Vitamin D attenuates Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and downregulates hepatic gluconeogenesis in obesity.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is often linked to vitamin D deficiency. Insulin resistance (IR) plays a central role in MASLD and is tied to an abnormal activation of hepatic gluconeogenesis, contributing to the hyperglycemia found in this condition. This study evaluated whether vitamin D supplementation improves MASLD and reduces hepatic glucose production in cafeteria diet-induced obese rats. Inflammation, oxidative stress, and IR were additionally assessed both systemically and in the liver. Gluconeogenic and glycogenolytic fluxes were measured in perfused livers. Wistar rats received a cafeteria or standard diet for 60 days and remained on these diets for another 5 weeks; during this period, a subgroup in each condition received weekly vitamin D (5,600 IU/kg) by oral gavage. The cafeteria diet promoted obesity, MASLD, IR, oxidative stress and inflammation. Obese rats displayed elevated hepatic gluconeogenesis from lactate and intensified glycogenolysis and glycolysis. Vitamin D supplementation reduced food intake and body weight gain and improved IR and glucose tolerance, changes accompanied by lower hepatic steatosis. The treatment decreased hepatic mRNA expression of NF-κB, TNFα, and IL-6, and increased Nrf2 expression. It also elevated vitamin D receptor, sirtuin-1 and FGF21/β-klotho axis expression, findings associated with higher IRS-2 and Nrf2 expression and lower NF-κB expression. Vitamin D reduced the elevated gluconeogenesis and glycogenolysis in obese rats, as determined by direct metabolic flux measurements, likely due to improvements in IR/MASLD. The results support the therapeutic potential of vitamin D in MASLD induced by a cafeteria diet that resembles obesogenic human dietary patterns and suggest benefits for controlling hyperglycemia in obesity.

Key Findings

• Vitamin D supplementation reduced food intake, body weight gain, and improved insulin resistance and glucose tolerance in obese rats.
• Vitamin D decreased hepatic steatosis and downregulated inflammatory markers NF-κB, TNFα, and IL-6 while increasing Nrf2 expression.
• Vitamin D treatment reduced hepatic gluconeogenesis and glycogenolysis, likely through modulation of Nrf2 and related metabolic pathways.

Clinical Significance

Citation

Cordeiro Maiara M, Lucredi Naiara Cristina, Pateis Vanesa Oliveiraet al.. Vitamin D attenuates Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and downregulates hepatic gluconeogenesis in obesity. The Journal of nutritional biochemistry. 2026-Jun-20.