Developmental origins of nonalcoholic fatty liver disease

Abstract

Obese pregnant women may transmit their metabolic phenotype to offspring, leading to a cycle of obesity and diabetes over generations. Early childhood obesity predicts nonalcoholic fatty liver disease (NAFLD), the most common chronic human liver disease. The fetus may be vulnerable to steatosis because immature fetal adipose depots are not available to buffer the excess transplacental lipid delivery in maternal obesity. In animal models, in utero high-fat diet exposure results in an increase in the accumulation of liver triglycerides in offspring and increased hepatic oxidative stress and apoptosis, perhaps priming the liver for later development of NAFLD. Innate immune dysfunction and necroinflammatory changes have been observed in postnatal offspring liver of animals born to high-fat-fed dams. Postweaning, livers of offspring exposed to maternal high-fat feeding in utero share pathophysiologic features with human NAFLD, including increased de novo lipogenesis and decreased free fatty acid oxidation. Human studies using magnetic resonance imaging have shown that maternal BMI predicts infant intrahepatocellular lipid storage, as seen in animal models. The generational transfer of NAFLD may occur via epigenetic changes in offspring liver. Transmission of microbiota from mother to infant may impact energy retention and immune function that contribute to a predisposition to NAFLD.

Figure 1

Maternal high-fat diet (HFD) feeding leads to lipid accumulation and activation of oxidative stress in fetal liver. (a and b) Oil Red O staining and (c and d) 4-hydroxynonenal staining (a and c) in fetal liver of controls and (b and d) offspring-HFD (O-HFD) animals. Original magnification, ×20. (e) Fetal liver triglycerides (TGs) were significantly elevated in both O–HFD-resistant (O-HFD R) and O–HFD-sensitive groups (O-HFD S). *P < 0.05 vs. control (one-way analysis of variance with Bonferroni post hoc analysis). (f) As a group, O-HFD animals had a significant increase in the ratio of p-JNK1 to total JNK1 levels. Representative western blots are also shown. *P < 0.05 (two-tailed Student’s t-test). For columns in e and f, black, control: hatched, O-HFD R; and white, O-HFD S. (g) There was a significant correlation between TG levels and the ratio of p-JNK1 to total JNK1 in fetal liver. r² = 0.27, P = 0.002, n = 6 (O–HFD R); 9 (control and O–HFD S). Reprinted with permission from ref. .

Figure 2

Proposed pathways by which nonalcoholic fatty liver disease is programmed in offspring of mothers with prepregnancy obesity and insulin resistance. The gestational environment drives increased metabolic fuel delivery to the fetus, leading to fetal hepatic fat accumulation. Via epigenetic changes acquired prenatally, the liver is now “primed” for postnatal fat storage and inflammation mediated by Kupffer cells. A childhood high-fat diet then triggers further steatosis, hepatocyte injury, inflammation, and fibrosis via activation of hepatic stellate cells. DAG, diacylglycerol; TG, triglyceride.