Type 2 diabetes and obesity are commonly accompanied by metabolic dysfunction–associated steatotic liver disease (MASLD), increasing the risk of developing metabolic dysfunction–associated steatohepatitis (MASH) and fibrosis. The early stages of MASLD are characterized by dysfunctional lipid metabolism, including remodeling of the hepatic lipidome. In this context, reductions in hepatic phosphatidylserine (PS) have been associated with increased hepatic steatosis, inflammation, and fibrosis. In this study, we investigated the impact of dietary PS supplementation on liver function and systemic metabolic homeostasis in mice with hepatic steatosis and MASH. Taking advantage of the MUP-uPA mouse model, including wild-type mice with hepatic steatosis and MUP-uPA mice with MASH and fibrosis, we showed that PS supplementation reduces hepatic triglyceride accumulation, inflammation, and fibrosis in male MUP-uPA mice. Supporting these data, PS supplementation suppressed fibrogenic gene expression in LX-2 hepatic stellate cells. We further showed that PS supplementation improved glycemic control and insulin sensitivity in male and female mice, which was associated with enhanced insulin signaling in muscle and liver, despite a pronounced suppression of glycolysis, glucose oxidation, and glycogen breakdown in liver, muscle, and/or adipose tissue. Metabolic flux analysis suggested a shift in substrate use, favoring fatty acid metabolism, particularly in muscle, while further pointing to marked improvements in mitochondrial function and oxidative capacity. These findings indicate that PS exerts multifaceted benefits by improving both MASH and whole-body glucose homeostasis, independent of conventional oxidative glucose metabolism. Our results support further investigation into dietary PS as a potential complementary strategy for MASH and glycemic control. Article Highlights The prevalence of metabolic dysfunction–associated steatohepatitis (MASH) and type 2 diabetes is increasing. We show that dietary phosphatidylserine (PS) supplementation reduces hepatic lipid accumulation, inflammation, and liver fibrosis, while further improving blood glucose control and insulin sensitivity in mice with MASH and insulin resistance. Improvements in glycemic control are present despite suppression of glycolysis, glucose oxidation, and glycogen breakdown in liver, skeletal muscle, and/or adipose tissue. In contrast, oxidative lipid metabolism and overall mitochondrial function are enhanced in skeletal muscle.
Lin et al. (2025) studied this question.