Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
Department of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.
Gastroenterology. 2021 Jun;160(7):2467-2482.e3. doi: 10.1053/j.gastro.2021.02.051. Epub 2021 Feb 27.
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).
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 co-immunoprecipitation 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.
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-κB 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).
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.
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。
我们使用肝细胞特异性 Sqle 过表达转基因（Sqle tg）小鼠以及给予高脂肪高胆固醇（HFHC）或蛋氨酸和胆碱缺乏（MCD）饮食的小鼠进行研究，以诱导 NASH。通过免疫共沉淀和 Western Blot 鉴定 SQLE 的下游靶标碳酸酐酶 III（CA3）。一些小鼠给予 SQLE 抑制剂（特比萘芬）和 CA3 抑制剂（乙酰唑胺）以研究 NASH 的治疗效果。分析了 217 个人类样本（包括 65 例脂肪变性、80 例 NASH 和 72 例健康对照者）的肝组织和血清中的 SQLE 水平。
SQLE 在人类 NASH 和 NASH 小鼠模型中高度上调。Sqle tg 小鼠自发引发胰岛素抵抗、肝脂肪变性、肝损伤，并加速 HFHC 或 MCD 饮食诱导的 NASH 发展。机制上，Sqle tg 小鼠引起肝胆固醇积累，从而引发促炎核因子-κB 信号和脂肪性肝炎。SQLE 直接与 CA3 结合，诱导固醇调节元件结合蛋白 1C 激活、乙酰辅酶 A 羧化酶、脂肪酸合酶和硬脂酰辅酶 A 去饱和酶 1 表达和新的肝内脂质生成。联合靶向 SQLE（特比萘芬）和 CA3（乙酰唑胺）协同改善了小鼠的 NASH，其疗效优于单独使用任一药物。血清 SQLE 与 CA3 可将 NASH 患者与脂肪变性和健康对照者区分开来（接受者操作特征曲线下面积，0.815；95%置信区间，0.758-0.871）。
SQLE 通过诱导胆固醇生物合成和 SQLE/CA3 轴介导的脂肪生成，驱动 NASH 的起始和进展。联合靶向 SQLE 和 CA3 可改善 NASH 的治疗效果。血清 SQLE 和 CA3 是用于非侵入性诊断 NASH 患者的新型生物标志物。
