Sex differences in hepatic regulation of cholesterol homeostasis

Abstract

Physiological sex differences may influence metabolic status and then alter the onset of some diseases. According to recent studies, it is now well established that females are more protected from hypercholesterolemia-related diseases, such as cardiovascular diseases until menopause. Female protection from hypercholesterolemia is mediated by the hypolipidemic properties of estrogens, even if mechanisms underlying this protection remain still debated. Even though the regulatory mechanisms of cholesterol homeostasis maintenance are well known, few data are available on the supposed differences between male and female in these processes. So, the aim of this work was to define, through an in vivo study, the putative sex-dependent regulation of the processes underlying cholesterol homeostasis maintenance. We examined 3-hydroxy 3-methylglutaryl coenzyme A reductase and its regulatory protein network as well as the amount of low-density lipoprotein receptor and cholesterol. The study was conducted in the liver and plasma of male and female rats, on adults and during postnatal development, and on 17-b-estradiol-treated male rats. Our data support that physiological differences in proteins involved in cholesterol balance are present between the sexes and, in particular, 3-hydroxy 3-methylglutaryl coenzyme A reductase shows lower activity and expression in female and 17-b-estradioltreated male rats than in adult untreated male. Our data suggest that sex differences in enzyme expression depend on variation in regulatory proteins and seem to be related to estrogen presence. This work adds new evidence in the complicated picture of sex-dependent cellular physiology and establishes a new role for reductase regulatory proteins as a link between estrogen protective effects and cholesterol homeostasis.

Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet

“…Accordingly, gender differences in BA synthesis might contribute to NASH development, and to fibrogenesis in HFC diet-fed SHRSP5/Dmcr rats. Physiologically, no gender differences in serum and hepatic TC are likely in adult rats, although TC levels were reportedly limited by 3-hydroxy 3-methylgultaryl coenzyme A reductase in livers of females [35]. Despite the reported relationship between this enzyme and estrogen expression levels, no gender differences in TC or TG levels were observed in serum and liver samples from SHRSP5/Dmcr rats fed the control diet.…”

“…In addition to differences in levels of the female sex hormone, nuclear receptor-regulated liver metabolic pathways for detoxification of toxic BAs, BA synthesis [34], and hepatic regulation of cholesterol homeostasis [35] are reported contributors to sexual differences [30]. In general, nuclear receptors play pivotal roles in gender-specific metabolic pathways, including those that influence liver function in animal models of health and disease.…”

“…Therefore, HFC-fed SHRSP5/Dmcr rats closely resemble NASH/NAFLD and offer a useful animal model for studies of gender differences in HFC-induced liver damage. HFC-diet feeding did not inhibit serum estradiol levels in female rats, indicating that this sex hormone is a pivotal mediator of gender differences in HFC-induced fibrotic steatohepatitis.In addition to differences in levels of the female sex hormone, nuclear receptor-regulated liver metabolic pathways for detoxification of toxic BAs, BA synthesis [34], and hepatic regulation of cholesterol homeostasis [35] are reported contributors to sexual differences [30]. In general, nuclear receptors play pivotal roles in gender-specific metabolic pathways, including those that influence liver function in animal models of health and disease.…”

Hypercholesterolemia and 3-hydroxy-3-methylglutaryl coenzyme A reductase regulation in aged female rats

“…To analyze the role of HMGR and its regulatory network during estropause, the validity of the experimental model first had to be confirmed, moreover data on 3 month-old male rats to confirm 10 previous and already published (De Marinis et a., 2008) results obtained on sex-related differences in hepatic regulation of cholesterol homeostasis have been added. Thus, 17-estradiol levels were analyzed.…”

“…This feature seems to depend on estrogen-dependent Insig 2 levels, which can affect enzyme transcription and degradation (De Marinis et al, 2008). We know of no report to date that analyzes the lack of estradiol during female ageing and putative changes in the protein able to regulate cholesterol homeostasis maintenance, as most existing research has examined males.…”