What question did this study set out to answer?

July 13, 2026Open Access

γ-GC mitigates MASLD by reducing CD36 palmitoylation and plasma membrane translocation mediated by AKT/KLF10/zDHHC7 axis

Key Points

This research aims to explore how γ-GC affects metabolic dysfunction-associated steatotic liver disease (MASLD) and identify the underlying molecular mechanisms.
In vivo model using mice fed a high-fat diet to study the impact of γ-GC on MASLD.
In vitro hepatocyte model treated with free fatty acids (FFA) to investigate molecular mechanisms.
Analysis of lipid metabolism and protein expression related to fatty acid uptake and deposition.
HFD mice showed dyslipidemia and increased hepatic steatosis due to obesity.
Treatment with γ-GC reduced CD36-mediated fatty acid uptake and decreased hepatic lipid deposition.
γ-GC activated AKT signaling, inhibiting KLF10-regulated zDHHC7 transcription and CD36 palmitoylation.

Abstract

Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide disease characterized by hepatic steatosis. γ-glutamylcysteine (γ-GC), a non-protein thiol peptide with nontoxic side effects, can alleviate insulin resistance (IR) and alcoholic liver disease (ALD). However, the role of γ-GC in MASLD remains elusive. Herein, the aim of this study was to reveal the effects and underlying molecular mechanisms of γ-GC in the progression of MASLD. Methods In vivo model of mice fed with high-fat diet (HFD) and in vitro model of hepatocytes treated with FFA (oleic acid/palmitic acid = 2/1) were established to examine the therapeutic effects and molecular mechanisms of γ-GC in MASLD. Results HFD mice develop dyslipidemia and hepatic steatosis due to obesity. Increased lipogenesis-related protein expression and aggravated fatty acid uptake are also observed in hepatocytes treated with FFA. Mechanistic studies suggest that γ-GC can alleviate hepatic lipid deposition and steatosis through balancing lipid metabolism. Importantly, γ-GC inhibits KLF10-regulated zDHHC7 transcription via activating AKT signaling, thereby suppressing zDHHC7-mediated CD36 palmitoylation and plasma membrane translocation. Ultimately, γ-GC reduces CD36-mediated fatty acid uptake and attenuates FFA-associated lipogenic signaling, resulting in the amelioration of MASLD. Conclusions In summary, our results support γ-GC as a candidate dipeptide for the treatment of MASLD, which alleviates hepatic lipid deposition and steatosis by inhibiting KLF10/zDHHC7-mediated CD36 palmitoylation and plasma membrane translocation through activation of AKT signaling.

KI fragen

Bookmark

View Full Paper