Ramakrishna Rachumallu, Kumar Durgesh, Bhateria Manisha, Gaikwad Anil Nilkanth, Bhatta Rabi Sankar
Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi 110001, India.
Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi 110001, India.
J Steroid Biochem Mol Biol. 2017 Apr;168:110-117. doi: 10.1016/j.jsbmb.2017.02.013. Epub 2017 Feb 20.
16-Dehydropregnenolone (DHP) has been developed and patented as a promising antihyperlipidemic agent by CSIR-Central Drug Research Institute (CSIR-CDRI), India. Although DHP is implicated in controlling cholesterol homeostasis, the mechanism underlying its pharmacological effect in hyperlipidemic disease models is poorly understood. In the present study, we postulated that DHP lowers serum lipids through regulating the key hepatic genes accountable for cholesterol metabolism. The hypothesis was tested on golden Syrian hamsters fed with high-fat diet (HFD) following oral administration of DHP at a dose of 72mg/kg body weight for a period of one week. The serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and total bile acids (TBA) in feces were measured. Real time comparative gene expression studies were performed for CYP7A1, LXRα and PPARα level in liver tissue of hamsters. The results revealed that the DHP profoundly decreased the levels of serum TC, TG, LDL-C and atherogenic index (AI), whilst elevated the HDL-C/TC ratio. Besides, DHP exhibited an anti-hyperlipidemic effect in the HFD induced hyperlipidemic hamsters by means of: (1) up-regulating the gene expression of CYP7A1 encoded cholesterol 7α-hydroxylase, that promotes the catabolism of cholesterol to bile acid; (2) inducing the gene expression of transcription factors LXRα and PPARα; (3) increasing the TBA excretion through feces. Collectively, the findings presented confer the hypolipidemic activity of DHP via up-regulation of hepatic CYP7A1 pathway that promotes cholesterol-to-bile acid conversion and bile acid excretion.
16-脱氢孕烯醇酮（DHP）已由印度科学与工业研究理事会中央药物研究所（CSIR-CDRI）研发并获得专利，是一种很有前景的抗高血脂药物。尽管DHP与控制胆固醇稳态有关，但其在高脂血症疾病模型中的药理作用机制仍知之甚少。在本研究中，我们推测DHP通过调节负责胆固醇代谢的关键肝脏基因来降低血脂。该假设在给予体重72mg/kg的DHP口服给药一周的高脂饮食（HFD）喂养的金黄叙利亚仓鼠上进行了测试。测量了血清总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）以及粪便中的总胆汁酸（TBA）。对仓鼠肝脏组织中CYP7A1、LXRα和PPARα水平进行了实时比较基因表达研究。结果显示，DHP显著降低了血清TC、TG、LDL-C水平和动脉粥样硬化指数（AI），同时提高了HDL-C/TC比值。此外，DHP通过以下方式在HFD诱导的高脂血症仓鼠中表现出抗高血脂作用：（1）上调编码胆固醇7α-羟化酶的CYP7A1的基因表达，可以促进胆固醇分解为胆汁酸；（2）诱导转录因子LXRα和PPARα的基因表达；（3）增加粪便中TBA的排泄。总的来说，这些研究结果表明DHP通过上调肝脏CYP7A1途径具有降血脂活性，该途径促进胆固醇向胆汁酸的转化和胆汁酸的排泄。
