Meda Clara, Benedusi Valeria, Cherubini Alessandro, Valenti Luca, Maggi Adriana, Della Torre Sara
Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy.
JHEP Rep. 2024 Jun 13;6(10):101143. doi: 10.1016/j.jhepr.2024.101143. eCollection 2024 Oct.
BACKGROUND & AIMS: The loss of ovarian functions defining menopause leads to profound metabolic changes and heightens the risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD). Although estrogens primarily act on the female liver through estrogen receptor alpha (ERα), the specific contribution of impaired ERα signaling in triggering MASLD after menopause remains unclear.
To address this gap in knowledge, we compared the liver transcriptomes of sham-operated (SHAM) and ovariectomized (OVX) control and liver ERα knockout (LERKO) female mice by performing RNA-Seq analysis.
OVX led to 1426 differentially expressed genes (DEGs) in the liver of control mice compared to 245 DEGs in LERKO mice. Gene ontology analysis revealed a distinct ovariectomy-induced modulation of the liver transcriptome in LERKO compared with controls, indicating that hepatic ERα is functional and necessary for the complete reprogramming of liver metabolism in response to estrogen depletion. Additionally, we observed an ovariectomy-dependent induction of male-biased genes, especially in the liver of control females, pointing to hepatic ERα involvement in the masculinization of the liver after estrogen loss. To investigate the translational relevance of such findings, we assessed liver samples from a cohort of 60 severely obese individuals (51 women; 9 men). Notably, a shift of the liver transcriptome toward a male-like profile was also observed only in obese women with MASLD (n = 43), especially in women ≥51 years old (15/15), suggesting that masculinization of the female liver contributes to MASLD development in obese women.
These results highlight the role of hepatic ERα in driving masculinization of the liver transcriptome following menopause, pointing to this receptor as a potential pharmacological target for preventing MASLD in post-menopausal women.
Despite the increased risk of developing MASLD after menopause, the specific contribution of impaired hepatic estrogen signaling in driving MASLD in females has not been a major research focus, and, thus, has limited the development of tailored strategies that address the specific mechanisms underlying MASLD in post-menopausal women. This study reveals the functional role of hepatic ERα in mediating liver metabolic changes in response to estrogens loss, leading to a shift in the liver transcriptome towards a male-like profile. In women with obesity, this shift is associated with the development of MASLD. These findings underscore the potential of targeting hepatic ERα as a promising approach for developing effective, sex-specific treatments to preserve liver health and prevent or limit the development and progression of MASLD in post-menopausal women.
定义更年期的卵巢功能丧失会导致深刻的代谢变化，并增加发生代谢功能障碍相关脂肪性肝病（MASLD）的风险。尽管雌激素主要通过雌激素受体α（ERα）作用于女性肝脏，但绝经后ERα信号受损在引发MASLD中的具体作用仍不清楚。
为了填补这一知识空白，我们通过RNA测序分析比较了假手术（SHAM）和去卵巢（OVX）对照雌性小鼠以及肝脏ERα基因敲除（LERKO）雌性小鼠的肝脏转录组。
与LERKO小鼠中的245个差异表达基因（DEG）相比，OVX导致对照小鼠肝脏中有1426个DEG。基因本体分析显示，与对照相比，LERKO中卵巢切除诱导的肝脏转录组有明显的调节，表明肝脏ERα具有功能，并且对于响应雌激素耗竭而对肝脏代谢进行完全重新编程是必要的。此外，我们观察到去卵巢依赖性的男性偏向基因的诱导，特别是在对照雌性小鼠的肝脏中，表明肝脏ERα参与雌激素丧失后肝脏的男性化。为了研究这些发现的转化相关性，我们评估了60名严重肥胖个体（51名女性；9名男性）的肝脏样本。值得注意的是，仅在患有MASLD的肥胖女性（n = 43）中，尤其是≥51岁的女性（15/15）中，也观察到肝脏转录组向男性样谱的转变，这表明女性肝脏的男性化有助于肥胖女性中MASLD的发展。
这些结果突出了肝脏ERα在绝经后驱动肝脏转录组男性化中的作用，表明该受体是预防绝经后女性MASLD的潜在药理学靶点。
尽管绝经后发生MASLD的风险增加，但肝脏雌激素信号受损在女性MASLD发生中的具体作用尚未成为主要研究重点，因此限制了针对绝经后女性MASLD潜在机制的定制策略的发展。本研究揭示了肝脏ERα在介导雌激素丧失引起的肝脏代谢变化中的功能作用，导致肝脏转录组向男性样谱转变。在肥胖女性中，这种转变与MASLD的发展有关。这些发现强调了靶向肝脏ERα作为开发有效、性别特异性治疗方法以保护肝脏健康并预防或限制绝经后女性MASLD发生和进展的有前景方法的潜力。
