PNPLA3 variant M148 causes resistance to starvation-mediated lipid droplet autophagy in human hepatocytes

Journal of Cellular Biochemistry
Florentina NegoitaHelena A Jones

Abstract

The mechanism of how patatin-like phospholipase domain-containing protein 3 (PNPLA3) variant M148 is associated with increased risk of development of hepatic steatosis is still debated. Here, we propose a novel role of PNPLA3 as a key player during autophagosome formation in the process of lipophagy. A human hepatocyte cell line, HepG2 cells, expressing recombinant I148 or 148M, was used to study lipophagy under energy deprived conditions, and lipid droplet morphology was investigated using florescence microscopy, image analysis and biochemical assays. Autophagic flux was studied using the golden-standard of LC3-II turnover in combination with the well characterized GFP-RFP-LC3 vector. To discriminate between, perturbed autophagic initiation and lysosome functionality, lysosomes were characterized by Lysotracker staining and LAMP1 protein levels as well as activity and activation of cathepsin B. For validation, human liver biopsies genotyped for I148 and 148M were analyzed for the presence of LC3-II and PNPLA3 on lipid droplets. We show that the M148-PNPLA3 variant is associated with lipid droplets that are resistant to starvation-mediated degradation. M148 expressing hepatocytes reveal decreased autophagic flux and reduced lip...Continue Reading

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Citations

Aug 6, 2019·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Linshan Shang, Douglas G Mashek
Feb 12, 2020·Liver International : Official Journal of the International Association for the Study of the Liver·Francesca V BruschiMichael Trauner
Feb 8, 2020·Journal of Lipid Research·Sookyoung Jeon, Rotonya Carr
Mar 15, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Silvia SookoianNicholas O Davidson
Apr 26, 2019·Proceedings of the National Academy of Sciences of the United States of America·Soumik BasuRayHelen H Hobbs
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Sep 26, 2019·Frontiers in Cell and Developmental Biology·Konstantinos KounakisNektarios Tavernarakis
Apr 5, 2020·International Journal of Molecular Sciences·Rohit A SinhaPaul M Yen
May 1, 2021·International Journal of Molecular Sciences·Siarhei A DabravolskiAlexander N Orekhov
Jan 1, 2020·Contact·Kristina Drizyte-MillerMark A McNiven
Nov 21, 2021·Nature Metabolism·Gernot F GrabnerRudolf Zechner

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