16-Dehydropregnenolone lowers serum cholesterol by up-regulation of CYP7A1 in hyperlipidemic male hamsters. Issue 168 (April 2017)

• Record Type: Journal Article
• Authors: Ramakrishna, Rachumallu; Kumar, Durgesh; Bhateria, Manisha; Gaikwad, Anil Nilkanth; Bhatta, Rabi Sankar
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 168(2017)
• Page Start: 110
• Page End: 117
• Publication Date: 2017-04
• Subjects: 16-Dehydropregnenolone -- Cholesterol -- Bile acid -- CYP7A1 -- LXRα -- PPARα -- HepG2; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2017.02.013
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: DHP decreases serum total cholesterol, triglycerides andLDL-cholesterol levels. DHP elevates the HDL-C/TC ratio, whilst it decreases the atherogenic index. DHP induces mRNA expression of CYP7A1, LXRα and PPARα in HFD-fed hamsters. DHP induces mRNA expression of CYP7A1 and PPARα in HepG2. DHP increases the total bile acid excretion through feces. Abstract: 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 72 mg/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.