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

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.

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.

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.

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