Sex-specific Alterations in Hepatic Cholesterol Metabolism in Young Uteroplacental Insufficiency-induced Low Birth Weight Adult Guinea Pig Offspring

Abstract

BackgroundIntrauterine growth restriction (IUGR) and low birth weight (LBW) have been widely reported as an independent risk factor for hypercholesterolemia and increased hepatic cholesterol underlying liver dysfunction in adulthood. However, the specific impact of uteroplacental insufficiency (UPI), a leading cause of LBW in developed world, on hepatic cholesterol metabolism in later life, is ill defined and is clinically relevant in understanding later life liver metabolic health trajectories. MethodsHepatic cholesterol metabolism pathways were studied in uterine artery ablation-induced LBW and normal birth weight (NBW) male and female guinea pig offspring at postnatal day 150. ResultsHepatic free and total cholesterol were increased in LBW versus NBW males. Transcriptome analysis of LBW versus NBW livers revealed that "Cholesterol metabolism" was an enriched pathway in LBW males but not females. Microsomal triglyceride transfer protein and cytochrome P450 7A1 protein, involved in hepatic cholesterol efflux and catabolism, respectively, and catalase activity were decreased in LBW male livers. Superoxide dismutase activity was reduced in LBW males but increased in LBW females. ConclusionsUPI environment is associated with a later life programed hepatic cholesterol accumulation via impaired cholesterol elimination, in a sex-specific manner. These programmed alterations could underlie later life cholesterol-induced hepatic lipotoxicity in LBW male offspring. Impact StatementO_LILow birth weight (LBW) is a risk factor for adult hypercholesterolemia and increased hepatic cholesterol. C_LIO_LIUteroplacental insufficiency (UPI) resulting in LBW increased hepatic cholesterol content, altered hepatic expression of cholesterol metabolism-related genes in young adult guinea pigs. C_LIO_LIUPI-induced LBW was also associated with markers of a compromised hepatic cholesterol elimination process and failing antioxidant system in young adult guinea pigs. C_LIO_LIThese changes, at the current age studied, were sex-specific, only being observed in LBW males and not LBW females. C_LIO_LIThese programmed alterations could lead to further hepatic damage and greater predisposition to liver diseases in UPI-induced LBW male offspring as they age. C_LI