Lipid droplet targeting of the lipase coactivator ABHD5 and the fatty liver disease-causing variant PNPLA3 I148M is required to promote liver steatosis

Authors

Grace Teskey, Henry Ford HealthFollow
Nivedita Tiwari, Henry Ford HealthFollow
Andrew J. Butcko, Henry Ford HealthFollow
Amit Kumar
Anuradha Yadav
Yu-Ming M Huang
Christopher V Kelly
James G Granneman
James W Perfield
Emilio P. Mottillo, Henry Ford HealthFollow

Recommended Citation

Teskey G, Tiwari N, Butcko AJ, Kumar A, Yadav A, Huang YM, Kelly CV, Granneman JG, Perfield JW, and Mottillo EP. Lipid droplet targeting of the lipase co-activator ABHD5 and the fatty liver disease-causing variant PNPLA3 I148M is required to promote liver steatosis. J Biol Chem 2025; 108186.

Document Type

Article

Publication Date

1-13-2025

Publication Title

The Journal of biological chemistry

Abstract

The storage and release of triacylglycerol (TAG) in lipid droplets (LDs) is regulated by dynamic protein interactions. α/β 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) 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 coactivation 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 residues in the C terminus of PNPLA3 for LD binding and fluorescence cross-correlation spectroscopy demonstrates that PNPLA3 I148M has greater association 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 the interaction of PNPLA3 I148M with ABHD5 on LD is required to promote liver steatosis.

PubMed ID

39814233

ePublication

ePub ahead of print

Volume

301

Issue

2

First Page

108186

Last Page

108186