An Essential Role for Liver ERα in Coupling Hepatic Metabolism to the Reproductive Cycle

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.

Role of Estrogens in the Regulation of Liver Lipid Metabolism

“…Using a mouse model with ERα-deficiency in hepatocytes, we demonstrated that the ability of estrogens to reduce liver steatosis is lost in with deletion of liver ERα, suggesting that estrogens are acting directly in liver to reduce TG content through ERα (Palmisano et al 2016; Zhu et al 2013; Villa et al 2012). As expected, loss of liver ERα results in increased expression of lipid synthesis genes (Bryzgalova et al 2006), loss of estrogen regulation of target genes (Palmisano et al 2016; Zhu et al 2013), and impaired estrogen regulation of other lipid metabolic target genes (Della Torre et al 2016). One proposed mechanism for ERα regulation of lipid synthesis targets involves estrogen-ERα regulation of the nuclear receptor Small Heterodimer Partner (SHP), a target gene of ERα (Palmisano et al 2016; Wang et al 2015).…”

Sex Differences: A Resultant of an Evolutionary Pressure?

“…As it is known that in females estrogens directly regulate large part of the genes above mentioned, the differential expression reported may be explained by the fact that, contrary to females, males have low circulating levels of estrogens, in the liver do not expressed the enzyme synthesizing estrogens from testosterone (aromatase) (Granata et al, 2009;Harada et al, 1993), and have an hepatic content of ER protein 3-5 fold lower than females (Della Torre et al, 2016). In mammals, however, other mechanisms regulating liver functions were established with evolution; first of all, the brain is sexually differentiated by the activity of male gonads in a window of time that occurs around birth.…”

“…In addition, studies in female mouse showed a specific synchrony of ER transcriptional activity in liver and reproductive tissues (Ciana et al, 2003;Della Torre et al, 2011a) with a rhythm imposed by the reproductive cycle. In this interplay, nutrient uptake was shown to be essential to maintain liver ER activity (Ciana et al, 2005;Della Torre et al, 2016;Della Torre et al, 2011b;Villa et al, 2012).…”

“…This appears to be achieved by the fact that the hepatic ER requires both liganded and unliganded stimulation for its full transcriptional activation. The unliganded ER stimulation occurs in the presence of dietary AA (possibly through the IGF-1/AKT/mTORpathway) and, if AA intake is low, ER cannot be activated by the gonadal estrogens to the extent necessary for the synthesis of the molecules required for the progression of the reproductive cycle and, likely, for the maturation of the egg (IGF-1, cholesterol, lipids and the apolipoproteins necessary for their transport to the gonads) (Della Torre et al, 2016;Della Torre et al, 2011b). It is worth to underline that the synthesis of vitellogenins in mammalian liver is replaced by the synthesis of another member of the vitellogenin gene family, apolipoprotein B (ApoB), the primary apolipoprotein of VLDL, IDL and LDL (very-low, intermediate and low-density lipoprotein) particles (Packard et al, 2000).…”

“…The structure of lipoproteins changes during the mammalian reproductive cycle and in relation to the state of ER transcriptional activation: during the maturation of the follicle the liver synthesizes the lipoproteins necessary for an efficient transport of cholesterol and lipids to the ovaries; after that, the apolipoproteins synthesized are aimed at generating HDL (high density lipoprotein) able to get back to the liver the excess of circulating cholesterol. This virtuous cycle prevents the accumulation of waste in tissues and guaranties the full exploitation of all available energies (Della Torre et al, 2016).…”