Nonalcoholic fatty liver disease (NAFLD) is an important public health issue closely associated with the pervasive epidemics of diabetes and obesity. Yet, despite NAFLD being among the most common of chronic liver diseases, the biological factors responsible for its transition from benign nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) remain unclear. This lack of knowledge leads to a decreased ability to find relevant animal models, predict disease progression or develop clinical treatments. In the current study, we used multiple mouse models of NAFLD, human correlation data, and selective gene overexpression of steroidogenic acute regulatory protein (StarD1) in mice to elucidate a plausible mechanistic pathway for promoting the transition from NAFL to NASH. We show that oxysterol 7α-hydroxylase (CYP7B1) controls the levels of intracellular regulatory oxysterols generated by the "acidic/alternative" pathway of cholesterol metabolism. Specifically, we report data showing that an inability to up-regulate CYP7B1, in the setting of insulin resistance, results in the accumulation of toxic intracellular cholesterol metabolites that promote inflammation and hepatocyte injury. This metabolic pathway, initiated and exacerbated by insulin resistance, offers insight into approaches for the treatment of NAFLD.

中文翻译：

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胰岛素抵抗使 CYP7B1 失调导致氧甾醇积累：NAFL 到 NASH 转变的途径。

非酒精性脂肪性肝病 (NAFLD) 是一个重要的公共卫生问题，与糖尿病和肥胖症的普遍流行密切相关。然而，尽管 NAFLD 是最常见的慢性肝病之一，但导致其从良性非酒精性脂肪肝 (NAFL) 转变为非酒精性脂肪性肝炎 (NASH) 的生物学因素仍不清楚。这种知识的缺乏导致寻找相关动物模型、预测疾病进展或开发临床治疗的能力下降。在目前的研究中，我们使用多个 NAFLD 小鼠模型、人类相关数据和小鼠类固醇生成急性调节蛋白 (StarD1) 的选择性基因过表达来阐明促进从 NAFL 向 NASH 转变的合理机制途径。我们表明氧甾醇 7α-羟化酶 (CYP7B1) 控制由胆固醇代谢的“酸性/替代”途径产生的细胞内调节氧甾醇的水平。具体而言，我们报告的数据显示，在胰岛素抵抗的情况下，无法上调 CYP7B1，会导致有毒的细胞内胆固醇代谢物积聚，从而促进炎症和肝细胞损伤。这种由胰岛素抵抗引发和加剧的代谢途径提供了对 NAFLD 治疗方法的深入了解。导致有毒细胞内胆固醇代谢物的积累，从而促进炎症和肝细胞损伤。这种由胰岛素抵抗引发和加剧的代谢途径提供了对 NAFLD 治疗方法的深入了解。导致有毒细胞内胆固醇代谢物的积累，从而促进炎症和肝细胞损伤。这种由胰岛素抵抗引发和加剧的代谢途径提供了对 NAFLD 治疗方法的深入了解。