Lipidome profiling in advanced metabolic liver disease identifies phosphatidylserine synthase 1 as a regulator of hepatic lipoprotein metabolism.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by defective lipid metabolism, which causes disease progression. MASH is also linked to various cardiometabolic risk factors, including obesity and type 2 diabetes. The contribution of defective lipid metabolism in MASH to cardiometabolic comorbidities is incompletely understood. Using hepatic lipidome profiling in eight mouse strains that differ in MASH susceptibility and patients with MASH, we show that phosphatidylserine (PS) accumulation and preservation of PS synthase 1 (PSS1) expression is associated with resistance to MASH and hypertriglyceridemia. Mechanistically, hepatocyte-specific PSS1 overexpression remodels the hepatic and very-low-density lipoprotein (VLDL) lipidome in mice with MASH. Specifically, we show an increase in VLDL ceramide that suppresses the expression and activity of lipoprotein lipase in skeletal muscle, thereby reducing VLDL-triglyceride clearance, fatty acid uptake, and lipid accumulation in muscle, overall exacerbating hypertriglyceridemia. Together, the results of this study identify hepatic PSS1 as a regulator of systemic lipoprotein metabolism.