Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition
Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition
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DOI：
10.1194/jlr.ra120000924
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发表时间：
2020-12-01
影响因子：
6.5
通讯作者：
Pandak, William M.
中科院分区：
文献类型：
--
作者：
Kakiyama, Genta;Marques, Dalila;Pandak, William M.
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，但其从良性非酒精性脂肪肝（NAFL）向NASH转变的生物学因素尚不清楚。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方法的能力下降。在目前的研究中，我们使用了多种NAFLD小鼠模型、人类相关数据和小鼠体内类固醇急性调节蛋白（StarD1）的选择性基因过表达来阐明促进NAFL向NASH转变的可能机制途径。我们发现，氧甾醇7 α -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。具体来说，我们报告的数据显示，在胰岛素抵抗的情况下，无法上调CYP7B1会导致细胞内有毒胆固醇代谢物的积累，从而促进炎症和肝细胞损伤。这种代谢途径由胰岛素抵抗引发并加剧，为NAFLD的治疗提供了新的思路。
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 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 7 alpha -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 upregulate 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.