Prenatal Exposure to a Maternal High Fat Diet Increases Hepatic Cholesterol Accumulation in Intrauterine Growth Restricted Rats in Part Through MicroRNA-122 Inhibition of Cyp7a1

Abstract

Intrauterine growth restriction (IUGR) and consumption of a high saturated fat diet (HFD) increase the risk of hypercholesterolemia, a leading cause of morbidity and mortality. The mechanism through which the cumulative impact of IUGR and in utero exposure to a maternal HFD increase cholesterol levels remains unknown. Cholesterol 7α hydroxylase (Cyp7a1) initiates catabolism of cholesterol to bile acids for elimination from the body, and is regulated by microRNA-122 (miR-122). We hypothesized that IUGR rats exposed to a maternal HFD would have increased cholesterol and decreased Cyp7a1 protein levels in juvenile rats, findings which would be normalized by administration of a miR-122 inhibitor. To test our hypothesis we used a rat model of surgically induced IUGR and fed the dams a regular diet or a HFD from prior to conception through lactation. At the time of weaning, IUGR female rats exposed to a maternal HFD had increased hepatic cholesterol, decreased hepatic Cyp7a1 protein and hepatic bile acids, and increased hepatic miR-122 compared to non-IUGR rats exposed to the same HFD. In vivo inhibition of miR-122 increased hepatic Cyp7a1 protein and decreased hepatic cholesterol. Our findings suggest that IUGR combined with a maternal HFD decreased cholesterol catabolism to bile acids, in part, via miR-122 inhibition of Cyp7a1.

DNA Methylation and gene expression patterns are widely altered in fetal growth restriction and associated with FGR development

“…We also discovered thatgenes overexpressed by DNA hypomethylation in placentae were enriched in the pathways related to a set of metabolism pathways, such as the ChREBPactivation of metabolic gene expression and thePI3K-Akt signaling pathway(Figure 3B). These metabolic pathways are known to have functional implications with FGR occurrence (Zinkhan et al 2018;Xing et al 2019). In the case of genes underexpressed by DNA hypermethylation in cord blood, pathways related to lipid metabolism, such as the glycerolipid biosynthetic process, glycerophospholipid metabolic process, phospholipid biosynthetic process, and the regulation of the lipid metabolic process, were found to be affected.…”

Uteroplacental Insufficiency Impairs Cholesterol Elimination in Adult Female Growth-Restricted Rat Offspring Fed a High-Fat Diet

“…Our previous study demonstrated an miR-122-dependent mechanism of inhibition of cholesterol catabolism to bile acids in IUGR rats at the time of weaning. 11 These findings suggest that the UPI-induced miR-122 inhibition of cholesterol catabolism is developmentally regulated. Cholesterol 7 alpha-hydroxylase-induced cholesterol catabolism to bile acids eliminates more than half of cholesterol undergoing catabolism.…”

“…We previously showed increased hepatic cholesterol accumulation in weanling female IUGR rats exposed to a maternal HFD. 11 A maternal HFD was used in our studies to more closely mimic the typical American diet than what is commonly found in a standard rat chow, which typically contains approximately 17% of kilocalories from fat and very little saturated fat. 8,9 In our study, the increase in cholesterol was in part through miR-122 inhibition of Cyp7a1.…”

Intravenous injection of post‑hemorrhagic shock mesenteric lymph induces multiple organ injury in rats

“…Urea and Cre, AST and TBA, and CK-MB are markers of renal function, hepatocyte necrosis and function, and cardiomyocyte injury, respectively (22)(23)(24). In the PHSML group, these indices were significantly increased compared with the control group (P<0.05).…”