Intrauterine growth restriction combined with a maternal high-fat diet increases hepatic cholesterol and low-density lipoprotein receptor activity in rats

Abstract

Intrauterine growth restriction (IUGR) and maternal consumption of a high‐saturated‐fat diet (HFD) increase the risk of hypercholesterolemia, a leading cause of morbidity and mortality. Many pregnant women eat a HFD, thus exposing the fetus to a HFD in utero. The cumulative effect of in utero exposure to IUGR and a HFD on offspring cholesterol levels remains unknown. Furthermore, little is known about the mechanism through which IUGR and maternal HFD consumption increase cholesterol. We hypothesize that IUGR combined with a maternal HFD would increase offspring serum and hepatic cholesterol accumulation via alteration in levels of key proteins involved in cholesterol metabolism. To test our hypothesis we used a rat model of surgically induced IUGR and fed the dams a regular diet or a HFD. HFD‐fed dams consumed the same kilocalories as regular diet‐fed dams, with no difference between surgical intervention groups. In the offspring, IUGR combined with a maternal HFD increased hepatic cholesterol levels, low‐density lipoprotein (LDL) receptor protein levels, and Ldlr activity in female rat offspring at birth and both sexes at postnatal day 14 relative to non‐IUGR offspring both from regular diet‐ and HFD‐fed dams. These findings suggest that IUGR combined with a maternal HFD increases hepatic cholesterol accumulation via increased LDL cholesterol uptake into the liver with resulting persistent increases in hepatic cholesterol accumulation.

Intrauterine growth restriction influences vascular remodeling and stiffening in the weanling rat more than sex or diet

“…Unless otherwise specified, at PND 21, offspring were separated from the dam, fasted overnight, and anesthetized with 8 mg/kg xylazine and 40 mg/kg ketamine before decapitation. We previously reported that dams fed the HFD had increased pregnancy weight gain by term gestation despite the same number of offspring per litter and same prepregnancy weight (72). Dams fed a HFD consumed the same calories as dams fed the regular diet, with no difference between dams who underwent uterine artery ligation and dams who had anesthesia as a control.…”

“…The University of Utah Animal Care Committee approved all animal procedures. The rat model of IUGR and a HFD was as previously described (72). In brief, 50-day-old male and nonpregnant female Sprague-Dawley CD rats were obtained from Charles River Laboratories (Wilmington, MA) and exposed to 12-h light-dark cycles.…”

“…At birth, the offspring had no change in serum lipids between groups and blood glucoses were elevated only in the IUGR ϩ HFD female rats (Table 1). By PND 21, offspring from mothers fed a HFD (Con ϩ HFD and IUGR ϩ HFD offspring rats) had increased non-HDL cholesterol compared with Con ϩ Reg rats (72). Only unrelated rats were used in these analyses, defined as one male and one female offspring rat per litter.…”

Maternal dyslipidaemic diet induces sex-specific alterations in intestinal function and lipid metabolism in rat offspring

“…These results may be justified by the lower consumption of DLP diet in most of the periods, possibly due to the satietyogenic effect caused by the higher fat content of this diet, indicating that a dyslipidaemic diet does not necessarily induce obesity (15,18) . Pups from DLP dams of both sexes had LBW, probably because of the imbalance in the fatty acid ratio (35) and the reduction in energy content from protein, which is typical of a dyslipidaemic diet, and consequently, the low consumption of this nutrient from the indicated diet (36) . Regarding weight gain, from weaning to adulthood, there was a higher percentage of weight gain in pups from DLP dams compared with that in pups from CTL dams, which could be one of the negative impacts of dyslipidaemic diet consumption by dams (37)(38)(39) .…”

“…This observation could be a consequence of the replacement of a DLP diet with a normal diet or of body homoeostatic regulation, as demonstrated in previous studies in which offspring from dyslipidaemic dams presented normal levels of TC, HDL, LDL and TAG from 90 d of age (18,26) . Another study showed that pups from dams that received a diet rich in saturated fat and nursed up to 14 d had LBW and elevated LDL-cholesterol levels due to the increase in levels of LDL receptor protein, a receptor responsible for the metabolism of LDL-cholesterol; its high levels are linked directly to cases of familial hypercholesterolaemia (36) . The altered lipid profile and dysbiosis most prominently observed at 30 d but not 90 d of age reinforces the potential influence of an altered microbiome on host lipid metabolism (59) .…”