Phosphatidylserine supplementation improves metabolic liver disease and glycaemic control in the presence of suppressed oxidative glucose metabolism

Authors:
  • LDLi Dong
    Li Dong
  • SLSihan Lin
    Sihan Lin
  • JSJohn Slavin
    John Slavin
  • SGSatya Gunnam
    Satya Gunnam
  • ZCZhili Cheng
    Zhili Cheng
  • SNShuai Nie
    Shuai Nie
  • MLMichael G. Leeming
    Michael G. Leeming
  • NWNicholas A. Williamson
    Nicholas A. Williamson
  • MMMagdalene K. Montgomery
    Magdalene K. Montgomery
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Abstract
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 remodelling 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 (WT) mice with hepatic steatosis and MUP-uPA mice with MASH and fibrosis, we show that PS supplementation reduces hepatic triglyceride accumulation, inflammation and fibrosis in male MUP-uPA mice. Supporting these data, PS supplementation suppresses fibrogenic gene expression in LX-2 hepatic stellate cells. We further show that PS supplementation improves glycaemic control and insulin sensitivity in male and female mice, which is associated with enhanced insulin signalling 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 suggests a shift in substrate utilization, favouring 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 glycaemic control.
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