Hepatic glycogenesis antagonizes lipogenesis by blocking S1P via UDPG

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2024-02-16 DOI:10.1126/science.adi3332

Jie Chen, Yabo Zhou, Zhuohang Liu, Yan Lu, Yishen Jiang, Kexin Cao, Nannan Zhou, Dianheng Wang, Chaoqi Zhang, Ning Zhou, Keqing Shi, Lu Zhang, Li Zhou, Zhenfeng Wang, Huafeng Zhang, Ke Tang, Jingwei Ma, Jiadi Lv, Bo Huang

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引用次数: 0

Abstract

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.

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肝糖生成通过 UDPG 阻断 S1P，从而拮抗脂肪生成。

确定肝细胞中以糖原而非脂肪形式储存葡萄糖碳的机制，对于预防非酒精性脂肪肝（NAFLD）和其他慢性代谢性疾病具有重要意义。在这项研究中，我们发现糖生成利用其中间代谢产物二磷酸尿苷葡萄糖（UDPG）来拮抗脂肪生成，从而引导小鼠和人类肝细胞将葡萄糖碳储存为糖原。其基本机制包括将 UDPG 运送到高尔基体，在那里它与位点-1 蛋白酶（S1P）结合，抑制 S1P 介导的固醇调节元件结合蛋白（SREBPs）的裂解，从而抑制肝细胞的脂肪生成。与这一机制相一致的是，服用 UDPG 能有效治疗小鼠模型和人体器官组织中的非酒精性脂肪肝。这些发现为改善肝脏中紊乱的脂肪代谢提供了潜在的机会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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