Chromosomal and gonadal sex drive sex differences in lipids and hepatic gene expression in response to hypercholesterolemia and statin treatment

Abstract

Background Biological sex impacts susceptibility and presentation of cardiovascular disease, which remains the leading cause of death for both sexes. To reduce cardiovascular disease risk, statin drugs are commonly prescribed to reduce circulating cholesterol levels through inhibition of cholesterol synthesis. The effectiveness of statin therapy differs between individuals with a sex bias in the frequency of adverse effects. Limited information is available regarding the mechanisms driving sex-specific responses to hypercholesterolemia or statin treatment. Methods Four Core Genotypes mice (XX and XY mice with ovaries and XX and XY mice with testes) on a hypercholesteremic Apoe–/– background were fed a chow diet without or with simvastatin for 8 weeks. Plasma lipid levels were quantified and hepatic differential gene expression was evaluated with RNA-sequencing to identify the independent effects of gonadal and chromosomal sex. Results In a hypercholesterolemic state, gonadal sex influenced the expression levels of more than 3000 genes, and chromosomal sex impacted expression of nearly 1400 genes, which were distributed across all autosomes as well as the sex chromosomes. Gonadal sex uniquely influenced the expression of ER stress response genes, whereas chromosomal and gonadal sex influenced fatty acid metabolism gene expression in hypercholesterolemic mice. Sex-specific effects on gene regulation in response to statin treatment included a compensatory upregulation of cholesterol biosynthetic gene expression in mice with XY chromosome complement, regardless of presence of ovaries or testes. Conclusion Gonadal and chromosomal sex have independent effects on the hepatic transcriptome to influence different cellular pathways in a hypercholesterolemic environment. Furthermore, chromosomal sex in particular impacted the cellular response to statin treatment. An improved understanding of how gonadal and chromosomal sex influence cellular response to disease conditions and in response to drug treatment is critical to optimize disease management for all individuals.

Responses to Many Anti-Aging Interventions Are Sexually Dimorphic

“…It appears likely the results of ongoing and future studies may lead to different recommendations for preservation of health during aging in women and men, and perhaps also to development of sex-specific interventions in human aging. Further studies, including approaches that can uncouple the impact of gonadal sex from chromosomal sex [ 88 89 ], will undoubtedly lend to much progress in identification of mechanisms responsible for sex differences in response to anti-aging interventions.…”

The role of gonadal hormones and sex chromosomes in sex-dependent effects of early nutrition on metabolic health

“…In this model of hypercholesterolemia, gonadal sex and chromosomal sex both widely influenced hepatic gene expression, with more than 3000 genes showing differential expression due to ovaries vs. testes, and ~1400 genes having differential expression in XX vs. XY mice (35). Importantly, differentially expressed genes influenced by gonadal and chromosomal sex were similarly distributed across autosomes and the X chromosome (35).…”

“…Similarly, the effects of chromosomes, gonadal sex, and gonadectomy on plasma lipid traits varied between regular and high cholesterol diets (29). In a model of hypercholesterolemia brought on by genetic deletion of apolipoprotein E, gonadal but not chromosomal sex had a significant effect on total plasma cholesterol and free fatty acids, with higher levels in gonadal males (35), as also occurs in wildtype mice (29). In this model of hypercholesterolemia, gonadal sex and chromosomal sex both widely influenced hepatic gene expression, with more than 3000 genes showing differential expression due to ovaries vs. testes, and ~1400 genes having differential expression in XX vs. XY mice (35).…”

“…In a model of hypercholesterolemia brought on by genetic deletion of apolipoprotein E, gonadal but not chromosomal sex had a significant effect on total plasma cholesterol and free fatty acids, with higher levels in gonadal males (35), as also occurs in wildtype mice (29). In this model of hypercholesterolemia, gonadal sex and chromosomal sex both widely influenced hepatic gene expression, with more than 3000 genes showing differential expression due to ovaries vs. testes, and ~1400 genes having differential expression in XX vs. XY mice (35). Importantly, differentially expressed genes influenced by gonadal and chromosomal sex were similarly distributed across autosomes and the X chromosome (35).…”

“…Identifying the roles of chromosomes and hormones in sexdependent effects of early nutrition on metabolic health may allow us to move beyond simply cataloging sex differences and to identify general patterns, such as whether sex differences due to hormones or chromosomes are more responsive to prenatal insults. Understanding these mechanisms could stimulate further areas of research, including identification of interactions between glucocorticoids and sex steroids in metabolic programming (98), sex-dependent responses to pharmaceutical intervention (35).…”