Hepatic glycogenesis antagonizes lipogenesis by blocking S1P via UDPG
成果类型：
Article
署名作者：
Chen, Jie; Zhou, Yabo; Liu, Zhuohang; Lu, Yan; Jiang, Yishen; Cao, Kexin; Zhou, Nannan; Wang, Dianheng; Zhang, Chaoqi; Zhou, Ning; Shi, Keqing; Zhang, Lu; Zhou, Li; Wang, Zhenfeng; Zhang, Huafeng; Tang, Ke; Ma, Jingwei; Lv, Jiadi; Huang, Bo
署名单位：
Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Cancer Institute & Hospital - CAMS; Wenzhou Medical University; Tianjin Center for Disease Control & Prevention; Huazhong University of Science & Technology; Huazhong University of Science & Technology; Huazhong University of Science & Technology
刊物名称：
SCIENCE
ISSN/ISSBN：
0036-10616
DOI：
10.1126/science.adi3332
发表日期：
2024-02-16
关键词：
de-novo lipogenesis
endoplasmic-reticulum
insulin-resistance
p2y(14) receptor
slc35 family
glucose
sugar
metabolism
binding
protein
摘要：
The identification of mechanisms to store glucose carbon in the form of glycogen rather than fat in hepatocytes has important implications for the prevention of nonalcoholic fatty liver disease (NAFLD) and other chronic metabolic diseases. In this work, we show that glycogenesis uses its intermediate metabolite uridine diphosphate glucose (UDPG) to antagonize lipogenesis, thus steering both mouse and human hepatocytes toward storing glucose carbon as glycogen. The underlying mechanism involves transport of UDPG to the Golgi apparatus, where it binds to site-1 protease (S1P) and inhibits S1P-mediated cleavage of sterol regulatory element-binding proteins (SREBPs), thereby inhibiting lipogenesis in hepatocytes. Consistent with this mechanism, UDPG administration is effective at treating NAFLD in a mouse model and human organoids. These findings indicate a potential opportunity to ameliorate disordered fat metabolism in the liver.