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Mitochondrial role in the neonatal predisposition to developing nonalcoholic fatty liver disease
Peter R. Baker II, Jacob E. Friedman
Peter R. Baker II, Jacob E. Friedman
Published August 31, 2018
Citation Information: J Clin Invest. 2018;128(9):3692-3703. https://doi.org/10.1172/JCI120846.
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Category: Review Series

Mitochondrial role in the neonatal predisposition to developing nonalcoholic fatty liver disease

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is a global epidemic in obese children and adults, and the onset might have fetal origins. A growing body of evidence supports the role of developmental programming, whereby the maternal environment affects fetal and infant development, altering the risk profile for disease later in life. Human and nonhuman primate studies of maternal obesity demonstrate that risk factors for pediatric obesity and NAFLD begin in utero. The pathologic mechanisms for NAFLD are multifactorial but have centered on altered mitochondrial function/dysfunction that might precede insulin resistance. Compared with the adult liver, the fetal liver has fewer mitochondria, low activity of the fatty acid metabolic enzyme carnitine palmitoyl-CoA transferase-1, and little or no gluconeogenesis. Exposure to excess maternal fuels during fetal life uniquely alters hepatic fatty acid oxidation, tricarboxylic acid cycle activity, de novo lipogenesis, and mitochondrial health. These events promote increased oxidative stress and excess triglyceride storage, and, together with altered immune function and epigenetic changes, they prime the fetal liver for NAFLD and might drive the risk for nonalcoholic steatohepatitis in the next generation.

Authors

Peter R. Baker II, Jacob E. Friedman

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Figure 2

Evidence of fetal programming in human mesenchymal stem cells.

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Evidence of fetal programming in human mesenchymal stem cells.
Human mes...
Human mesenchymal stem cells (MSCs), progenitors to hepatic stellate cells (HSCs), demonstrate evidence of fetal programming in relation to maternal obesity, maternal circulating lipids, and neonatal adiposity and adiposity gain over time. These cells have exhibited lipid transport and accumulation, incomplete β-oxidation, increased anaplerosis, and diminished ETC activity. Oxidative stress is coupled with increased GSH metabolism, and gene expression indicates alterations in nutrient sensing along with increased apoptotic and inflammatory signaling. OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane; CACT, carnitine-acylcarnitine translocase; DCAC, dicarboxylic acylcarnitines.
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