Rationale: Men and postmenopausal women are more prone to developing non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) than premenopausal women. However, the pathological links and underlying mechanisms of this disparity are still elusive. The sex-difference in hepatic very low-density lipoprotein (VLDL) assembly and secretion may contribute to NAFLD development. Estrogen-related receptor alpha (ERRα) is a key regulator of several metabolic processes. We hypothesized that ERRα plays a role contributing to the sex-difference in hepatic VLDL assembly and secretion./nMethods: VLDL secretion and essential genes governing said process were assessed in male and female mice. Liver-specific ERRα-deficient (ERRαLKO) mice were generated to assess the rate of hepatic VLDL secretion and alteration in target gene expression. Overexpression of either microsomal triglyceride transfer protein (Mttp) or phospholipase A2 G12B (Pla2g12b) by adenovirus was performed to test if the fatty liver phenotype in male ERRαLKO mice was due to defects in hepatic VLDL secretion. Female ERRαLKO mice were put on a diet high in saturated fat, fructose and cholesterol (HFHC) to promote NASH development. Wild type female mice were either ovariectomized or treated with tamoxifen to induce a state of estrogen deficiency or disruption in estrogen signaling. Adenovirus was used to overexpress ERRα in these mice to test if ERRα was sufficient to rescue the suppressed VLDL secretion due to estrogen dysfunction. Finally, wild type male mice on a high-fat diet (HFD) were treated with an ERRα inverse agonist to assess if suppressing ERRα activity pharmacologically would lead to fatty liver development./nResults: ERRα is an indispensable mediator modulating hepatic triglyceride-rich very low-density lipoprotein (VLDL-TG) assembly and secretion through coordinately controlling target genes apolipoprotein B (Apob), Mttp and Pla2g12b in a sex-different manner. Hepatic VLDL-TG secretion is blunted in ERRαLKO mice, leading to hepatosteatosis which exacerbates endoplasmic reticulum stress and inflammation paving ways for NASH development. Importantly, ERRα acts downstream of estrogen/ERα signaling in contributing to the sex-difference in hepatic VLDL secretion effecting hepatic lipid homeostasis./nConclusions: Our results highlight ERRα as a key mediator which contributes to the sex disparity in NAFLD development, suggesting that selectively restoring ERRα activity in the liver may be a novel strategy for treating NAFLD/NASH.

中文翻译：

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雌激素相关受体 α 依赖性肝脏 VLDL 分泌功能障碍导致 NAFLD/NASH 发展中的性别差异


理由：男性和绝经后女性比绝经前女性更容易患非酒精性脂肪肝/脂肪性肝炎 (NAFLD/NASH)。然而，这种差异的病理联系和潜在机制仍然难以捉摸。肝脏极低密度脂蛋白（VLDL）组装和分泌的性别差异可能导致 NAFLD 的发展。雌激素相关受体 α (ERRα) 是多种代谢过程的关键调节因子。我们假设 ERRα 在肝脏 VLDL 组装和分泌中的性别差异中发挥着重要作用。/n 方法：在雄性和雌性小鼠中评估了 VLDL 分泌和控制所述过程的必需基因。生成肝脏特异性 ERRα 缺陷 (ERRαLKO) 小鼠来评估肝脏 VLDL 分泌率和靶基因表达的变化。通过腺病毒过度表达微粒体甘油三酯转移蛋白 ( Mttp ) 或磷脂酶 A2 G12B ( Pla2g12b )，以测试雄性 ERRαLKO 小鼠的脂肪肝表型是否是由于肝脏 VLDL 分泌缺陷所致。雌性 ERRαLKO 小鼠被摄入高饱和脂肪、果糖和胆固醇 (HFHC) 的饮食，以促进 NASH 的发展。野生型雌性小鼠要么被切除卵巢，要么用他莫昔芬治疗，以诱导雌激素缺乏或雌激素信号传导中断的状态。使用腺病毒在这些小鼠中过度表达 ERRα，以测试 ERRα 是否足以挽救由于雌激素功能障碍而受到抑制的 VLDL 分泌。最后，用 ERRα 反向激动剂治疗高脂饮食 (HFD) 的野生型雄性小鼠，以评估药理学上抑制 ERRα 活性是否会导致脂肪肝的发生。/n结果： ERRα 是调节肝脏富含甘油三酯的极低密度脂蛋白 (VLDL-TG) 组装和分泌的不可或缺的介质，通过以性别不同的方式协调控制靶基因载脂蛋白 B ( Apob )、 Mttp和Pla2g12b 。 ERRαLKO 小鼠肝脏 VLDL-TG 分​​泌减弱，导致肝脂肪变性，加剧内质网应激和炎症，为 NASH 的发展铺平道路。重要的是，ERRα 作用于雌激素/ERα 信号传导的下游，导致肝脏 VLDL 分泌的性别差异，从而影响肝脏脂质稳态。/n结论：我们的结果强调 ERRα 是导致 NAFLD 发展中性别差异的关键介质，这表明选择性恢复肝脏中的 ERRα 活性可能是治疗 NAFLD/NASH 的新策略。