Lipid-lowering effects of farnesylquinone and related analogues from the marine-derived Streptomyces nitrosporeus

• Published in: Bioorganic & Medicinal Chemistry Letters
• Main Authors: Liu, Dong, Yang, Aigang, Wu, Chongming, Guo, Peng, Proksch, Peter, Lin, Wenhan
• Other Authors: Guo, P (reprint author), Chinese Acad Med Sci, Peking Union Med Coll, Inst Med Plant Dev, Pharmacol & Toxicol Res Ctr, Beijing 100193, Peoples R China., Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China., Chinese Acad Med Sci, Peking Union Med Coll, Inst Med Plant Dev, Pharmacol & Toxicol Res Ctr, Beijing 100193, Peoples R China., Univ Dusseldorf, Inst Pharmazeut Biol & Biotechnol, D-40225 Dusseldorf, Germany.
• Format: Journal/Newspaper
• Language: English
• Published: 生物有机化学与医药化学通讯 2014
• Subjects: Streptomyces nitrosporeus; Nitrosporeunols A-G; Farnesylquinone; Lowering lipid effect; PPAR alpha pathway; CHOLESTEROL-METABOLISM; DERIVATIVES; ANTAGONISTS; DISCOVERY; LIPOLYSIS; RECEPTOR; PATHWAY; CELLS; Arctic
• Online Access: https://hdl.handle.net/20.500.11897/156305; https://doi.org/10.1016/j.bmcl.2014.09.049

Bioassay-guided fractionation of the fermentation broth of Arctic Streptomyces nitrosporeus YBH10-5 resulted in the isolation of seven new compounds named nitrosporeunols A-G (1-7), together with seven known analogues (8-14). Their structures were determined based on extensive spectroscopic analysis. Compounds 1-14 were evaluated for the lowering lipid effects, while two compounds (10 and 12) remarkably decreased lipid levels including total cholesterol (TC) and triglycerides (TG) in HepG2 cells. Quantitative realtime PCR and Western blot indicated that farnesylquinone (12) increased the expression of the key proteins including peroxisome proliferator-activated receptor-alpha (PPAR alpha), peroxisome proliferator-activated receptor-gamma, and coactivator 1 alpha (PGC-1 alpha), as well as their downstream genes carnitine palmitoyltransterase-1 (CPT-1), acyl-coenzyme A oxidase 1 (ACOX), malonyl CoA decarboxylase 1 (MCD1), pyruvate dehydrogenase kinase 4 (PDK4), and cholesterol 7 alpha-hydroxylase (CYP7A1). Luciferase assay showed that 12 increased the transcriptional activity of PPAR alpha, while its lipid-lowering effect was abolished by PPAR alpha inhibitor, MK886, in HepG2 cells. These findings suggested that 12 is a potent lipid-lowering agent which may decrease lipid levels through upregulation of PPAR alpha pathway. (C) 2014 Elsevier Ltd. All rights reserved. http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000343901400032&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701 Chemistry, Medicinal Chemistry, Organic SCI(E) PubMed 2 ARTICLE [e-mail]; [e-mail] 22 5288-5293 24