Hepatic glutathione depletion ameliorates MASLD through selective protein oxidation and inhibition of lipogenesis
Xiang-Yu Liu, Guoxiao Wang, Yingying Yu, Haopeng Xiao, Kentaro Oh-hashi, Xu Shi, Shuning Zheng, Robert Gerszten, C. Ronald Kahn
Xiang-Yu Liu, Guoxiao Wang, Yingying Yu, Haopeng Xiao, Kentaro Oh-hashi, Xu Shi, Shuning Zheng, Robert Gerszten, C. Ronald Kahn
View: Text | PDF
Research Article Cell biology Hepatology Metabolism

Hepatic glutathione depletion ameliorates MASLD through selective protein oxidation and inhibition of lipogenesis

Abstract

Glutathione (GSH) maintains a reduced cellular environment and is widely believed to mitigate disease-associated oxidative damage to proteins, thereby protecting against metabolic dysfunction–associated steatotic liver disease (MASLD). However, this widely accepted assumption remains largely untested because of challenges in physiologically manipulating hepatic GSH levels during disease development. Here, we have utilized liver-specific overexpression of cation transport regulator homolog 1 (Chac1), a recently identified intracellular GSH-degrading enzyme, to induce hepatic GSH depletion during MASLD progression. Contrary to canonical doctrine, GSH depletion unexpectedly protects against MASLD by substantially decreasing hepatic lipogenesis and fibrosis without triggering an oxidative stress response. Mechanistically, GSH depletion does not cause global protein oxidation but instead selectively oxidizes and destabilizes fatty acid synthase while decreasing lipogenic gene expression at the transcriptional level, collectively suppressing lipogenesis. Interestingly, Chac1 expression is decreased in livers of patients with MASLD, highlighting its potential therapeutic relevance. These findings revise the conventional view of GSH in protein redox and demonstrate that targeted redox manipulation through GSH depletion protects against MASLD.

Authors

Xiang-Yu Liu, Guoxiao Wang, Yingying Yu, Haopeng Xiao, Kentaro Oh-hashi, Xu Shi, Shuning Zheng, Robert Gerszten, C. Ronald Kahn

×

Figure 3

Hepatic GSH depletion suppresses lipogenesis and fibrosis.

Options: View larger image (or click on image) Download as PowerPoint
Hepatic GSH depletion suppresses lipogenesis and fibrosis. (A) Relative ...
(A) Relative expression levels of key genes controlling lipogenesis, β-oxidation, gluconeogenesis, and fibrosis in livers of mice under chow diet. Expression was assessed by qRT-PCR (n = 9–11). Mice were fed a chow diet and were sacrificed 8 weeks after infection with AAV. (B) Relative expression levels of key genes controlling lipogenesis, β-oxidation, gluconeogenesis, and fibrosis in livers of mice after 10 weeks on HFD. Expression was assessed by qRT-PCR (n = 7). Mice were fed an HFD for 2 weeks before infection with AAV and were sacrificed 8 weeks later. (C) Protein levels of SREBP-1c, SCD1, and CHAC1 in livers of mice under HFD. (D) Relative expression levels of Chac1-regulated genes in primary hepatocytes under 100 μM free fatty acid (FA) treatment. Expression was assessed by qRT-PCR (n = 3). Adenovirus (Adv): 400 μL/mL medium. Cells were harvested 3 days postinfection. (E) Protein levels of SPP1, SCD1, and CHAC1 in primary hepatocytes under 100 μM free FA treatment. Primary hepatocytes were infected with Adv overexpressing GFP or Chac1. Adv: 400 μL/mL medium. Cells were harvested 3 days postinfection. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.