title: Lipid-lowering effects of farnesylquinone and related analogues from the marine-derived Streptomyces nitrosporeus.
abstract: 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-α (PPARα), peroxisome proliferator-activated receptor-γ, and coactivator 1α (PGC-1α), 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 7α -hydroxylase (CYP7A1). Luciferase assay showed that 12 increased the transcriptional activity of PPARα, while its lipid-lowering effect was abolished by PPARα inhibitor, MK886, in HepG2 cells. These findings suggested that 12 is a potent lipid-lowering agent which may decrease lipid levels through upregulation of PPARα pathway.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China.
authors.forename: Aigang
authors.initials: A
authors.lastname: Yang
authors.affiliation: Pharmacology and Toxicology Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, PR China.
authors.forename: Chongming
authors.initials: C
authors.lastname: Wu
authors.affiliation: Pharmacology and Toxicology Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, PR China. Electronic address: pguo@implad.ac.cn.
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.affiliation: Institute für Pharmazeutische Biologie und Biotechnologie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, Geb.26.23, 40225 Düsseldorf, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Proksch
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China. Electronic address: whlin@bjmu.edu.cn.
authors.forename: Wenhan
authors.initials: W
authors.lastname: Lin
mesh_terms: D002784:Cholesterol / Q000378:metabolism; D002942:Circular Dichroism; D056945:Hep G2 Cells; D006801:Humans; D000960:Hypolipidemic Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D011809:Quinones / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D013302:Streptomyces / Q000737:chemistry* / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D002722:Chlorobenzenes
chemical_list: D002784:Cholesterol; D000960:Hypolipidemic Agents; D007211:Indoles; D047493:PPAR alpha; D011809:Quinones; D014280:Triglycerides; C060893:MK-886; D002722:Chlorobenzenes
keywords: Farnesylquinone; Lowering lipid effect; Nitrosporeunols A–G; PPARα pathway; Streptomyces nitrosporeus