PNPLA3, CGI-58, and Inhibition of Hepatic Triglyceride Hydrolysis in Mice

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Yang WangHelen H Hobbs

Abstract

A variant (148M) in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is a major risk factor for fatty liver disease. Despite its clinical importance, the pathogenic mechanism linking the variant to liver disease remains poorly defined. Previously, we showed that PNPLA3(148M) accumulates to high levels on hepatic lipid droplets (LDs). Here we examined the effect of that accumulation on triglyceride (TG) hydrolysis by adipose triglyceride lipase (ATGL), the major lipase in the liver. As expected, overexpression of ATGL in cultured hepatoma (HuH-7) cells depleted the cells of LDs, but unexpectedly, co-expression of PNPLA3(wild type [WT] or 148M) with ATGL inhibited that depletion. The inhibitory effect of PNPLA3 was not caused by the displacement of ATGL from LDs. We tested the hypothesis that PNPLA3 interferes with ATGL activity by interacting with its cofactor, comparative gene identification-58 (CGI-58). Evidence supporting such an interaction came from two findings. First, co-expression of PNPLA3 and CGI-58 resulted in LD depletion in cultured cells, but expression of PNPLA3 alone did not. Second, PNPLA3 failed to localize to hepatic LDs in liver-specific Cgi-58 knockout (KO) mice. Moreover, overexpression of PN...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
Nov 11, 2019·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Aynur Unalp-Arida, Constance E Ruhl
Mar 14, 2020·The Biochemical Journal·Alexander Yang, Emilio P Mottillo
Mar 4, 2020·Liver International : Official Journal of the International Association for the Study of the Liver·Alessandro MantovaniGiovanni Targher
Apr 29, 2020·Liver International : Official Journal of the International Association for the Study of the Liver·Yuya SekoYoshito Itoh
Jul 12, 2020·The Journal of Nutrition·Michelle A Van NameNicola Santoro
Mar 15, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Silvia SookoianNicholas O Davidson
Aug 20, 2020·American Journal of Physiology. Gastrointestinal and Liver Physiology·Simone CarottiUmberto Vespasiani-Gentilucci
Apr 3, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Matteo TardelliMichael Trauner
Mar 20, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Helene Gellert-KristensenStefan Stender
Apr 26, 2019·Proceedings of the National Academy of Sciences of the United States of America·Soumik BasuRayHelen H Hobbs
Sep 14, 2019·Liver International : Official Journal of the International Association for the Study of the Liver·Dan-Qin SunMing-Hua Zheng
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Feb 18, 2021·Infection and Immunity·Zhixin WanJinfeng Miao
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May 1, 2021·International Journal of Molecular Sciences·Miriam LongoPaola Dongiovanni
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Aug 20, 2021·Journal of Internal Medicine·Jan BorénMarja-Riitta Taskinen
Nov 21, 2021·Nature Metabolism·Gernot F GrabnerRudolf Zechner

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Methods Mentioned

BETA
Transfection
FCS
light microscopy
confocal microscopy
Immunoprecipitation
fluorescence microscopy
transgenic
PCR

Software Mentioned

GraphPad Prism
GraphPad
ImageJ

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