Hart-Unger S, Arao Y, Hamilton K J, Lierz S L, Malarkey D E, Hewitt S C, Freemark M, Korach K S
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.
Int J Obes (Lond). 2017 Jun;41(6):945-954. doi: 10.1038/ijo.2017.50. Epub 2017 Feb 21.
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.
对绝经早期女性使用雌激素可预防肝脂肪变性和非酒精性脂肪性肝病的发生，但雌激素具有不良副作用，这抵消了其在绝经前和绝经后女性中的有益作用。靶向治疗需要更好地了解雌激素信号在女性中发挥保护作用的靶点和机制。雌激素受体α（ERα）被认为是雌激素信号预防肝脂肪变性的主要介质。ERα有几种信号转导机制：（1）通过直接结合特定DNA序列诱导基因转录，（2）与其他DNA结合因子诱导拴系转录，以及（3）通过膜相关ERα刺激非基因组作用。然而，尚不清楚哪些机制介导了ERα依赖性预防肝脂肪变性。
为了解雌激素信号预防雌性肝脂肪变性的机制，我们分析了喂食高脂饮食（HFD）的全身性ERα基因敲除小鼠（αERKO）、ERαDNA结合结构域突变小鼠（KIKO）和肝脏特异性ERα基因敲除小鼠（LERKO）。KIKO小鼠破坏了直接DNA结合转录活性，但保留了拴系转录调控和非基因组作用。通过对大泡性和小泡性脂肪变性以及血清丙氨酸氨基转移酶（ALT）水平进行评分来评估肝脂肪变性。我们分析血清睾酮以评估其与肝脂肪变性的相关性。
喂食HFD的αERKO和KIKO雌性小鼠的肝脏脂肪积累远多于喂食HFD的野生型（WT）对照。相反，喂食HFD的LERKO雌性小鼠没有积累过多的肝脏脂肪。喂食HFD的αERKO和KIKO雌性小鼠的小泡性脂肪变性和ALT水平高于WT对照，这与血清睾酮水平升高相关。
非肝脏组织中ERα介导的直接转录对于雌激素介导的预防喂食HFD雌性小鼠的肝脂肪变性至关重要。非肝脏雌激素信号与肝脏或非肝脏睾酮作用之间的平衡可能控制肝脂肪变性。
