title: Hormone signaling and fatty liver in females: analysis of estrogen receptor α mutant mice.
abstract: Treatment with estrogen in early menopausal women protects against development of hepatic steatosis and nonalcoholic fatty liver disease but estrogen has undesirable side effects, which negate its beneficial effects in premenopausal and postmenopausal women. Targeted therapies require better understanding of the target sites and mechanisms by which estrogen signaling exerts its protective effects in women. Estrogen receptor α (ERα) is thought to be the primary mediator for estrogen signaling to protect against hepatic steatosis. ERα has several mechanisms for signal transduction: (1) inducing gene transcription by direct binding to specific DNA sequences, (2) inducing tethered transcription with other DNA-binding factors, and (3) stimulating nongenomic action through membrane-associated ERα. However, it is still unclear which mechanisms mediate ERα-dependent protection against hepatic steatosis.
  
  
  
  To understand the mechanisms of estrogen signaling for protection against hepatic steatosis in females, we analyzed the global ERα knockout mouse (αERKO), ERα DNA-binding domain mutant mouse (KIKO) and liver-specific ERα knockout mouse (LERKO) fed high-fat diets (HFD). The KIKO mouse disrupts the direct DNA-binding transcription activity but retains tethered transcription regulation and nongenomic action. Hepatic steatosis was evaluated by scoring the macrovesicular and microvesicular steatosis as well as serum alanine aminotransferase (ALT) levels. We analyzed serum testosterone to assess its correlation with hepatic steatosis.
  
  
  
  Liver fat accumulation was far greater in HFD-fed αERKO and KIKO females than in HFD-fed wild-type (WT) controls. Conversely, HFD-fed LERKO females did not accumulate excess liver fat. HFD-fed αERKO and KIKO females showed higher microvesicular steatosis and ALT levels than WT controls that correlated with increased serum testosterone levels.
  
  
  
  ERα-mediated direct transcription in non-hepatic tissues is essential for estrogen-mediated protection against hepatic steatosis in HFD-fed females. The balance between non-hepatic estrogen signaling and hepatic or non-hepatic testosterone action may control hepatic steatosis.
authors.affiliation: Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC, USA.|Division of Pediatric Endocrinology and Diabetes, Duke University Medical Center, Durham, NC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hart-Unger
authors.affiliation: Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC, USA.
authors.forename: Y
authors.identifier: 0000-0003-1560-351X
authors.initials: Y
authors.lastname: Arao
authors.affiliation: Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Hamilton
authors.affiliation: Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Lierz
authors.affiliation: National Toxicology Program Pathology Group, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Malarkey
authors.affiliation: Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Hewitt
authors.affiliation: Division of Pediatric Endocrinology and Diabetes, Duke University Medical Center, Durham, NC, USA.
authors.forename: M
authors.initials: M
authors.lastname: Freemark
authors.affiliation: Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Korach
mesh_terms: D050154:Adiposity; D000818:Animals; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000235:genetics*; D004967:Estrogens / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D014157:Transcription Factors