title: Kaempferol ameliorates symptoms of metabolic syndrome by regulating activities of liver X receptor-β.
abstract: Kaempferol is a dietary flavonol previously shown to regulate cellular lipid and glucose metabolism. However, its molecular mechanisms of action and target proteins have remained elusive, probably due to the involvement of multiple proteins. This study investigated the molecular targets of kaempferol. Ligand binding of kaempferol to liver X receptors (LXRs) was quantified by time-resolved fluorescence resonance energy transfer and surface plasmon resonance analyses. Kaempferol directly binds to and induces the transactivation of LXRs, with stronger specificity for the β-subtype (EC50 = 0.33 μM). The oral administration of kaempferol in apolipoprotein-E-deficient mice (150 mg/day/kg body weight) significantly reduced plasma glucose and increased high-density lipoprotein cholesterol levels and insulin sensitivity compared with the vehicle-fed control. Kaempferol also reduced plasma triglyceride concentrations and did not cause liver steatosis, a common side effect of potent LXR activation. In immunoblotting analysis, kaempferol reduced the nuclear accumulation of sterol regulatory element-binding protein-1 (SREBP-1). Our results show that the suppression of SREBP-1 activity and the selectivity for LXR-β over LXR-α by kaempferol contribute to the reductions of plasma and hepatic triglyceride concentrations in mice fed kaempferol. They also suggest that kaempferol activates LXR-β and suppresses SREBP-1 to enhance symptoms in metabolic syndrome.
authors.affiliation: Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea; Department of Food Bioscience and Technology, College of Life Sciences and Technology, Korea University, Seoul 136-713, Republic of Korea.
authors.forename: Minh-Hien
authors.initials: MH
authors.lastname: Hoang
authors.affiliation: Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea; Department of Food Bioscience and Technology, College of Life Sciences and Technology, Korea University, Seoul 136-713, Republic of Korea.
authors.forename: Yaoyao
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea; Department of Food Bioscience and Technology, College of Life Sciences and Technology, Korea University, Seoul 136-713, Republic of Korea.
authors.forename: Boram
authors.initials: B
authors.lastname: Mok
authors.affiliation: Life Science Institute, Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Hee-jin
authors.initials: HJ
authors.lastname: Jun
authors.affiliation: Division of Biotechnology, College of Life Sciences and Technology, Korea University, Seoul 136-713, Republic of Korea.
authors.forename: Kwang-Yeon
authors.initials: KY
authors.lastname: Hwang
authors.affiliation: Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea; Department of Food Bioscience and Technology, College of Life Sciences and Technology, Korea University, Seoul 136-713, Republic of Korea. Electronic address: junelee@korea.ac.kr.
authors.forename: Sung-Joon
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001057:Apolipoproteins E / Q000097:blood / Q000172:deficiency; D001786:Blood Glucose / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D015870:Gene Expression; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D044949:Kaempferols / Q000494:pharmacology*; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000037:antagonists & inhibitors / Q000097:blood; D020349:Surface Plasmon Resonance; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D001786:Blood Glucose; D002790:Cholesterol 7-alpha-Hydroxylase; D044949:Kaempferols; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse; C000605214:Nr1h3 protein, mouse; C497388:Srebf1 protein, mouse; C006552:kaempferol; C502772:Cyp7a1 protein, mouse
keywords: Kaempferol; Liver X receptor; Metabolic syndrome; Peroxisome proliferation-activated receptor; Sterol regulatory element-binding protein-1c, Lipid metabolism