体内蛋白质半衰期分析表明，在临床前酒精性大鼠模型中，SREBF1-SLC27a5轴调控抗氧化反应。

In vivo protein half-life analysis identifies the SREBF1-SLC27a5 axis governs antioxidant response in preclinical alcoholic rat model.

作者信息

Sharma Nupur, Bhat Sadam H, Chaudhary Shweta, Mathew Babu, Pandey Sushmita, Yadav Sanju, Yadav Manisha, Bindal Vasundhra, Tripathi Gaurav, Sharma Neha, Sharma Vipul, Gupta Abhishak, Nanda Ranjan, Kumari Anupama, Sharma Shvetank, Maras Jaswinder Singh

机构信息

Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.

Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.

出版信息

Redox Biol. 2025 May 17;85:103674. doi: 10.1016/j.redox.2025.103674.

BACKGROUND

ALD causes liver dysfunction with inflammation, steatosis, and fibrosis. While abstinence reverses damage, its effect on protein half-lives remains unclear. This study examines site-specific protein half-life changes, transcription regulation, and recovery mechanisms.

METHOD

Long-Evans rats were fed ethanol or control diets for 24 weeks to induce ALD, with some switched to a control diet for 7 days to model abstinence. Protein half-lives, pathways, and transcription factors were analyzed using deuterium labeling and were validated in ALD rats, abstinent rats, and human biopsies.

RESULTS

Liver histology showed increased steatosis (28 %) and fibrosis (15 %) in ALD rats, both reduced with abstinence (<20 %, <12 %, p < 0.05). Liver function and lipid profiles improved, while alcohol-metabolizing and inflammatory markers were decreased (>1.5-fold, p < 0.05) following abstinence. ALD induced change in protein half-life specific to liver (82↑, 54↓), intestine (26↑, 30↓), and plasma (11↑, 17↓). Abstinence modulated; liver (64↑, 62↓), intestine (13↑, 25↓), and plasma (10↑, 12↓; FC > 1.5, p < 0.05). Specifically, abstinence reversed protein half-lives linked to lipid metabolism in the liver, neurodegeneration in the intestine, and NET formation in plasma (p < 0.05). Abstinence restored protein half-lives of Cyp2d10, Ugt1a1, Slc27a5, and Hsp90b1, regulated by Srebf1. Proteomic validation confirmed increased Acat1, Ugt1a1, and Slc27a5 in ALD, linked to steatosis and inflammation, which decreased with abstinence. Severe alcoholic hepatitis patients also documented that abstinence work on modulating protein turnover under the Srebf1-Slc27a5 axis and thereby ameliorate liver damage.

CONCLUSION

Alcohol abstinence modulates protein half-lives through Srebf1-Slc27a5 axis, reducing inflammation, steatosis, and oxidative stress, potentially aiding in alcohol-induced liver damage treatment.

背景

酒精性肝病（ALD）会导致肝功能障碍，并伴有炎症、脂肪变性和纤维化。虽然戒酒可逆转损伤，但其对蛋白质半衰期的影响尚不清楚。本研究探讨了特定部位蛋白质半衰期的变化、转录调控及恢复机制。

方法

将长 Evans 大鼠喂食乙醇或对照饮食 24 周以诱导 ALD，部分大鼠切换至对照饮食 7 天以模拟戒酒。使用氘标记分析蛋白质半衰期、信号通路和转录因子，并在 ALD 大鼠、戒酒大鼠和人体活检组织中进行验证。

结果

肝脏组织学检查显示，ALD 大鼠的脂肪变性（28%）和纤维化（15%）增加，戒酒可使其减轻（<20%，<12%，p<0.05）。戒酒可改善肝功能和血脂谱，同时降低酒精代谢和炎症标志物（>1.5 倍，p<0.05）。ALD 导致肝脏（82 种增加，54 种减少）、肠道（26 种增加，30 种减少）和血浆（11 种增加，17 种减少）中蛋白质半衰期发生特异性变化。戒酒可调节这些变化；肝脏（64 种增加，62 种减少）、肠道（13 种增加，25 种减少）和血浆（10 种增加，12 种减少；FC>1.5，p<0.05）。具体而言，戒酒可逆转与肝脏脂质代谢、肠道神经变性和血浆中性粒细胞胞外陷阱（NET）形成相关的蛋白质半衰期（p<0.05）。戒酒可恢复受固醇调节元件结合转录因子（Srebf1）调控的细胞色素 P450 2D10（Cyp2d10）、尿苷二磷酸葡萄糖醛酸基转移酶 1A1（Ugt1a1）、脂肪酸转运蛋白 5（Slc27a5）和热休克蛋白 90β1（Hsp90b1）的蛋白质半衰期。蛋白质组学验证证实，ALD 中酰基辅酶 A：胆固醇酰基转移酶 1（Acat1）、Ugt1a1 和 Slc27a5 增加，与脂肪变性和炎症相关，戒酒可使其降低。重症酒精性肝炎患者的研究也表明，戒酒可通过 Srebf1-Slc27a5 轴调节蛋白质周转，从而改善肝损伤。