# Deficiency of glycogen synthase promotes lipid accumulation through ChREBP and AKT-mTOR1-SREBP1 axis activation in mice

## TL;DR

Reduced glycogen synthase in the liver promotes fat buildup and liver damage in mice, suggesting new treatment targets for fatty liver disease.

## Contribution

This study identifies GS deficiency as a novel driver of MASLD through specific molecular pathways involving ChREBP and AKT-mTOR1-SREBP1.

## Key findings

- GS-deficient mice on a normal diet showed increased liver fat and injury.
- GS deficiency activates pathways that boost fatty acid production in the liver.
- Forcing GS expression in diabetic mice reduced liver fat accumulation.

## Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become highly prevalent worldwide, largely as a consequence of the global obesity epidemic. This research endeavors to elucidate the role and molecular mechanisms of hepatic glycogen synthase (GS) in MASLD progression. Published transcriptomic data reveal a downward trend in GYS2 gene expression in patients with obesity, MASLD, and metabolic dysfunction-associated steatohepatitis. In mouse models of MASLD, GYS2 gene or protein expression was downregulated, consistent with the human data. Here, GS-deficient mice fed with a normal diet displayed hepatic lipid accumulation and liver injury, whereas hepatic steatosis progression and inflammation were aggravated in mice fed with a high-fat diet. Loss of hepatic GS stimulated fatty acid de novo synthesis through carbohydrate-response element-binding protein and AKT-mTOR1-sterol regulatory element-binding protein 1 axis pathways. In GS-deficient mice, lipid accumulation in the hepatocytes significantly decreased when carbohydrate-response element-binding protein and sterol regulatory element-binding protein 1 levels were suppressed to levels comparable to those of cytotoxic T lymphocyte hepatocytes. Forced expression of hepatic GS by adeno-associated virus in db/db mice ameliorated lipid accumulation in male mice. Our findings provide proof of concept whereby targeting glycogen metabolism in hepatocytes may offer potential therapeutic avenues to treat MASLD.