The influence of biological sex and sex hormones on bile acid synthesis and cholesterol homeostasis

Abstract

Obesity and elevated serum lipids are associated with a threefold increase in the risk of developing atherosclerosis, a condition that underlies stroke, myocardial infarction, and sudden cardiac death. Strategies that aim to reduce serum cholesterol through modulation of liver enzymes have been successful in decreasing the risk of developing atherosclerosis and reducing mortality. Statins, which inhibit cholesterol biosynthesis in the liver, are considered among the most successful compounds developed for the treatment of cardiovascular disease. However, recent debate surrounding their effectiveness and safety prompts consideration of alternative cholesterol-lowering therapies, including increasing cholesterol catabolism through bile acid (BA) synthesis. Targeting the enzymes that convert cholesterol to BAs represents a promising alternative to other cholesterol-lowering approaches that treat atherosclerosis as well as fatty liver diseases and diabetes mellitus. Compounds that modify the activity of these pathways have been developed; however, there remains a lack of consideration of biological sex. This is necessary in light of strong evidence for sexual dimorphisms not only in the incidence and progression of the diseases they influence but also in the expression and activity of the proteins affected and in the manner in which men and women respond to drugs that modify lipid handling in the liver. A thorough understanding of the enzymes involved in cholesterol catabolism and modulation by biological sex is necessary to maximize their therapeutic potential.

Perfluorooctanoic acid activates multiple nuclear receptor pathways and skews expression of genes regulating cholesterol homeostasis in liver of humanized PPARα mice fed an American diet

“…Cholesterol is converted to bile acids, a major mechanism for removal of cholesterol from the body, through two primary molecular pathways with CYP7A1 being the rate limiting enzyme in the primary pathway (Dietschy and Turley 2002). In humans, the CYP7A1-mediated primary pathway accounts for 90% of bile acid production whereas it only accounts for 60% in mice (Phelps et al 2019). Further, CYP7A1 is a major factor regulating lipoprotein synthesis and assembly (Wang et al 1997).…”

Capsaicin improves glucose homeostasis by enhancing glucagon‐like peptide‐1 secretion through the regulation of bile acid metabolism via the remodeling of the gut microbiota in male mice

“…We cannot fully exclude the possibility that the effects of CAP on GLP‐1 secretion may be mediated via pathways that do not involve BA/TGR5. In addition, there is a growing body of evidence for the sex differences in BA metabolism 44 . The size of BA pool of female mice is 60% larger and more hydrophobic than that in males and higher levels of fecal BAs are also observed in females 44‐46 and the composition of the bile acid pool is also sexually dimorphic with females producing more CDCA than males 47 .…”

Metabolomic differences between critically Ill women and men

“…Though sex-specific differences in bile acid synthesis are reported 52 , such differences in bile acid homeostasis are not well characterized 53 . It is shown that cytochrome P450 enzymes are important for bile synthesis 52 and regulated in a sex-specific manner 54 , 55 . Bile acids activate the nuclear receptors farnesoid X receptor, pregnane X receptor and vitamin D receptor as well as the G-protein-coupled receptor TGR5.…”