title: Transcriptional regulation of human and rat hepatic lipid metabolism by the grapefruit flavonoid naringenin: role of PPARalpha, PPARgamma and LXRalpha.
abstract: Disruption of lipid and carbohydrate homeostasis is an important factor in the development of prevalent metabolic diseases such as diabetes, obesity, and atherosclerosis. Therefore, small molecules that could reduce insulin dependence and regulate dyslipidemia could have a dramatic effect on public health. The grapefruit flavonoid naringenin has been shown to normalize lipids in diabetes and hypercholesterolemia, as well as inhibit the production of HCV. Here, we demonstrate that naringenin regulates the activity of nuclear receptors PPARalpha, PPARgamma, and LXRalpha. We show it activates the ligand-binding domain of both PPARalpha and PPARgamma, while inhibiting LXRalpha in GAL4-fusion reporters. Using TR-FRET, we show that naringenin is a partial agonist of LXRalpha, inhibiting its association with Trap220 co-activator in the presence of TO901317. In addition, naringenin induces the expression of PPARalpha co-activator, PGC1alpha. The flavonoid activates PPAR response element (PPRE) while suppressing LXRalpha response element (LXRE) in human hepatocytes, translating into the induction of PPAR-regulated fatty acid oxidation genes such as CYP4A11, ACOX, UCP1 and ApoAI, and inhibition of LXRalpha-regulated lipogenesis genes, such as FAS, ABCA1, ABCG1, and HMGR. This effect results in the induction of a fasted-like state in primary rat hepatocytes in which fatty acid oxidation increases, while cholesterol and bile acid production decreases. Our findings explain the myriad effects of naringenin and support its continued clinical development. Of note, this is the first description of a non-toxic, naturally occurring LXRalpha inhibitor.
authors.affiliation: Center for Engineering in Medicine, Shriners Burns Hospital, Boston, Massachusetts, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Goldwasser
authors.forename: Pazit Y
authors.initials: PY
authors.lastname: Cohen
authors.forename: Eric
authors.initials: E
authors.lastname: Yang
authors.forename: Patrick
authors.initials: P
authors.lastname: Balaguer
authors.forename: Martin L
authors.initials: ML
authors.lastname: Yarmush
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Nahmias
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis; D032083:Citrus paradisi / Q000737:chemistry*; D015536:Down-Regulation / Q000187:drug effects; D005215:Fasting; D005227:Fatty Acids / Q000096:biosynthesis / Q000378:metabolism; D044950:Flavanones / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007657:Ketone Bodies / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D014280:Triglycerides / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001647:Bile Acids and Salts; D005227:Fatty Acids; D044950:Flavanones; D007657:Ketone Bodies; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D014280:Triglycerides; D002784:Cholesterol; C005273:naringenin
references.citation: J Virol. 2008 Mar;82(5):2120-9
references.pmid: 18077707
references.citation: Biochem Biophys Res Commun. 2002 Apr 26;293(1):338-43
references.pmid: 12054605
references.citation: Cell Signal. 2003 Apr;15(4):355-66
references.pmid: 12618210
references.citation: Biochim Biophys Acta. 2003 Mar 17;1631(2):107-18
references.pmid: 12633677
references.citation: Mol Endocrinol. 2003 Jun;17(6):1019-26
references.pmid: 12663743
references.citation: Clin Nutr. 2003 Dec;22(6):561-8
references.pmid: 14613759
references.citation: Chem Pharm Bull (Tokyo). 2007 Dec;55(12):1750-4
references.pmid: 18057753
references.citation: Vascul Pharmacol. 2002 Apr;38(4):249-56
references.pmid: 12449021
references.citation: J Biol Chem. 2003 Oct 17;278(42):40736-43
references.pmid: 12917410
references.citation: Nat Rev Drug Discov. 2004 Nov;3(11):950-64
