Endogenous oxalate synthesis in mouse models of metabolic dysfunction-associated steatotic liver disease.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) may lead to increased urinary oxalate excretion, a risk factor for calcium oxalate kidney stone formation, and progression of chronic kidney disease. We used mouse models of diet-induced obesity to examine the impact of MASLD on endogenous oxalate synthesis and urinary oxalate excretion. Mice were either fed a high-fat diet to induce mild MASLD, or a high-fat, sucrose, and cholesterol diet (Western diet) to produce metabolic dysfunction-associated steatohepatitis (MASH), a more severe form of MASLD. Liver tissue was collected to measure activities of liver enzymes involved in endogenous oxalate synthesis and oxalate content. Blood and urine were obtained to measure serum creatinine and urinary oxalate excretion. Urinary oxalate excretion was also assessed after administration of hydroxyproline, a known endogenous oxalate precursor. High-fat feeding led to an increase in liver enzymes involved in glyoxylate detoxification and a significant, but modest (∼20%) increase in urinary oxalate excretion compared with control animals. In contrast, Western diet feeding led to a decrease in these enzyme activities and a 47% increase in urinary oxalate excretion compared with controls. Challenging mice with hydroxyproline resulted in significantly higher urinary oxalate excretion in Western diet-fed mice, but not high-fat-fed mice. Mild MASLD modestly increases endogenous oxalate synthesis, whereas MASH results in a profound increase in endogenous oxalate synthesis attributed to significant decreases in activity of hepatic enzymes involved in glyoxylate detoxification.Metabolic dysfunction-associated steatotic liver disease (MASLD) has been reported to lead to increased oxalate synthesis in mouse models. We show here that changes in oxalate synthesis, mediated by complex changes in enzymes involved in glyoxylate metabolism, are dependent on the degree of severity of MASLD, resulting in limited increases in urinary oxalate in mild MASLD, but marked increases in steatohepatitis.