Abstract
SummaryLipoprotein synthesis is controlled by estrogens, but the exact mechanisms underpinning this regulation and the role of the hepatic estrogen receptor α (ERα) in cholesterol physiology are unclear. Utilizing a mouse model involving selective ablation of ERα in the liver, we demonstrate that hepatic ERα couples lipid metabolism to the reproductive cycle. We show that this receptor regulates the synthesis of cholesterol transport proteins, enzymes for lipoprotein remodeling, and receptors for cholesterol uptake. Additionally, ERα is indispensable during proestrus for the generation of high-density lipoproteins efficient in eliciting cholesterol efflux from macrophages. We propose that a specific interaction with liver X receptor α (LXRα) mediates the broad effects of ERα on the hepatic lipid metabolism.
Highlights
The liver plays a unique, central role in the regulation of fatty acid (FA) and cholesterol (CH) metabolism
Several lines of evidence indicate that estrogens are involved in the prevention of hepatic fat deposits: (1) estrogens reduce hepatic lipid synthesis and increase the transport of triglycerides (TGs); (2) sex and the reproductive state influence the prevalence of non-alcoholic fatty liver disease (NAFLD) and the degree of fibrosis in patients with its more severe form, non-alcoholic steatohepatitis (NASH); and (3) pathologies characterized by ovarian dysfunction, such as polycystic ovary syndrome and Turner syndrome, are generally associated with NAFLD (Clegg, 2012; GambarinGelwan et al, 2007; Gutierrez-Grobe et al, 2010; Ostberg et al, 2005)
Such changes were further suggested by the observation that, overall, the oil-red-O-stained lipid droplets were larger in the LERKO than in the SYN mice and that Masson’s trichrome staining of the LERKO livers revealed portal infiltration of mononuclear leukocytes and portal or centrilobular collagen deposition
Summary
The liver plays a unique, central role in the regulation of fatty acid (FA) and cholesterol (CH) metabolism. Alterations in the homeostatic control of lipid metabolism have severe pathological repercussions, as the accumulation of fat in the hepatocytes is associated with non-alcoholic fatty liver disease (NAFLD), metabolic disease, and cardiovascular disease (CVD). Several lines of evidence indicate that estrogens are involved in the prevention of hepatic fat deposits: (1) estrogens reduce hepatic lipid synthesis and increase the transport of triglycerides (TGs); (2) sex and the reproductive state influence the prevalence of NAFLD and the degree of fibrosis in patients with its more severe form, non-alcoholic steatohepatitis (NASH); and (3) pathologies characterized by ovarian dysfunction, such as polycystic ovary syndrome and Turner syndrome, are generally associated with NAFLD (Clegg, 2012; GambarinGelwan et al, 2007; Gutierrez-Grobe et al, 2010; Ostberg et al, 2005). Understanding the physiology of estrogen-dependent regulation of energy metabolism in the female liver is necessary for the development of new therapies, for the treatment of metabolic disorders associated with menopause and ovarian dysfunction
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