Developmental programming of NAFLD.pdf (98.6 kB)

Potential mechanisms in developmental programming of NAFLD

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posted on 29.03.2015 by Minglan Li

Please cite the original paper.

Published in the following review article:

Minglan Li, Clare M. Reynolds, Stephanie A. Segovia, Clint Gray, and Mark H. Vickers, “Developmental Programming of Nonalcoholic Fatty Liver Disease: The Effect of Early Life Nutrition on Susceptibility and Disease Severity in Later Life,” BioMed Research International, Article ID 437107, in press.

(1) Maternal obesity and high fat diet induced mitochondrial dysfunction may be programmed in the fetus; (2) maternal circulating lipids are shuttled to the fetal liver contributing to mitochondrial oxidative stress; this is characterised by reduced MRC activity, overproduction of ROS, and mitochondrial DNA damage. Increased concentrations of TAG and FFA contribute to ER stress which can induce additional oxidative stress, increase de novo lipogenesis, and activate inflammatory responses via JNK/NF-κB pathway. Lipid toxicity can active inflammation via TLR4 signalling pathway in both Kupffer cells and hepatocytes, where the former is a major source of proinflammatory cytokines including TNFα, IL1β, and IL6. Chronic low-level hepatic NF-κB activation further contributes to local and systemic insulin resistance, which in turn influences de novo lipogenesis. (3) Maternal undernutrition can reduce 11-β-hydroxysteroid dehydrogenase (11-β-HSD) in the placenta and therefore increase fetal exposure to maternal glucocorticoids. Increased glucocorticoids can lead to fetal de novolipogenesis. Markers that indicate ER stress and de novo lipogenesis can be modified by early life epigenetic mechanism which may represent a path for intergenerational transmission of disease risk. MRC: mitochondrial respiratory chain; ROS: reactive oxygen species; TAG: triglyceride; FFA: free fatty acid; ER: endoplasmic reticulum; SREBP: sterol regulatory element binding protein; JNK: c-Jun N-terminal kinase; IKK: IκB kinase; NF-κB: nuclear factor kappaB; AP-1: activator protein 1; TLR4: Toll-like receptor 4; LXRα: Liver X receptor-α; PPARs peroxisome proliferator-activated receptors; ChREBP: carbohydrate-responsive element-binding protein; FASN: fatty acid synthase; SCD1: stearoyl-CoA desaturase-1; ACC1: acetyl-CoA carboxylase; 11-β-HSD: 11-β-hydroxysteroid dehydrogenase.