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Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro

Pirazzi, Carlo; Adiels, Martin; Burza, Maria Antonella; Mancina, Rosellina Margherita; Levin, Malin; Stahlman, Marcus; Taskinen, Marja-Riitta; Orho-Melander, Marju LU ; Perman, Jeanna and Pujia, Arturo, et al. (2012) In Journal of Hepatology 57(6). p.1276-1282
Abstract
Background & Aims: The robust association between non-alcoholic fatty liver disease (NAFLD) and the genetic variant I148M (rs738409) in PNPLA3 has been widely replicated. The aim of this study was to investigate the effect of the PNPLA3 I148M mutation on: (1) hepatic secretion of very low density lipoproteins (VLDL) in humans; and (2) secretion of apolipoprotein B (apoB) from McA-RH 7777 cells, which secrete VLDL-sized apoB-containing lipoproteins. Methods: VLDL kinetics was analyzed after a bolus infusion of stable isotopes in 55 overweight/obese men genotyped for the PNPLA3 I148M variant. Intracellular lipid content, apoB secretion and glycerolipid metabolism were studied in McA-RH 7777 cells overexpressing the human 1481 wild type... (More)
Background & Aims: The robust association between non-alcoholic fatty liver disease (NAFLD) and the genetic variant I148M (rs738409) in PNPLA3 has been widely replicated. The aim of this study was to investigate the effect of the PNPLA3 I148M mutation on: (1) hepatic secretion of very low density lipoproteins (VLDL) in humans; and (2) secretion of apolipoprotein B (apoB) from McA-RH 7777 cells, which secrete VLDL-sized apoB-containing lipoproteins. Methods: VLDL kinetics was analyzed after a bolus infusion of stable isotopes in 55 overweight/obese men genotyped for the PNPLA3 I148M variant. Intracellular lipid content, apoB secretion and glycerolipid metabolism were studied in McA-RH 7777 cells overexpressing the human 1481 wild type or 148M mutant PNPLA3 protein. Results: In humans, carriers of the PNPLA3 148M allele had increased liver fat compared to 1481 homozygotes, and kinetic analysis showed a relatively lower secretion of the large, triglyceride-rich VLDL (VLDL1) in 148M carriers vs. 1481 homozygotes for the same amount of liver fat. McA-RH 7777 cells overexpressing the 148M mutant protein showed a higher intracellular triglyceride content with a lower apoB secretion and fatty acid efflux, compared to cells overexpressing the 1481 wild type protein. The responses with 148M matched those observed in cells expressing the empty vector, indicating that the mutation results in loss of function. Conclusions: We have shown that PNPLA3 affects the secretion of apoB-containing lipoproteins both in humans and in vitro and that the 148M protein is a loss-of-function mutation. We propose that PNPLA3 148M promotes intracellular lipid accumulation in the liver by reducing the lipidation of VLDL. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. (Less)
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keywords
Genetic variant, Patatin-like phospholipase domain-containing 3, Liver, fat content, VLDL secretion, Apolipoprotein B, Lipolysis
in
Journal of Hepatology
volume
57
issue
6
pages
1276 - 1282
publisher
Elsevier
external identifiers
  • wos:000311771300018
  • scopus:84869224701
ISSN
0168-8278
DOI
10.1016/jjhep.2012.07.030
language
English
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yes
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69a2097a-56f0-4998-9810-8ae478c1d049 (old id 3372720)
date added to LUP
2013-02-01 07:00:22
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2017-10-22 03:24:45
@article{69a2097a-56f0-4998-9810-8ae478c1d049,
  abstract     = {Background & Aims: The robust association between non-alcoholic fatty liver disease (NAFLD) and the genetic variant I148M (rs738409) in PNPLA3 has been widely replicated. The aim of this study was to investigate the effect of the PNPLA3 I148M mutation on: (1) hepatic secretion of very low density lipoproteins (VLDL) in humans; and (2) secretion of apolipoprotein B (apoB) from McA-RH 7777 cells, which secrete VLDL-sized apoB-containing lipoproteins. Methods: VLDL kinetics was analyzed after a bolus infusion of stable isotopes in 55 overweight/obese men genotyped for the PNPLA3 I148M variant. Intracellular lipid content, apoB secretion and glycerolipid metabolism were studied in McA-RH 7777 cells overexpressing the human 1481 wild type or 148M mutant PNPLA3 protein. Results: In humans, carriers of the PNPLA3 148M allele had increased liver fat compared to 1481 homozygotes, and kinetic analysis showed a relatively lower secretion of the large, triglyceride-rich VLDL (VLDL1) in 148M carriers vs. 1481 homozygotes for the same amount of liver fat. McA-RH 7777 cells overexpressing the 148M mutant protein showed a higher intracellular triglyceride content with a lower apoB secretion and fatty acid efflux, compared to cells overexpressing the 1481 wild type protein. The responses with 148M matched those observed in cells expressing the empty vector, indicating that the mutation results in loss of function. Conclusions: We have shown that PNPLA3 affects the secretion of apoB-containing lipoproteins both in humans and in vitro and that the 148M protein is a loss-of-function mutation. We propose that PNPLA3 148M promotes intracellular lipid accumulation in the liver by reducing the lipidation of VLDL. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.},
  author       = {Pirazzi, Carlo and Adiels, Martin and Burza, Maria Antonella and Mancina, Rosellina Margherita and Levin, Malin and Stahlman, Marcus and Taskinen, Marja-Riitta and Orho-Melander, Marju and Perman, Jeanna and Pujia, Arturo and Andersson, Linda and Maglio, Cristina and Montalcini, Tiziana and Wiklund, Olov and Boren, Jan and Romeo, Stefano},
  issn         = {0168-8278},
  keyword      = {Genetic variant,Patatin-like phospholipase domain-containing 3,Liver,fat content,VLDL secretion,Apolipoprotein B,Lipolysis},
  language     = {eng},
  number       = {6},
  pages        = {1276--1282},
  publisher    = {Elsevier},
  series       = {Journal of Hepatology},
  title        = {Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro},
  url          = {http://dx.doi.org/10.1016/jjhep.2012.07.030},
  volume       = {57},
  year         = {2012},
}