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The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans

Luukkonen, Panu K. ; Porthan, Kimmo ; Ahlholm, Noora ; Rosqvist, Fredrik ; Dufour, Sylvie ; Zhang, Xian Man ; Lehtimäki, Tiina E. ; Seppänen, Wenla ; Orho-Melander, Marju LU and Hodson, Leanne , et al. (2023) In Cell Metabolism 35(11). p.5-1896
Abstract

The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty acids were channeled toward ketogenesis in carriers, which was associated with an increase in hepatic mitochondrial redox state. During a ketogenic diet, carriers manifested increased rates of intrahepatic lipolysis, increased... (More)

The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty acids were channeled toward ketogenesis in carriers, which was associated with an increase in hepatic mitochondrial redox state. During a ketogenic diet, carriers manifested increased rates of intrahepatic lipolysis, increased plasma β-hydroxybutyrate concentrations, and decreased rates of hepatic mitochondrial citrate synthase flux. These studies demonstrate that homozygous PNPLA3 I148M carriers have hepatic mitochondrial dysfunction leading to reduced DNL and channeling of carbons to ketogenesis. These findings have implications for understanding why the PNPLA3 variant predisposes to progressive liver disease.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
GDF-15, ketogenic diet, mitochondrial dysfunction, NAD+, NADH, NAFLD, NASH, patatin-like phospholipase domain containing protein 3, redox, reductive stress
in
Cell Metabolism
volume
35
issue
11
pages
5 - 1896
publisher
Cell Press
external identifiers
  • pmid:37909034
  • scopus:85175563210
ISSN
1550-4131
DOI
10.1016/j.cmet.2023.10.008
language
English
LU publication?
yes
id
95b1d0a2-c837-4af4-ad42-92fb48bad9ec
date added to LUP
2023-11-24 14:35:23
date last changed
2024-04-21 18:29:19
@article{95b1d0a2-c837-4af4-ad42-92fb48bad9ec,
  abstract     = {{<p>The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty acids were channeled toward ketogenesis in carriers, which was associated with an increase in hepatic mitochondrial redox state. During a ketogenic diet, carriers manifested increased rates of intrahepatic lipolysis, increased plasma β-hydroxybutyrate concentrations, and decreased rates of hepatic mitochondrial citrate synthase flux. These studies demonstrate that homozygous PNPLA3 I148M carriers have hepatic mitochondrial dysfunction leading to reduced DNL and channeling of carbons to ketogenesis. These findings have implications for understanding why the PNPLA3 variant predisposes to progressive liver disease.</p>}},
  author       = {{Luukkonen, Panu K. and Porthan, Kimmo and Ahlholm, Noora and Rosqvist, Fredrik and Dufour, Sylvie and Zhang, Xian Man and Lehtimäki, Tiina E. and Seppänen, Wenla and Orho-Melander, Marju and Hodson, Leanne and Petersen, Kitt Falk and Shulman, Gerald I. and Yki-Järvinen, Hannele}},
  issn         = {{1550-4131}},
  keywords     = {{GDF-15; ketogenic diet; mitochondrial dysfunction; NAD+; NADH; NAFLD; NASH; patatin-like phospholipase domain containing protein 3; redox; reductive stress}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{5--1896}},
  publisher    = {{Cell Press}},
  series       = {{Cell Metabolism}},
  title        = {{The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans}},
  url          = {{http://dx.doi.org/10.1016/j.cmet.2023.10.008}},
  doi          = {{10.1016/j.cmet.2023.10.008}},
  volume       = {{35}},
  year         = {{2023}},
}