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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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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 1

Overview of the early development of NAFLD and progression to NASH in offspring of overnourished mothers.

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Overview of the early development of NAFLD and progression to NASH in of...
Based on nonhuman primate and limited human data, offspring exposed to overnutrition in utero have increased hepatic lipid storage and de novo lipogenesis, coupled with incomplete β-oxidation and diminished electron transport chain (ETC) activity, leading to accumulation of long-chain acylcarnitines (LCACs) and diminished ATP production. Anaplerosis through branched-chain amino acid (BCAA) catabolism compensates for limitations in TCA cycle intermediates. This fuel overload and excess in lipid result in production of ROS. Damage is mitigated by glutathione (GSH) and upregulation of SIRT1 (SRT). Hepatic apoptosis is minimal (but existing). As time progresses and damage, inflammation, and lipid accumulation worsen, mitochondria develop structural abnormalities and diminish in content and activity. This is exacerbated by diet and the microbiome. β-Oxidative function and ETC activity worsen. Intramitochondrial lipid and acylcarnitine accumulation leads to increased ROS and reactive nitrogen species (RNS) production. Glycogen and smooth ER accumulate. BCAA catabolism is less efficient and is unable to supplement the TCA cycle, and GSH is no longer able to dampen oxidative damage. Inflammation due to infiltration and activation of immune cells and apoptosis worsen, leading to liver injury and fibrosis. FA, fatty acid; TG, triglyceride.
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