Hepatocyte estrogen receptor alpha mediates estrogen action to promote reverse cholesterol transport during Western-type diet feeding

Abstract

ObjectiveHepatocyte deletion of estrogen receptor alpha (LKO-ERα) worsens fatty liver, dyslipidemia, and insulin resistance in high-fat diet fed female mice. However, whether or not hepatocyte ERα regulates reverse cholesterol transport (RCT) in mice has not yet been reported.Methods and resultsUsing LKO-ERα mice and wild-type (WT) littermates fed a Western-type diet, we found that deletion of hepatocyte ERα impaired in vivo RCT measured by the removal of 3H-cholesterol from macrophages to the liver, and subsequently to feces, in female mice but not in male mice. Deletion of hepatocyte ERα decreased the capacity of isolated HDL to efflux cholesterol from macrophages and reduced the ability of isolated hepatocytes to accept cholesterol from HDL ex vivo in both sexes. However, only in female mice, LKO-ERα increased serum cholesterol levels and increased HDL particle sizes. Deletion of hepatocyte ERα increased adiposity and worsened insulin resistance to a greater degree in female than male mice. All of the changes lead to a 5.6-fold increase in the size of early atherosclerotic lesions in female LKO-ERα mice compared to WT controls.ConclusionsEstrogen signaling through hepatocyte ERα plays an important role in RCT and is protective against lipid retention in the artery wall during early stages of atherosclerosis in female mice fed a Western-type diet.

Notoginsenoside R1 Protects Against Diabetic Cardiomyopathy Through Activating Estrogen Receptor α and Its Downstream Signaling

“…NGR1 promoted lipid metabolism in an ERα-dependent pathway. Importantly, ERα plays a role in reverse cholesterol transport and its deletion causes increased adiposity and enhanced insulin resistance ( Zhu et al, 2018 ). Thus, NGR1 may upregulate ERα expression to accelerate TCH and TG metabolism, which could supply energy for the heart.…”

Sex differences in lipid and lipoprotein metabolism

“…Liver estrogen signaling through ERα has been shown to regulate hepatic cholesterol uptake and the efflux capacity of HDL from macrophages during the proestrus period when estrogen levels are high [77] . Female mice have increased total-body RCT compared to males fed a western diet [94] . In this study, liver deletion of ERα impaired total body RCT in female mice, suggesting that liver ERα is required for females to enhance total body RCT [94] .…”

“…Female mice have increased total-body RCT compared to males fed a western diet [94] . In this study, liver deletion of ERα impaired total body RCT in female mice, suggesting that liver ERα is required for females to enhance total body RCT [94] . Estradiol and PPT treatment of mice both promote liver secretion of cholesterol into bile, a process that is prevented by concurrent treatment with an ERα antagonist [95] .…”

Mechanisms for estrogen receptor expression in human cancer

“…Estrogen and its receptors may improve memory and social behaviors, regulate brain lipid metabolism and prevent cortical damage following an ischemic episode [ 45 – 47 ]. In addition, estrogen and ER are important for bone homeostasis, hepatic lipid metabolism and reverse cholesterol transport [ 48 , 49 ]. While the liver predominatly expresses ERα, the gastointestinal tract and the lung exclusively harbour ERβ [ 50 ].…”