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

Autor: Johnson SM; Department of Biochemistry and Molecular Biology; Mayo Clinic College of Medicine & Science, Rochester, MN, 55905, USA.; Mayo Clinic Graduate School of Biomedical Sciences; Mayo Clinic College of Medicine & Science, Rochester, MN, 55905, USA.; Department of Cell Biology; University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Bao H; Barshop Institute for Longevity and Aging Studies and Department of Medicine, Division of Diabetes; University of Texas Health San Antonio, San Antonio, TX, 78229, USA., McMahon CE; Molecular Biology and Genetics Department; Cornell College of Agriculture and Life Sciences, Ithaca, NY, 14853, USA., Chen Y; Department of Biochemistry and Molecular Biology; Mayo Clinic College of Medicine & Science, Rochester, MN, 55905, USA., Burr SD; Department of Biochemistry and Molecular Biology; Mayo Clinic College of Medicine & Science, Rochester, MN, 55905, USA., Anderson AM; Department of Developmental Biology; Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA., Madeyski-Bengtson K; Translational Genomics, Discovery Sciences; BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Lindén D; Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM); BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.; Division of Endocrinology, Department of Neuroscience and Physiology; Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden., Han X; Barshop Institute for Longevity and Aging Studies and Department of Medicine, Division of Diabetes; University of Texas Health San Antonio, San Antonio, TX, 78229, USA., Liu J; Department of Biochemistry and Molecular Biology; Mayo Clinic College of Medicine & Science, Rochester, MN, 55905, USA. liu.jun@mayo.edu.; Division of Endocrinology, Diabetes, Metabolism and Nutrition; Mayo Clinic in Rochester, Rochester, MN, 55905, USA. liu.jun@mayo.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jun 06; Vol. 15 (1), pp. 4847. Date of Electronic Publication: 2024 Jun 06.
DOI: 10.1038/s41467-024-49224-x
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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