Center E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
Metabolism. 2021 Mar;116:154464. doi: 10.1016/j.metabol.2020.154464. Epub 2020 Dec 9.
CER-001 is an HDL mimetic that has been tested in different pathological conditions, but never with LCAT deficiency. This study was designed to investigate whether the absence of LCAT affects the catabolic fate of CER-001, and to evaluate the effects of CER-001 on kidney disease associated with LCAT deficiency.
Lcat and wild-type mice received CER-001 (2.5, 5, 10 mg/kg) intravenously for 2 weeks. The plasma lipid/ lipoprotein profile and HDL subclasses were analyzed. In a second set of experiments, Lcat mice were injected with LpX to induce renal disease and treated with CER-001 and then the plasma lipid profile, lipid accumulation in the kidney, albuminuria and glomerular podocyte markers were evaluated.
In Lcat mice a decrease in total cholesterol and triglycerides, and an increase in HDL-c was observed after CER-001 treatment. While in wild-type mice CER-001 entered the classical HDL remodeling pathway, in the absence of LCAT it disappeared from the plasma shortly after injection and ended up in the kidney. In a mouse model of renal disease in LCAT deficiency, treatment with CER-001 at 10 mg/kg for one month had beneficial effects not only on the lipid profile, but also on renal disease, by limiting albuminuria and podocyte dysfunction.
Treatment with CER-001 ameliorates the dyslipidemia typically associated with LCAT deficiency and more importantly limits renal damage in a mouse model of renal disease in LCAT deficiency. The present results provide a rationale for using CER-001 in FLD patients.
CER-001 是一种高密度脂蛋白模拟物，已在多种病理情况下进行了测试，但从未在卵磷脂胆固醇酰基转移酶（LCAT）缺乏症的情况下进行过测试。本研究旨在探讨 LCAT 缺乏是否会影响 CER-001 的代谢命运，并评估 CER-001 对与 LCAT 缺乏相关的肾脏疾病的影响。
Lcat 基因敲除小鼠和野生型小鼠分别静脉注射 CER-001（2.5、5、10mg/kg）2 周，分析其血浆脂质/脂蛋白谱和高密度脂蛋白亚类。在第二组实验中，用 LpX 注射诱导 Lcat 基因敲除小鼠肾脏疾病，并用 CER-001 治疗，然后评估血浆脂质谱、肾脏脂质蓄积、白蛋白尿和肾小球足细胞标志物。
在 Lcat 基因敲除小鼠中，CER-001 治疗后观察到总胆固醇和甘油三酯降低，高密度脂蛋白胆固醇升高。而在野生型小鼠中，CER-001 进入经典的高密度脂蛋白重塑途径，在缺乏 LCAT 的情况下，它在注射后不久就从血浆中消失，并最终进入肾脏。在 LCAT 缺乏的肾脏疾病小鼠模型中，CER-001 以 10mg/kg 的剂量治疗 1 个月不仅对脂质谱有有益影响，而且通过限制白蛋白尿和足细胞功能障碍，对肾脏疾病也有有益影响。
CER-001 治疗可改善与 LCAT 缺乏相关的血脂异常，更重要的是，可限制 LCAT 缺乏的肾脏疾病小鼠模型中的肾脏损伤。这些结果为在脂肪性肝病患者中使用 CER-001 提供了依据。
