Squalene Epoxidase Induces Nonalcoholic Steatohepatitis Via Binding to Carbonic Anhydrase III and is a Therapeutic Target
Squalene Epoxidase Induces Nonalcoholic Steatohepatitis Via Binding to Carbonic Anhydrase III and is a Therapeutic Target
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DOI：
10.1053/j.gastro.2021.02.051
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发表时间：
2021-05-26
期刊：
影响因子：
29.4
通讯作者：
Yu, Jun
中科院分区：
文献类型：
--
作者：
Liu, Dabin;Wong, Chi Chun;Yu, Jun
目的：角鲨烯环氧酶（SQLE）是胆固醇生物合成的限速酶。我们阐明了SQLE在非酒精性脂肪性肝炎（NASH）中的功能意义、分子机制和临床影响。方法：我们对肝细胞特异性Sqle过表达转基因（Sqle tg）小鼠和给予高脂高胆固醇（HFHC）或蛋氨酸和胆碱缺乏（MCD）饮食诱导NASH的小鼠进行了研究。SQLE下游靶碳酸酐酶III（CA 3）的鉴定使用免疫共沉淀和蛋白质印迹。部分小鼠给予SQLE抑制剂（特比萘芬）和CA 3抑制剂（乙酰唑胺）以研究NASH的治疗作用。分析包括65例脂肪病、80例NASH和72例健康对照的人样品（N = 217）的肝组织和血清中的SQLE水平。结果：SQLE在人NASH和NASH小鼠模型中高度上调。Sqle tg小鼠引发自发性胰岛素抵抗、肝脂肪变性、肝损伤，并加速HFHC或MCD饮食诱导的NASH发展。从机制上讲，SQLE tg小鼠引起肝脏胆固醇蓄积，从而触发促炎性核因子-kB信号传导和脂肪性肝炎。SQLE直接与CA 3结合，CA 3诱导固醇调节元件结合蛋白1C活化、乙酰辅酶A羧化酶、脂肪酸合成酶和硬脂酰辅酶A去饱和酶1表达以及从头肝脂肪生成。联合靶向SQLE（特比萘芬）和CA 3（乙酰唑胺）协同改善小鼠的NASH，其疗效上级单独使用任何一种药物。血清SQLE与CA 3可以区分NASH患者与脂肪变性和健康对照（受试者工作特征曲线下面积，0.815; 95%置信区间，0.758-0.871）。结论：SQLE通过诱导胆固醇生物合成和SQLE/CA 3轴介导的脂肪生成来驱动NASH的发生和发展。SQLE和CA 3的组合靶向在NASH中赋予治疗益处。血清SQLE和CA 3是NASH患者非侵入性诊断的新生物标志物。
BACKGROUNDS & AIMS: Squalene epoxidase (SQLE) is the rate-limiting enzyme for cholesterol biosynthesis. We elucidated the functional significance, molecular mechanisms, and clinical impact of SQLE in nonalcoholic steatohepatitis (NASH). METHODS: We performed studies with hepatocyte-specific Sqle overexpression transgenic (Sqle tg) mice and mice given high-fat high-cholesterol (HFHC) or methionine- and choline-deficient (MCD) diet to induce NASH. SQLE downstream target carbonic anhydrase III (CA3) was identified using coimmunoprecipitation and Western Blot. Some mice were given SQLE inhibitor (terbinafine) and CA3 inhibitor (acetazolamide) to study the therapeutic effects in NASH. Human samples (N = 217) including 65 steatoses, 80 NASH, and 72 healthy controls were analyzed for SQLE levels in liver tissue and in serum. RESULTS: SQLE is highly up-regulated in human NASH and mouse models of NASH. Sqle tg mice triggered spontaneous insulin resistance, hepatic steatosis, liver injury, and accelerated HFHC or MCD diet-induced NASH development. Mechanistically, SQLE tg mice caused hepatic cholesterol accumulation, thereby triggering proinflammatory nuclear factor-kB signaling and steatohepatitis. SQLE directly bound to CA3, which induced sterol regulatory element-binding protein 1C activation, acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase1 expression and de novo hepatic lipogenesis. Combined targeting SQLE (terbinafine) and CA3 (acetazolamide) synergistically ameliorated NASH in mice with superior efficacy to either drug alone. Serum SQLE with CA3 could distinguish patients with NASH from steatosis and healthy controls (area under the receiver operating characteristic curve, 0.815; 95% confidence interval, 0.758-0.871). CONCLUSIONS: SQLE drives the initiation and progression of NASH through inducing cholesterol biosynthesis, and SQLE/CA3 axis-mediated lipogenesis. Combined targeting of SQLE and CA3 confers therapeutic benefit in NASH. Serum SQLE and CA3 are novel biomarkers for the noninvasive diagnosis of patients with NASH.