Sex-specific alterations in hepatic cholesterol metabolism in low birth weight adult guinea pigs

Ousseynou Sarr; Katherine E Mathers; Christina Vanderboor; Kristina Wiggers; Aditya Devgan; Daniel B Hardy; Lin Zhao; Timothy R H Regnault

doi:10.1038/s41390-021-01491-w

Sex-specific alterations in hepatic cholesterol metabolism in low birth weight adult guinea pigs

Pediatr Res. 2022 Apr;91(5):1078-1089. doi: 10.1038/s41390-021-01491-w. Epub 2021 Jul 6.

Authors

Ousseynou Sarr¹, Katherine E Mathers¹, Christina Vanderboor¹, Kristina Wiggers¹, Aditya Devgan¹, Daniel B Hardy^{1

2

3}, Lin Zhao¹, Timothy R H Regnault^{4

5

6}

Affiliations

¹ Department of Physiology and Pharmacology, Western University, London, ON, Canada.
² Department of Obstetrics and Gynaecology, Western University, London, ON, Canada.
³ Lawson Health Research Institute and Children's Health Research Institute, London, ON, Canada.
⁴ Department of Physiology and Pharmacology, Western University, London, ON, Canada. tim.regnault@uwo.ca.
⁵ Department of Obstetrics and Gynaecology, Western University, London, ON, Canada. tim.regnault@uwo.ca.
⁶ Lawson Health Research Institute and Children's Health Research Institute, London, ON, Canada. tim.regnault@uwo.ca.

PMID: 34230622
DOI: 10.1038/s41390-021-01491-w

Abstract

Background: Intrauterine growth restriction and low birth weight (LBW) have been widely reported as an independent risk factor for adult hypercholesterolaemia and increased hepatic cholesterol in a sex-specific manner. 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.

Methods: Hepatic cholesterol, transcriptome, cholesterol homoeostasis regulatory proteins, and antioxidant markers were studied in UPI-induced LBW and normal birth weight (NBW) male and female guinea pigs at 150 days.

Results: Hepatic 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 in 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.

Conclusions: UPI 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: Low birth weight (LBW) is a risk factor for increased hepatic cholesterol. Uteroplacental insufficiency (UPI) resulting in LBW increased hepatic cholesterol content, altered hepatic expression of cholesterol metabolism-related genes in young adult guinea pigs. UPI-induced LBW was also associated with markers of a compromised hepatic cholesterol elimination process and failing antioxidant system in young adult guinea pigs. These changes, at the current age studied, were sex-specific, only being observed in LBW males and not in LBW females. These programmed alterations could lead to further hepatic damage and greater predisposition to liver diseases in UPI-induced LBW male offspring as they age.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antioxidants*
Birth Weight
Cholesterol
Cytochrome P-450 Enzyme System
Female
Guinea Pigs
Humans
Infant, Low Birth Weight
Infant, Newborn
Liver Diseases*
Male

Substances

Antioxidants
Cytochrome P-450 Enzyme System
Cholesterol

Grants and funding

MOP-209113/CIHR/Canada