Maternal Hypoxia Increases the Susceptibility of Adult Rat Male Offspring to High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease

Abstract

Exposure to an adverse intrauterine environment increases the risk for adult metabolic syndrome. However, the influence of prenatal hypoxia on the risk of fatty liver disease in offspring is unclear. The purpose of the present study was to evaluate the role of reduced fetal oxygen on the development and severity of high-fat (HF) diet-induced nonalcoholic fatty liver disease (NAFLD). Based on design implicating 2 factors, ie, maternal hypoxia (MH) and postnatal HF diet, blood lipid and insulin levels, hepatic histology, and potential molecular targets were evaluated in male Sprague Dawley rat offspring. MH associated with postnatal HF diet caused a significant increase in plasma concentration of triglycerides, free fatty acids, low-density lipoprotein cholesterol, and insulin. Histologically, a more severe form of NAFLD with hepatic inflammation, hepatic resident macrophage infiltration, and progression toward nonalcoholic steatohepatitis was observed. The lipid homeostasis changes and insulin resistance caused by MH plus HF were accompanied by a significant down-regulation of insulin receptor substrate 2 (IRS-2), phosphoinositide-3 kinase p110 catalytic subunit, and protein kinase B. In MH rats, insulin-stimulated IRS-2 and protein kinase B (AKT) phosphorylation were significantly blunted as well as insulin suppression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Meanwhile, a significant up-regulation of lipogenic pathways was noticed, including sterol-regulatory element-binding protein-1 and fatty acid synthase in liver. Our results indicate that maternal hypoxia enhances dysmetabolic liver injury in response to an HF diet. Therefore, the offspring born in the context of maternal hypoxia may require special attention and follow-up to prevent the early development of NAFLD.

Prenatal hypoxia plus postnatal high‐fat diet exacerbated vascular dysfunction via up‐regulated vascular Cav1.2 channels in offspring rats

“…Through the catch-up growth, the prenatal hypoxia offspring had comparable weights to controls after 1 month old. Consistent with previous reports, 22,23 the present study showed that more weight gain was found in the HF-exposed offspring, which might be due to significantly increased caloric intake. In addition, the offspring with both prenatal hypoxia and postnatal hyper-caloric HF diets showed much higher triacylglycerol, cholesterol, low-density lipoprotein-cholesterol, and free fatty acids in circulation, suggesting that the synergistic effects of prenatal hypoxia and postnatal HF diet were associated with an early onset of dyslipidemia in this model.…”

Combination of intrauterine growth restriction and a high-fat diet impairs cholesterol elimination in rats

“…Furthermore, HFD feeding alone increased markers of hepatic injury, as seen with oil red o staining and enzyme markers of hepatic injury in our study, with no difference between IUGR-HFD and Con-HFD. Similarly, maternal hypoxia increased fatty liver in HFD fed mice (15). HFD feeding alone decreased proteins involved in de novo cholesterol synthesis, LDL-C uptake from blood, and export of HDL-C and VLD-C export to the blood.…”

The effect of periconceptional alcohol exposure on renal and cardiovascular development and function

“…Diets high in salt and sugar are common in western communities as are diets high in fat. Increased incidence of fatty liver (Su et al, 2013;Gardebjer et al, 2017), cardiovascular pathology (Rueda-Clausen et al, 2012), adrenal sensitivity (He et al, 2017) and metabolic syndrome (Rueda-Clausen et al, 2011) have all been demonstrated with a prenatal perturbation in combination with a postnatal diet high in fat.…”

“…Following maternal hypoxia of 10±1% oxygen from day 7 of pregnancy, rat offspring fed a high fat diet had increased plasma triglycerides, altered response to a glucose tolerance test and more severe non-alcoholic fatty liver disease (Su et al, 2013).…”