AdipoRon mitigates liver fibrosis by suppressing serine/glycine biosynthesis through ATF4-dependent glutaminolysis

IF 6.1 2区环境科学与生态学 Q1 ENVIRONMENTAL SCIENCES

Ecotoxicology and Environmental Safety Pub Date : 2025-01-01 DOI:10.1016/j.ecoenv.2024.117511

Xiangting Zhang , Yuan Zeng , Huiya Ying , Yiwen Hong , Jun Xu , Rong Lin , Yuhao Chen , Xiao Wu , Weimin Cai , Ziqiang Xia , Qian Zhao , Yixiao Wang , Ruoru Zhou , Dandan Zhu , Fujun Yu

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引用次数: 0

Abstract

AdipoRon has been validated for its ability to reverse liver fibrosis, yet the underlying mechanisms remain to be thoroughly investigated. Collagen, predominantly synthesized and secreted in hepatic stellate cells (HSCs), relies on glycine as a crucial constituent. Activating transcription factor 4 (ATF4) serves as a pivotal transcriptional regulator in amino acid metabolism. Therefore, our objective is to explore the impact of AdipoRon on ATF4-mediated endoplasmic reticulum stress and amino acid metabolism in HSCs. We induced liver fibrosis in mice through intraperitoneal injection of CCl₄ and administered AdipoRon (50 mg/kg) via gavage. In vitro studies were predominantly conducted using LX-2 cells. Our findings demonstrated that AdipoRon effectively suppressed ATF4-mediated endoplasmic reticulum stress in HSCs and assumed a crucial role in hindering serine/glycine biosynthesis. Interestingly, this inhibitory effect of AdipoRon on serine/glycine biosynthesis is regulated by PSAT1-mediated glutaminolysis, resulting in a subsequent decrease in collagen synthesis within HSCs. This study provides potential mechanistic insights into the treatment of liver fibrosis with AdipoRon.

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AdipoRon通过atf4依赖性谷氨酰胺水解抑制丝氨酸/甘氨酸生物合成，从而减轻肝纤维化。

AdipoRon已被证实具有逆转肝纤维化的能力，但其潜在机制仍有待深入研究。胶原蛋白主要在肝星状细胞（hsc）中合成和分泌，依赖于甘氨酸作为关键成分。激活转录因子4 （ATF4）在氨基酸代谢中起着关键的转录调节作用。因此，我们的目的是探讨AdipoRon对造血干细胞中atf4介导的内质网应激和氨基酸代谢的影响。我们通过腹腔注射CCl4诱导小鼠肝纤维化，并灌胃给予AdipoRon（50 mg/kg）。体外研究主要使用LX-2细胞进行。我们的研究结果表明，AdipoRon有效地抑制了造血干细胞中atf4介导的内质网应激，并在阻碍丝氨酸/甘氨酸的生物合成中发挥了关键作用。有趣的是，AdipoRon对丝氨酸/甘氨酸生物合成的抑制作用是由psat1介导的谷氨酰胺溶解调节的，从而导致hsc内胶原合成的减少。这项研究为AdipoRon治疗肝纤维化提供了潜在的机制见解。

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

Ecotoxicology and Environmental Safety 环境科学-毒理学

CiteScore

12.10

自引率

5.90%

发文量

1234

审稿时长

88 days

期刊介绍： Ecotoxicology and Environmental Safety is a multi-disciplinary journal that focuses on understanding the exposure and effects of environmental contamination on organisms including human health. The scope of the journal covers three main themes. The topics within these themes, indicated below, include (but are not limited to) the following: Ecotoxicology、Environmental Chemistry、Environmental Safety etc.