Figure 6. Effects of increased maternal/fetal lipid supply on hepatic lipotoxicity in the fetus.

An increase in the availability of lipids to the fetus during early development prior to adipose tissue accretion results in lipid accumulation in nonadipose fetal tissues, leading to toxic effects. In O-HFD fetal liver, there was a significant increase in fetal hepatic TG accumulation that correlated with increased JNK activation. Liver staining revealed substantial elevations in markers of oxidative stress and damage in O-HFD livers. It is likely that the elevated TG levels lead to macrophage infiltration and contribute to the liver inflammation. Liver TG accumulation and inflammation are important events underlying NAFLD. The elevation in liver stress activates heat shock proteins (HSPs), which have previously been shown to be involved in chromatin remodeling (epigenetic programming; ref. 98). Oxidative stress and JNK activation triggers transcription for genes involved in gluconeogenesis as well as inflammation. Upregulation of inflammatory cytokines likely contributes to the progression of NAFLD, while early activation of gluconeogenic genes, such as PCK1, in fetal liver may predispose offspring for increased hepatic gluconeogenesis and insulin resistance.