Role of amino acids in the regulation of hepatic gluconeogenesis and lipogenesis in metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its relatively advanced form, metabolic dysfunction-associated steatohepatitis (MASH), are becoming increasingly prevalent worldwide, making their prevention and management an urgent global health priority. Central to their development are key metabolic defects, including abnormal concentrations of monosaccharides, fatty acids, and amino acids, but the complex relationships between these substances within the hepatic microenvironment remain only partially understood. Dysregulated glucose metabolism and selective insulin resistance (IR) promote hepatic gluconeogenesis, glycolysis, and de novo lipogenesis (DNL); and excessive concentrations of free fatty acids from the diet and adipose tissue drive steatosis. Emerging evidence also implies that amino acid metabolism affects mitochondrial function and redox balance. Dysfunctional mitochondrial oxidative phosphorylation and the associated increase in reactive oxygen species production further exacerbate the cellular stress, inflammation, and fibrosis. However, compared with monosaccharide and fatty acid metabolism, the role of amino acid metabolism in MASLD/MASH remains less well understood. A better understanding of the role of such metabolic dysfunction in liver pathobiology should aid the identification of more useful biomarkers and precision therapies for MASLD/MASH.