Maternal Protein Restriction Elevates Cholesterol in Adult Rat Offspring Due to Repressive Changes in Histone Modifications at the Cholesterol 7α-Hydroxylase Promoter

Abstract

Adverse events in utero, such as intrauterine growth restriction (IUGR), can permanently alter epigenetic mechanisms leading to the metabolic syndrome, which encompasses a variety of symptoms including augmented cholesterol. The major site for cholesterol homeostasis occurs via the actions of hepatic cholesterol 7α-hydroxylase (Cyp7a1), which catabolizes cholesterol to bile acids. To determine whether posttranslational histone modifications influence the long-term expression of Cyp7a1 in IUGR, we used a protein restriction model in rats. This diet during pregnancy and lactation led to IUGR offspring with decreased liver to body weight ratios, followed by increased circulating and hepatic cholesterol levels in both sexes at d 21 and exclusively in the male offspring at d 130. The augmented cholesterol was associated with decreases in the expression of Cyp7a1. Chromatin immunoprecipitation revealed that this was concomitant with diminished acetylation and enhanced methylation of histone H3 lysine 9 [K9,14], markers of chromatin silencing, surrounding the promoter region of Cyp7a1. These epigenetic modifications originate in part due to dietary-induced decreases in fetal hepatic Jmjd2a expression, a histone H3 [K9] demethylase. Collectively, these findings suggest that the augmented cholesterol observed in low-protein diet-derived offspring is due to permanent repressive posttranslational histone modifications at the promoter of Cyp7a1. Moreover, this is the first study to demonstrate that maternal undernutrition leads to long-term cholesterol dysregulation in the offspring via epigenetic mechanisms.

Maternal protein restriction leads to enhanced hepatic gluconeogenic gene expression in adult male rat offspring due to impaired expression of the liver X receptor

“…All diets and water were administered ad libitum. Previous studies by our laboratory have demonstrated that the food intake between both offspring groups is practically identical (Sohi et al 2011).…”

“…The decrease in Cyp7a1 leads to hypercholesterolemia in male offspring by 4 months (Sohi et al 2011). This was found to be due, in part, to repressive changes in histone modifications at the LXRE site of the Cyp7a1 promoter.…”

“…Low protein dams received an 8% protein diet until birth of the offspring, followed by a 20% protein diet during the weaning period (until postnatal day 21). We decided to examine the effects of restoring protein immediately after birth as opposed to waiting until after the weaning period because we have already demonstrated that earlier restoration of protein promotes accelerated catch-up growth (Sohi et al 2011). Moreover, postnatal accelerated growth of IUGR offspring has been demonstrated to exacerbate the effects of IUGR-related programming and reduce the lifespans of these offspring (Ozanne & Hales 2004, Chen et al 2009, Tarry-Adkins et al 2013).…”

Plasma lipid levels and body weight altered by intrauterine growth restriction and postnatal fructose diet in adult rats

“…IUGR could affect lipid metabolism possibly through altered liver growth or liver development or altered endogenous cholesterol synthesis or absorption. In addition, epigenetic mechanisms may be a part of the programming, given that, e.g., a recent report revealed histone modifications surrounding the Cyp7a1 promoter in hypercholesterolemic IUGR pups of protein-restricted dams (15). We did not determine how the food restriction during pregnancy affected the milk quality of the lactating dams.…”

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

“…Thus, in liver, maternal low protein intake alters gene expression of Igf2 and H19 by regulating DNA methylation (Gong et al, 2010) and induces changes in histone acetylation and methylation that affect genes regulating the amino acid response pathway (Zhou and Pan, 2011). Maternal low protein diet also elevates cholesterol in the offspring and induces changes in liver histone methylation status (Sohi et al, 2011). In skeletal muscle, it increases acetylated histone 3 and acetylated histone 4 at the C/EBPβ (Zheng et al, 2011b) and GLUT4 promoter regions (Zheng et al, 2011c) but only in female pups, indicating a sex-dependent adaptation.…”