Short-term exercise improves liver health by modulating amino acid metabolism

Background and aims

Metabolic-associated steatohepatitis (MASH) is an advanced and progressive liver disease that potentially causes cirrhosis and hepatocellular carcinoma. Exercise is a crucial and effective intervention for ameliorating metabolic dysfunction-associated steatotic liver disease. This study aimed to provide a comprehensive understanding of the underlying mechanisms of MASH, which benefit a broad spectrum of MASH patients, including those who have difficulty engaging in physical activity.

Methods

We established a mouse model of MASH and selectively knocked down L-type amino acid transporter 1 and alanine-serine-cysteine transporter 2. Mice were fed a high-fat high-cholesterol diet and subjected to either short- or long-term exercise regimens. We assessed the phosphorylation and activity of branched-chain alpha-keto acid dehydrogenase (BCKDH) as well as branched-chain amino acid (BCAA) content in skeletal muscle following exercise.

Results

Short-term exercise significantly reduced hepatic steatosis and inflammation without causing notable changes in body weight. It also enhanced BCKDH activity in skeletal muscle and decreased hepatic BCAA accumulation. Muscle-specific overexpression of BCKDH further promoted BCAA catabolism and significantly attenuated hepatic steatosis and inflammation in high-fat high-cholesterol-fed mice. In contrast, muscle-specific L-type amino acid transporter 1 knockdown, which suppresses BCAA uptake, markedly abolished these beneficial effects. Interestingly, BCKDH overexpression in muscle increased glutamine levels in both the blood and liver. Hepatic alanine-serine-cysteine transporter 2 knockdown, which inhibited glutamine uptake, lessened the protective effect of exercise on MASH. Further in vitro study revealed that glutamine derived from myocytes improved redox homeostasis and inhibited lipid accumulation in hepatocytes.

Conclusions

In our study, enhanced BCAA oxidation in skeletal muscle following short-term exercise increased glutamine production, which circulated to the liver and helped ameliorate MASH by promoting redox balance. This mechanism offers a novel perspective and a promising therapeutic target for MASH treatment, with significant implications for future clinical interventions and drug development.