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

ABSTRACT: OBJECTIVE:Hepatocyte deletion of estrogen receptor alpha (LKO-ER?) worsens fatty liver, dyslipidemia, and insulin resistance in high-fat diet fed female mice. However, whether or not hepatocyte ER? regulates reverse cholesterol transport (RCT) in mice has not yet been reported. METHODS AND RESULTS:Using LKO-ER? mice and wild-type (WT) littermates fed a Western-type diet, we found that deletion of hepatocyte ER? 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 ER? 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-ER? increased serum cholesterol levels and increased HDL particle sizes. Deletion of hepatocyte ER? 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-ER? mice compared to WT controls. CONCLUSIONS:Estrogen signaling through hepatocyte ER? 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.

SUBMITTER: Zhu L 

PROVIDER: S-EPMC5985047 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature