Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro
Artikel i vetenskaplig tidskrift, 2012

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.

Patatin-like phospholipase domain-containing 3

cell-line

adiponutrin

VLDL secretion

Genetic variant

fatty liver-disease

triacylglycerol

low-density lipoprotein

obese subjects

Liver fat content

b-containing lipoproteins

apolipoprotein-b

triglyceride hydrolysis

hypobetalipoproteinemia

Författare

Carlo Pirazzi

Göteborgs universitet

Martin Adiels

Göteborgs universitet

Chalmers, Matematiska vetenskaper

Maria A Burza

Göteborgs universitet

Rosellina Margherita Mancina

Göteborgs universitet

Max Levin

Göteborgs universitet

Marcus Ståhlman

Göteborgs universitet

M. R. Taskinen

M. Orho-Melander

Jeanna Perman

Göteborgs universitet

A. Pujia

Linda Andersson

Göteborgs universitet

Cristina Maglio

Göteborgs universitet

T. Montalcini

Olov Wiklund

Göteborgs universitet

Jan Borén

Göteborgs universitet

Stefano Romeo

Göteborgs universitet

Journal of Hepatology

0168-8278 (ISSN) 1600-0641 (eISSN)

Vol. 57 6 1276-1282

Ämneskategorier

Kardiologi

DOI

10.1016/j.jhep.2012.07.030

Mer information

Skapat

2017-10-06