Exercise combined with dietary switch improves MASLD by suppressing hepatic MOGAT1 and modulating metabolic stress pathways in HFD-fed mice.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive liver disorder that can lead to irreversible hepatic damage when chronic inflammation and fibrosis develop. Exercise and dietary switch have been suggested as effective strategies for improving MASLD. However, their effects in severe MASLD induced by long-term obesity remain unclear. Therefore, this study investigated the combined effects of exercise and dietary switch in a mouse model of severe MASLD induced by long-term high-fat diet feeding. The combined intervention significantly reduced body weight and improved glucose tolerance compared with either intervention alone. In addition, exercise combined with a dietary switch was associated with reduced expression of lipogenesis-related proteins, including monoacylglycerol O-acyltransferase 1. The intervention was also accompanied by alterations in proteins related to mitochondrial regulation, antioxidant defense, and autophagy. Histological analysis further demonstrated improvements in hepatic steatosis and MASLD activity scores. In mice with severe MASLD, the combination of exercise and dietary switch was more effective than either intervention alone in improving hepatic lipid accumulation and molecular markers associated with MASLD.NEW & NOTEWORTHY In severe metabolic dysfunction-associated steatotic liver disease (MASLD) induced by long-term obesity, exercise or dietary switch alone had limited effects on hepatic steatosis. However, the combination of exercise and dietary switch significantly improved MASLD and was associated with reduced hepatic monoacylglycerol O-acyltransferase 1 expression and alterations in mitochondrial-, antioxidant-, and autophagy-related proteins. These findings highlight the importance of combined lifestyle interventions in advanced MASLD.