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

Area of Science:

• Hepatology
• Cardiology
• Genetics

Background:

• PNPLA3-I148M is a major genetic risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD).
• Paradoxically, this variant is associated with reduced cardiovascular disease (CVD) risk, but the underlying mechanisms remain unclear.

Purpose of the Study:

• To investigate how PNPLA3-I148M affects hepatic triacylglycerol (TAG) metabolism.
• To determine the influence of PNPLA3-I148M on cardiac function, particularly during diet-induced liver stress.

Main Methods:

• Human WT-PNPLA3, PNPLA3-I148M, or GFP were expressed in the liver of PNPLA3-/- mice.
• Mice were fed either a standard chow or a Metabolic Dysfunction-Associated Steatohepatitis (MASH) diet at thermoneutrality for 4 or 16 weeks.
• Hepatic TAG metabolism, cardiac function (left ventricular mass, E/A ratios), and lipidome were analyzed.

Main Results:

• PNPLA3-I148M expression reduced hepatic TAG secretion under MASH diet conditions.
• WT-PNPLA3 mice showed cardiac dysfunction (increased left ventricular mass, reduced E/A ratios) after 16 weeks on MASH diet, while PNPLA3-I148M mice were protected.
• PNPLA3-I148M altered hepatic and plasma lipid profiles but had minimal impact on cardiac lipids or atherosclerosis.

Conclusions:

• PNPLA3-I148M impairs hepatic TAG efflux.
• This impaired TAG efflux may protect left ventricular diastolic function during diet-induced steatotic stress.
• The findings elucidate a potential mechanism linking fatty liver genetics to cardiovascular protection.