Effects of UBE3A on Cell and Liver Metabolism through the Ubiquitination of PDHA1 and ACAT1.
Effects of UBE3A on Cell and Liver Metabolism through the Ubiquitination of PDHA1 and ACAT1.
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DOI：
10.1021/acs.biochem.2c00624
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发表时间：
2023-04-04
期刊：
影响因子：
2.9
通讯作者：
Yin, Jun
中科院分区：
文献类型：
--
作者：
Peng, Kangli;Wang, Shirong;Liu, Ruochuan;Zhou, Li;Jeong, Geon H.;Jeong, In Ho;Liu, Xianpeng;Kiyokawa, Hiroaki;Xue, Bingzhong;Zhao, Bo;Shi, Hang;Yin, Jun
非酒精性脂肪性肝病（NAFLD）是通过肝脏代谢途径的重新编程来证实的，其破坏了脂质和葡萄糖代谢的稳态，从而促进了疾病的进展。与NAFLD相关的代谢途径在从基因转录到各种翻译后修饰（包括泛素化）的不同水平上受到调节。在这里，我们使用了一种新的正交泛素转移平台，以确定丙酮酸脱氢酶A1（PDHA 1）和乙酰辅酶A乙酰转移酶1（ACAT 1），两个重要的酶，调节糖酵解和生酮，作为底物的E3泛素连接酶UBE 3A/E6 AP。我们发现UBE 3A的过表达加速了HEK 293细胞中PDHA 1的降解，并促进了糖酵解活性。此外，高脂饮食抑制了小鼠肝脏中UBE 3A的表达，这与ACAT 1蛋白水平的增加有关，而小鼠肝脏中UBE 3A的强制表达导致ACAT 1蛋白含量的降低。结果，肝脏中强制表达UBE 3A的小鼠表现出甘油三酯、胆固醇和酮体的积累增加。这些结果揭示了UBE 3A通过诱导肝脏中ACAT 1的降解和促进脂质储存在NAFLD发展中的作用。总的来说，我们的工作揭示了一个重要的机制，通过UBE 3A介导的PDHA 1和ACAT 1的泛素化来调节糖酵解和脂质代谢，以调节它们在细胞中的稳定性和酶活性。
Nonalcoholic fatty liver disease (NAFLD) is substantiated by the reprogramming of liver metabolic pathways that disrupts the homeostasis of lipid and glucose metabolism and thus promotes the progression of the disease. The metabolic pathways associated with NAFLD are regulated at different levels from gene transcription to various post-translational modifications including ubiquitination. Here, we used a novel orthogonal ubiquitin transfer platform to identify pyruvate dehydrogenase A1 (PDHA1) and acetyl-CoA acetyltransferase 1 (ACAT1), two important enzymes that regulate glycolysis and ketogenesis, as substrates of E3 ubiquitin ligase UBE3A/E6AP. We found that overexpression of UBE3A accelerated the degradation of PDHA1 and promoted glycolytic activities in HEK293 cells. Furthermore, a high-fat diet suppressed the expression of UBE3A in the mouse liver, which was associated with increased ACAT1 protein levels, while forced expression of UBE3A in the mouse liver resulted in decreased ACAT1 protein contents. As a result, the mice with forced expression of UBE3A in the liver exhibited enhanced accumulation of triglycerides, cholesterol, and ketone bodies. These results reveal the role of UBE3A in NAFLD development by inducing the degradation of ACAT1 in the liver and promoting lipid storage. Overall, our work uncovers an important mechanism underlying the regulation of glycolysis and lipid metabolism through UBE3A-mediated ubiquitination of PDHA1 and ACAT1 to regulate their stabilities and enzymatic activities in the cell.
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影响因子：
5.2
作者：
Gillessen-Kaesbach, G;Demuth, S;Horsthemke, B
通讯作者：
Horsthemke, B
影响因子：
4.2
作者：
Ducich, Nicole H.;Mears, Jason A.;Bedoyan, Jirair K.
通讯作者：
Bedoyan, Jirair K.
DOI：
10.1016/j.apsb.2021.09.019
发表时间：
2022-03
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
Du D;Liu C;Qin M;Zhang X;Xi T;Yuan S;Hao H;Xiong J
通讯作者：
Xiong J
影响因子：
16
作者：
Fan, Jun;Shan, Changliang;Kang, Hee-Bum;Elf, Shannon;Xie, Jianxin;Tucker, Meghan;Gu, Ting-Lei;Aguiar, Mike;Lonning, Scott;Chen, Huaibin;Mohammadi, Moosa;Britton, Laura-Mae P.;Garcia, Benjamin A.;Aleckovic, Masa;Kang, Yibin;Kaluz, Stefan;Devi, Nara;Van Meir, Erwin G.;Hitosugi, Taro;Seo, Jae Ho;Lonial, Sagar;Gaddh, Manila;Arellano, Martha;Khoury, Hanna J.;Khuri, Fadlo R.;Boggon, Titus J.;Kang, Sumin;Chen, Jing
通讯作者：
Chen, Jing
人类脂肪肝病：旧问题和新见解。
DOI：
10.1126/science.1204265
发表时间：
2011-06-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cohen JC;Horton JD;Hobbs HH
通讯作者：
Hobbs HH