PNPLA3 I148M Promotes Fatty Liver Disease While Preserving Cardiac Health

Metabolic-associated fatty liver disease (MAFLD) and cardiovascular disease (CVD) are commonly associated comorbidities. A common genetic variant in the PNPLA3 gene, rs738409 (I148M), is the greatest genetic risk factor for development and progression of MAFLD; however, MAFLD patients expressing PNPLA3 I148M display modest protection against coronary artery disease (CAD) and adverse cardiovascular events relative to wildtype carriers. Currently, the exact mechanisms by which PNPLA3 I148M causes MAFLD and preserves cardiac health are not well understood. Previous work suggests that the variant increases susceptibility to fatty liver disease by altering hepatic lipid metabolism, which may explain a potential mechanism for its cardioprotective effects. In order to investigate how PNPLA3 I148M might increase susceptibility to MAFLD while reducing risk of CVD we expressed either human wildtype (WT) PNPLA3 or PNPLA3 I148M as well as a GFP control specifically in the livers of PNPLA3 knockout mice. Our data demonstrate that hepatic expression of PNPLA3 I148M reduces secretion of VLDL TAGs from adipose tissue derived fatty acids. In agreement with prior investigations, mice expressing PNPLA3 I148M and fed a chow diet demonstrated significant increases in hepatic accumulation of neutral lipids (triglycerides & cholesterol esters) relative to WT and GFP expressing mice. Similarly, when fed a fatty liver promoting diet (D009100310) high in fructose, cholesterol, and saturated fats there remained a strong trend for greater liver to body weight ratios and hepatic TAGs in mice expressing the variant when compared to WT expressing mice (p=0.052 and p=0.071 respectively). Changes in hepatic lipid accumulation were not due to any alterations in insulin sensitivity, daily food consumption, energy expenditure or oxygen consumption between WT and I148M groups. Echocardiography revealed that hearts of mice expressing WT PNPLA3 had increases in left ventricular thickness (p=0.051) and left ventricle weights following dietary treatment that was not apparent in the I148M expressing mice. Moreover, there was a reduction in E/A ratios, a sensitive measure of diastolic functioning, in GFP and WT expressing mice post-treatment, that was not seen in the I148M mice. Overall, these findings indicate that PNPLA3 I148M promotes fatty liver, yet protects against diet-induced effects on ventricular remodeling and diastolic functioning. Our next steps will be to assess measures of atherosclerotic plaque formation around major blood vessels and investigate the metabolic pathways altered by PNPLA3 I148M. NIH R00 DK114471 NIH R01 DK126743 USDA grant no. 2021-09425 Pilot feasibility grant from University of Michigan: P30DK020572 Detroit Cardiovascular Training grant NIH 2T32HL120822. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.