references.pmid: 15520817
references.citation: Nat Clin Pract Endocrinol Metab. 2007 Feb;3(2):145-56
references.pmid: 17237841
references.citation: Endocrinology. 2003 Jun;144(6):2201-7
references.pmid: 12746275
references.citation: J Med Food. 2006 Winter;9(4):582-6
references.pmid: 17201649
references.citation: Pharm Res. 2004 Sep;21(9):1531-8
references.pmid: 15497675
references.citation: Nature. 2007 Jan 11;445(7124):219-23
references.pmid: 17187055
references.citation: Cancer Inform. 2008;6:381-7
references.pmid: 19259418
references.citation: Biochem Biophys Res Commun. 2001 Jun 15;284(3):681-8
references.pmid: 11396955
references.citation: Diabetes Care. 2003 Mar;26(3):917-32
references.pmid: 12610059
references.citation: Cell. 2002 Feb 22;108(4):465-74
references.pmid: 11909518
references.citation: Annu Rev Biochem. 1980;49:395-420
references.pmid: 6157353
references.citation: J Lipid Res. 2001 May;42(5):725-34
references.pmid: 11352979
references.citation: Mol Endocrinol. 2003 Jul;17(7):1255-67
references.pmid: 12730332
references.citation: J Lipid Res. 2002 Sep;43(9):1544-54
references.pmid: 12235187
references.citation: Hepatology. 2007 Mar;45(3):767-77
references.pmid: 17326203
references.citation: Lipids. 2004 Feb;39(2):143-51
references.pmid: 15134141
references.citation: Nutrition. 2006 May;22(5):546-52
references.pmid: 16483743
references.citation: Mol Cell Biol. 2000 Mar;20(5):1868-76
references.pmid: 10669761
references.citation: Proc Natl Acad Sci U S A. 1992 May 15;89(10):4653-7
references.pmid: 1316614
references.citation: J Biol Chem. 1996 Apr 19;271(16):9189-92
references.pmid: 8621574
references.citation: Cell. 2000 Sep 15;102(6):731-44
references.pmid: 11030617
references.citation: Mol Endocrinol. 2000 May;14(5):741-52
references.pmid: 10809236
references.citation: Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5723-7
references.pmid: 8390676
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5848-53
references.pmid: 17376867
references.citation: Mol Cell Biol. 2001 Nov;21(22):7558-68
references.pmid: 11604492
references.citation: Mol Endocrinol. 2003 Jul;17(7):1240-54
references.pmid: 12730331
references.citation: Diabetes. 2003 Oct;52(10):2554-61
references.pmid: 14514640
references.citation: Nat Prod Rep. 2009 Aug;26(8):1001-43
references.pmid: 19636448
references.citation: Biochem Biophys Res Commun. 2009 Jul 3;384(3):389-93
references.pmid: 19410560
references.citation: Hepatology. 2009 Apr;49(4):1122-31
references.pmid: 19105208
references.citation: Biochem J. 2008 Dec 1;416(2):219-30
references.pmid: 18782084
references.citation: Ann Pharmacother. 2007 Jun;41(6):973-83
references.pmid: 17519293
references.citation: Hepatology. 2009 Jan;49(1):306-17
references.pmid: 19065650
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10588-93
references.pmid: 9380679
references.citation: Diabetes. 2009 Oct;58(10):2198-210
references.pmid: 19592617
references.citation: Drug Discov Today. 2008 Mar;13(5-6):211-8
references.pmid: 18342796
references.citation: Hepatology. 2008 May;47(5):1437-45
references.pmid: 18393287
references.citation: Mol Cell Biol. 2001 May;21(9):2991-3000
references.pmid: 11287605
references.citation: Circ Res. 2004 Oct 1;95(7):660-70
references.pmid: 15459087
references.citation: Anal Biochem. 2005 Sep 1;344(1):8-15
references.pmid: 16038868
references.citation: Diabetes. 2005 Jun;54(6):1676-83
references.pmid: 15919788
references.citation: Hepatology. 2009 May;49(5):1537-44
references.pmid: 19291789
references.citation: Phytother Res. 2008 Oct;22(10):1400-3
references.pmid: 18690615
references.citation: Ann Nutr Metab. 1999;43(3):173-80
references.pmid: 10545673
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15714-9
references.pmid: 19720996
references.citation: Transl Res. 2007 Jan;149(1):15-21
references.pmid: 17196518