Hepatic amino acid metabolism in liver, cardiovascular, kidney and metabolic diseases.

Amino acids are crucial metabolites with many roles in metabolism and signaling, especially in the liver. Positioned just after the portal vein, the liver controls the flow of amino acids from the diet to the body based on their degree of uptake. It is also the site of several critical metabolic processes for systemic homeostasis, including glutathione production and the urea cycle. When these processes are disrupted, often the case in metabolic dysfunction-associated steatotic liver disease (MASLD), subsequent dysregulation can contribute to co-existing systemic pathologies, including cardiovascular, kidney, and metabolic diseases, altogether termed CKLM. Gluconeogenesis in the liver, fueled by alanine, is elevated in MASLD, promoting progression of insulin resistance. The consequences of resulting hyperglycemia are implicated in chronic kidney disease (CKD) and cardiovascular disease (CVD), including atherosclerosis. The urea cycle, which clears toxic ammonia from the body, is reduced in MASLD, resulting in higher ammonia levels and lower citrulline levels. Since citrulline decreases reactive oxygen species (ROS), lower citrulline levels may contribute to CVD. Another combatant of ROS, glutathione, is also reduced in MASLD, as well as in CKD and CVD. The resultant oxidative stress can further exacerbate these diseases and contribute to diabetes, atherosclerosis, and heart failure. Finally, one carbon metabolism, which provides functional groups for methylation reactions, is reduced in MASLD, resulting in elevated circulating methionine, cysteine, and homocysteine. These elevations are associated with CVD, obesity, and diabetes. Altogether, alterations in hepatic amino acid metabolism are observed in and may contribute not only to MASLD, but also to co-existing CKLM diseases.