PNPLA3-I148M reduces hepatic triacylglycerol secretion and mitigates diet induced left ventricular diastolic dysfunction

PNPLA3-I148M, the greatest genetic determinant for metabolic dysfunction-associated steatotic liver disease (MASLD), paradoxically associates with reduced cardiovascular disease (CVD); however, the mechanisms are poorly understood. To investigate how PNPLA3-I148M alters hepatic triacylglycerol (TAG) metabolism and influences cardiac function, we expressed human WT-PNPLA3, PNPLA3-I148M, or GFP in the liver of PNPLA3-/- mice and fed them chow or Metabolic Dysfunction-Associated Steatohepatitis (MASH) diet at thermoneutrality. After 4 weeks of MASH diet, PNPLA3‑I148M mice showed reduced hepatic TAG secretion, an effect not observed on chow. Following β3‑adrenergic stimulation to enhance adipose‑derived fatty acid flux, chow‑fed PNPLA3‑I148M mice exhibited additional reductions in TAG secretion and increased hepatosteatosis. After 16 weeks of MASH diet, WT‑PNPLA3 mice developed increased left ventricular mass and reduced E/A ratios, whereas PNPLA3‑I148M mice were protected from both outcomes. No differences in left ventricular function were observed in mice under 16 weeks of chow diet. PNPLA3‑I148M also reshaped the hepatic and plasma lipidome, with minimal effects on cardiac lipids, and did not alter atherosclerotic plaque formation under MASH diet conditions. These findings indicate that PNPLA3-I148M impairs hepatic TAG efflux, which may preserve left ventricular diastolic function during diet-induced steatotic stress.