Hormone signaling and fatty liver in females: analysis of estrogen receptor α mutant mice

BACKGROUND: Treatment with estrogen in early menopausal women protects against development of hepatic steatosis and NAFLD but estrogen has undesirable side effects which negate its beneficial effects in pre- and post-menopausal women. Targeted therapies require better understanding of the target sites and mechanisms by which estrogen signaling exerts its protective effects in women. 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 3) stimulating nongenomic action through membrane associated ERα. However, it is still unclear which mechanisms mediate ERα dependent protection against hepatic steatosis. METHODS: 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 ALT levels. We analyzed serum testosterone to assess its correlation with hepatic steatosis. RESULTS: Liver fat accumulation was far greater in HFD-fed αERKO and KIKO females than in HFD-fed 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 which correlated with increased serum testosterone levels. CONCLUSIONS: 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.