PPARɑ variant V227A reduces plasma triglycerides through enhanced lipoprotein lipolysis

Human single nucleotide variants in peroxisome proliferator-activated receptor-ɑ (PPARɑ) have been associated with beneficial metabolic phenotypes yet their physiologic impact is unclear. Here, we developed a mouse model of a human PPARɑ variant encoding a substitution of valine for alanine at position 227 (V227A) to explore the role of this variant on systemic metabolism. While the variant did not alter body mass or liver lipid accumulation, this variant reduced plasma triglycerides, consistent with human cohort observations. Gene expression analysis revealed that the variant enhances Ppara target gene expression in the liver in a manner consistent with PPARɑ synthetic agonist treatment. The variant increased hepatic transcript expression of Lpl, the predominant enzyme responsible for circulating triglyceride hydrolysis. Further characterization revealed that heart tissue from variant mice exhibited increased Lpl expression and triglyceride hydrolysis activity, indicating that the heart serves as a major mediator of circulating triglyceride clearance. These findings validate human observational studies and clarify the physiological impact of this variant on plasma triglycerides.