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

• Liver ERα couples lipid metabolism to the reproductive cycle
• Liver ERα regulates lipoprotein remodeling enzymes
• Liver ERα elicits the cyclic synthesis of highly efficient HDL
• Liver ERα regulates female hepatic metabolism through interaction with LXRα

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.

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