Biology subjects

Butcko, A. J.

Publications and source records attributed to Butcko, A. J..

2 recordsLinked to original sources

bioRxiv2025

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

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.

physiology↗

bioRxiv2024

Lipid Droplet Targeting of ABHD5 and PNPLA3 I148M is required to promote liver steatosis

The storage and release of triacylglycerol (TAG) in lipid droplets (LDs) is regulated by dynamic protein interactions. /{beta} hydrolase domain-containing protein 5 (ABHD5; also known as CGI-58) is a membrane/LD bound protein that functions as a co-activator of Patatin Like Phospholipase Domain Containing 2 (PNPLA2; also known as Adipose triglyceride lipase, ATGL) the rate-limiting enzyme for TAG hydrolysis. The dysregulation of TAG hydrolysis is involved in various metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD). We previously demonstrated that ABHD5 interacted with PNPLA3, a closely related family member to PNPLA2. Importantly, a common missense variant in PNPLA3 (I148M) is the greatest genetic risk factor for MASLD. PNPLA3 148M functions to sequester ABHD5 and prevent co-activation of PNPLA2, which has implications for initiating MASLD; however, the exact mechanisms involved are not understood. Here we demonstrate that LD targeting of both ABHD5 and PNPLA3 I148M is required for the interaction. Molecular modeling demonstrates important resides in the C-terminus of PNPLA3 for LD binding and fluorescence cross-correlation spectroscopy demonstrates that PNPLA3 I148M greater associates with ABHD5 than WT PNPLA3. Moreover, the C-terminus of PNPLA3 is sufficient for functional targeting of PNPLAs to LD and the interaction with ABHD5. In addition, ABHD5 is a general binding partner of LD-bound PNPLAs. Finally, PNPLA3 I148M targeting to LD is required to promote steatosis in vitro and in the liver. Overall results suggest that PNPLA3 I148M is a gain of function mutation and that the interaction with ABHD5 on LD is required to promote liver steatosis.

cell biology↗