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

Abstract

Background: Intrauterine growth restriction (IUGR) increases the risk of adult-onset hypercholesterolemia. High-fat diet (HFD) consumption potentiates IUGR-induced increased cholesterol. Cholesterol is converted to bile acids by Cyp7a1 in preparation for excretion. We hypothesized that IUGR rats fed a HFD will have increased cholesterol, decreased Cyp7a1 protein levels, and decreased bile acids compared to control rats fed a HFD. Methods: At day 21, IUGR and control pups were placed on one of three diets: a regular chow or one of two HFDs containing 1% or 2% cholesterol. Cholesterol levels and hepatic Cyp7a1 protein levels were quantified a postnatal week 28. results: Both HFDs increased serum cholesterol levels in control rats, and HFD fed IUGR rats had further increased serum cholesterol up to 35-fold. Both HFDs increased hepatic cholesterol levels, and IUGR further increased hepatic cholesterol levels up to fivefold. IUGR decreased hepatic Cyp7a1 protein up to 75%, and hepatic bile acids up to 54%. conclusion: IUGR increased cholesterol and bile acids and decreased Cyp7a1 protein in rats fed a HFD without changing food intake. These findings suggest that IUGR increases the vulnerability of HFD fed rats to hypercholesterolemia via decreased cholesterol conversion to bile acids. i ntrauterine growth restriction (IUGR) predisposes to adultonset hypercholesterolemia (1,2). Epidemiologic studies demonstrate that late-gestation exposure to famine makes individuals more susceptible to hypercholesterolemia only when combined with postnatal consumption of a high-fat diet (HFD) (3). These results suggest that the postnatal nutritional environment impacts cholesterol metabolism differently in IUGR individuals compared their normally grown peers. A better understanding of the mechanism through which IUGR combined with a postnatal HFD impacts cholesterol metabolism would provide a foundation to pursue further research into preventing hypercholesterolemia in IUGR individuals.While the effects of HFD consumption in individuals born IUGR are not well understood, the detrimental effects of HFD consumption in the general population has been extensively documented. HFD consumption often leads to hypercholesterolemia and eventually cardiovascular disease (4). Higher cholesterol levels increase the risk of cardiovascular disease in a continuous, graded fashion (5,6). IUGR may potentiate hypercholesterolemia in individuals that consume a HFD and thus increase morbidity and mortality in this population. The impact of IUGR on cholesterol levels in humans is more evident in the recent decades due to the changing Western diet (7). Average daily fat and cholesterol intake in the United States is ~23-33 g of saturated fat and up to 400 mg cholesterol, both well above the recommended daily intake of ~16 g or no more than 7% of caloric intake for saturated fat and 200 mg cholesterol (7).The liver is the primary organ for regulating both serum and hepatic cholesterol levels. Cholesterol homeostasis is regulated by a series of hepatic genes...

Fecal Microbiota Transplantation Can Alleviate Gastrointestinal Transit in Rats with High-Fat Diet-Induced Obesity via Regulation of Serotonin Biosynthesis

“…In this study, we found that the increase in the serotonin and TPH1 levels was accompanied by an increase in CA and DCA levels in the HFD-fed rats. These results were consistent with previous results, which suggested that a high-fat diet could result in the accumulation of CA and secondary bile acids [ 41 , 42 ]. A high-fat diet could increase the levels of cholesterol in the liver, which is required for the synthesis of bile acids [ 43 ].…”

“…After FMT for only two weeks, the TPH1 expression, and the concentration of serotonin in the small intestinal tissues reduced. Furthermore, our results showed that FMT was also able to reduce the DCA and CA concentration of the intestinal contents in the HFD-fed rats, which may be the factors that could downregulate TPH1 expression [ 38 , 42 ]. This indicated that FMT could impact the biotransformation of the bile acids, and this may have a close association with the intestinal microbiota.…”

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

“…Several research studies suggest that IUGR predisposes individuals to hypercholesterolemia susceptibility compared with their normally grown peers (3,23,53). We have shown that IUGR animals challenged with a postnatal HFD have increased cholesterol compared with control animals with a HFD alone (71). Additionally, maternal obesity and HFD consumption during pregnancy increase the risk of placental insufficiency and independently program CVD in the offspring (24,38,49).…”

Roles of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase in Angiogenesis: Isoform-Specific Effects

“…NoxO1 is believed to be a regulatory subunit mainly for the NOX1 [81], but is not necessary for NOX1 activation since its homologue, p47 phox , can also activate NOX1. In addition, it is recognized that NoxO1 activates NOX3 and NOX2 [82], but less efficiently than p47 phox activates NOX2 [83]. Therefore, differential enzyme activity of other NOX isoforms, like NOX3 and NOX2, may contribute to different angiogenic phenotypes seen in Nox1 −/− and NoxO1 −/− mice.…”