific peptidase 20 (USP20) stabilizes HMG-CoA reductase (HMGCR), the rate-limiting enzyme in the cholesterol biosynthetic pathway, in the feeding state. The post-prandial increase in insulin and glucose concentration stimulates mTORC1 to phosphorylate USP20 at S132 and S134; USP20 is recruited to the HMGCR complex and antagonizes its degradation. The feeding-induced stabilization of HMGCR is abolished in mice with liver-specific Usp20 deletion and in USP20(S132A/S134A) knock-in mice. Genetic deletion or pharmacological inhibition of USP20 markedly decreases diet-induced body weight gain, reduces lipid levels in the serum and liver, improves insulin sensitivity and increases energy expenditure. These metabolic changes are reversed by expression of the constitutively stable HMGCR(K248R). This study reveals an unexpected regulatory axis from mTORC1 to HMGCR via USP20 phosphorylation and suggests that inhibitors of USP20 could be used to lower cholesterol levels to treat metabolic diseases including hyperlipidaemia, liver steatosis, obesity and diabetes. mTORC1 stabilizes HMG-CoA reductase, a rate-limiting enzyme in the cholesterol biosynthesis pathway, via the deubiquitylase USP20 in response to feeding.

中文翻译:

喂养通过 mTORC1-USP20-HMGCR 轴诱导胆固醇生物合成

胆固醇是一种必需的脂质,其合成在营养和能量上都非常昂贵 1, 2 。在哺乳动物中,胆固醇生物合成在进食后增加,并在禁食条件下被抑制 3。然而,对空腹-进食过渡阶段胆固醇生物合成的调控机制仍知之甚少。在这里,我们展示了去泛素化酶泛素特异性肽酶 20 (USP20) 在进食状态下稳定 HMG-CoA 还原酶 (HMGCR),胆固醇生物合成途径中的限速酶。餐后胰岛素和葡萄糖浓度的增加刺激 mTORC1 在 S132 和 S134 磷酸化 USP20;USP20 被募集到 HMGCR 复合物并对抗其降解。在肝脏特异性 Usp20 缺失小鼠和 USP20(S132A/S134A) 敲入小鼠中,喂养诱导的 HMGCR 稳定性被消除。USP20 的基因缺失或药理学抑制显着降低饮食诱导的体重增加,降低血清和肝脏中的脂质水平,提高胰岛素敏感性并增加能量消耗。这些代谢变化被组成性稳定的 HMGCR(K248R) 的表达逆转。该研究揭示了通过 USP20 磷酸化从 mTORC1 到 HMGCR 的意外调节轴,并表明 USP20 抑制剂可用于降低胆固醇水平以治疗代谢疾病,包括高脂血症、肝脂肪变性、肥胖症和糖尿病。mTORC1 稳定 HMG-CoA 还原酶,这是胆固醇生物合成途径中的限速酶,
更新日期:2020-11-11
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