PNPLA3 is a triglyceride lipase that mobilizes polyunsaturated fatty acids to facilitate hepatic secretion of large-sized very low-density lipoprotein

Scott M. Johnson, Hanmei Bao, Cailin E. McMahon, Yongbin Chen, Stephanie D. Burr, Aaron M. Anderson, Katja Madeyski-Bengtson, Daniel Lindén, Xianlin Han and Jun Liu ()
Additional contact information
Scott M. Johnson: Department of Biochemistry and Molecular Biology; Mayo Clinic College of Medicine & Science
Hanmei Bao: Division of Diabetes; University of Texas Health San Antonio
Cailin E. McMahon: Molecular Biology and Genetics Department; Cornell College of Agriculture and Life Sciences
Yongbin Chen: Department of Biochemistry and Molecular Biology; Mayo Clinic College of Medicine & Science
Stephanie D. Burr: Department of Biochemistry and Molecular Biology; Mayo Clinic College of Medicine & Science
Aaron M. Anderson: Department of Developmental Biology; Washington University School of Medicine in St. Louis
Katja Madeyski-Bengtson: AstraZeneca
Daniel Lindén: AstraZeneca
Xianlin Han: Division of Diabetes; University of Texas Health San Antonio
Jun Liu: Department of Biochemistry and Molecular Biology; Mayo Clinic College of Medicine & Science

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract The I148M variant of PNPLA3 is closely associated with hepatic steatosis. Recent evidence indicates that the I148M mutant functions as an inhibitor of PNPLA2/ATGL-mediated lipolysis, leaving the role of wild-type PNPLA3 undefined. Despite showing a triglyceride hydrolase activity in vitro, PNPLA3 has yet to be established as a lipase in vivo. Here, we show that PNPLA3 preferentially hydrolyzes polyunsaturated triglycerides, mobilizing polyunsaturated fatty acids for phospholipid desaturation and enhancing hepatic secretion of triglyceride-rich lipoproteins. Under lipogenic conditions, mice with liver-specific knockout or acute knockdown of PNPLA3 exhibit aggravated liver steatosis and reduced plasma VLDL-triglyceride levels. Similarly, I148M-knockin mice show decreased hepatic triglyceride secretion during lipogenic stimulation. Our results highlight a specific context whereby the wild-type PNPLA3 facilitates the balance between hepatic triglyceride storage and secretion, and suggest the potential contribution of a loss-of-function by the I148M variant to the development of fatty liver disease in humans.

Date: 2024
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-49224-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49224-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-49224-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().