title: 16-Dehydropregnenolone lowers serum cholesterol by up-regulation of CYP7A1 in hyperlipidemic male hamsters.
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 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.
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi 110001, India.
authors.forename: Rachumallu
authors.initials: R
authors.lastname: Ramakrishna
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi 110001, India.
authors.forename: Durgesh
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi 110001, India.
authors.forename: Manisha
authors.initials: M
authors.lastname: Bhateria
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi 110001, India.
authors.forename: Anil Nilkanth
authors.initials: AN
authors.lastname: Gaikwad
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi 110001, India. Electronic address: rabi_bhatta@cdri.res.in.
authors.forename: Rabi Sankar
authors.initials: RS
authors.lastname: Bhatta
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry; D002784:Cholesterol / Q000097:blood*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000097:blood; D006224:Cricetinae; D005243:Feces; D056945:Hep G2 Cells; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood*; D000071518:Liver X Receptors / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D047493:PPAR alpha / Q000378:metabolism*; D011284:Pregnenolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
chemical_list: D001647:Bile Acids and Salts; D008078:Cholesterol, LDL; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D047493:PPAR alpha; D014280:Triglycerides; C003592:16-dehydropregnenolone; D011284:Pregnenolone; D002784:Cholesterol; C553219:CYP7A1 protein, human; D002790:Cholesterol 7-alpha-Hydroxylase
keywords: 16-Dehydropregnenolone; Bile acid; CYP7A1; Cholesterol; HepG2; LXRα; PPARα