PNPLA3 I148M Reduces Hepatic Triacylglycerol Secretion and Mitigates Left Ventricular Diastolic Dysfunction in MASH Diet Mice

Abstract

Cardiovascular disease (CVD) is a leading cause of mortality among individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). Paradoxically, the strongest genetic risk factor for MASLD, PNPLA3-I148M, is associated with a reduced risk of CVD. The mechanisms for how PNPLA3-I148M causes MASLD and preserves cardiac health are not well understood. To further investigate cardioprotective effects of PNPLA3-I148M we expressed human WT-PNPLA3, PNPLA3-I148M or a GFP control in the livers of PNPLA3-/- mice. In agreement with prior investigations, mice expressing PNPLA3-I148M displayed greater hepatic neutral lipid accumulation on chow and a Metabolic Dysfunction-Associated Steatohepatitis (MASH) promoting diet. Changes in hepatosteatosis between the groups was not due to alterations in whole body metabolic parameters, although WT-PNPLA3 promoted greater glucose intolerance on a MASH diet. Echocardiography revealed that hearts from PNPLA3-WT mice had changes in left ventricular mass and thickness following 16-weeks of MASH, but not chow diet, which was not seen in the GFP or PNPLA3-I148M groups. Moreover, PNPLA3-WT and GFP mice had reduced E/A ratios (diastolic function), post MASH diet, which was not detected in PNPLA3-I148M mice. In addition, PNPLA3-I148M reduced hepatic secretion of TAGs under a MASH, but not chow diet. The expression of PNPLA3-I148M modified the liver lipidome, while minimal effects were observed in the heart. No differences in atherosclerotic plaque formation were observed following 24 weeks of MASH diet. These findings indicate that hepatic PNPLA3-I148M promotes hepatosteatosis yet protects against diet induced cardiac remodeling and diastolic dysfunction primarily through reductions in hepatic TAG secretion.