Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands; Corcept Therapeutics, Menlo Park, CA, USA.
Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Eur J Pharmacol. 2023 Oct 15;957:176012. doi: 10.1016/j.ejphar.2023.176012. Epub 2023 Aug 25.
Non-alcoholic fatty liver disease (NAFLD) is a common condition that can progress to the more severe conditions like non-alcoholic steatohepatitis (NASH) for which limited effective therapeutic options are available. In this study, we set out to evaluate the novel glucocorticoid receptor modulator CORT125385, an analogue of the previously studied miricorilant but without mineralocorticoid receptor binding activity. Male and female mice that received high-fat diet and fructose water were treated with either vehicle, CORT125385 or mifepristone. We found that CORT125385 significantly lowered hepatic triglyceride levels in male mice, and hepatic triglyceride and cholesterol levels in female mice. Mifepristone treatment had no effect in male mice, but significantly lowered hepatic triglyceride and cholesterol levels in female mice. In reporter assays in vitro, CORT125385 showed weak partial agonism on the progesterone receptor (PR) at high doses, as well as PR antagonism at a potency 1000-fold lower than mifepristone. In vivo, CORT125385 treatment did not influence PR-responsive gene expression in the oviduct, while mifepristone treatment strongly influenced these genes in the oviduct, thus excluding in vivo PR cross-reactivity of CORT125385 at a therapeutically active dose. We conclude that CORT125385 is a promising glucocorticoid receptor modulator that effectively reduces liver steatosis in male and female mice without affecting other steroid receptors at doses that lower hepatic lipid content.
非酒精性脂肪性肝病（NAFLD）是一种常见疾病，可进展为更严重的疾病，如非酒精性脂肪性肝炎（NASH），目前对此类疾病的有效治疗方法有限。在本研究中，我们评估了新型糖皮质激素受体调节剂 CORT125385，它是先前研究的米利酮类似物，但没有盐皮质激素受体结合活性。接受高脂肪饮食和果糖水的雄性和雌性小鼠分别用载体、CORT125385 或米非司酮治疗。我们发现 CORT125385 可显著降低雄性小鼠的肝甘油三酯水平，并降低雌性小鼠的肝甘油三酯和胆固醇水平。米非司酮治疗对雄性小鼠没有影响，但可显著降低雌性小鼠的肝甘油三酯和胆固醇水平。在体外报告基因检测中，CORT125385 在高剂量下对孕激素受体（PR）显示出较弱的部分激动作用，并且其对 PR 的拮抗作用比米非司酮低 1000 倍。在体内，CORT125385 处理不会影响输卵管中 PR 反应性基因的表达，而米非司酮处理强烈影响输卵管中的这些基因，因此排除了 CORT125385 在治疗有效剂量下对 PR 的体内交叉反应性。我们得出结论，CORT125385 是一种很有前途的糖皮质激素受体调节剂，可有效降低雄性和雌性小鼠的肝脂肪变性，而在降低肝脂质含量的剂量下，不会影响其他甾体受体。
