Transcriptional regulation of human and rat hepatic lipid metabolism by the grapefruit flavonoid naringenin: Role of PPARα, PPARγ and LXRα

PLoS ONE

Volumn 5, Issue 8, 2010, Pages

  Goldwasser, Jonathan ^a,b   Cohen, Pazit Y ^c   Yang, Eric ^a,d   Balaguer, Patrick ^e   Yarmush, Martin L ^a,d   Nahmias, Yaakov ^a,c,d  

^a SHRINERS HOSPITALS FOR CHILDREN   (United States)

^b HARVARD MIT DIVISION OF HEALTH SCIENCES AND TECHNOLOGY   (United States)

^c HEBREW UNIVERSITY OF JERUSALEM   (Israel)

^d MASSACHUSETTS GENERAL HOSPITAL   (United States)

^e INSERM   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ABC TRANSPORTER A1; ABC TRANSPORTER G1; ACYL COENZYME A OXIDASE; APOLIPOPROTEIN A1; BILE ACID; CYTOCHROME P450 4A11; FAS ANTIGEN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE; KETONE BODY; LIPID; LIVER X RECEPTOR ALPHA; NARINGENIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; TRANSCRIPTION FACTOR GAL4; TRIACYLGLYCEROL; UNCOUPLING PROTEIN 1; UREA; CHOLESTEROL; FATTY ACID; FLAVANONE DERIVATIVE; LIVER X RECEPTOR; ORPHAN NUCLEAR RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BILE ACID SYNTHESIS; BINDING SITE; CELL METABOLISM; CHOLESTEROL SYNTHESIS; CONCENTRATION RESPONSE; CONTROLLED STUDY; DOWN REGULATION; DRUG EFFECT; DRUG MECHANISM; FATTY ACID OXIDATION; FEMALE; FLUORESCENCE RESONANCE ENERGY TRANSFER; GENE EXPRESSION REGULATION; GENE INDUCTION; GRAPEFRUIT; HORMONE INHIBITION; HORMONE RESPONSIVE ELEMENT; HUMAN; HUMAN CELL; HUMAN VERSUS ANIMAL COMPARISON; IN VITRO STUDY; LIGAND BINDING; LIPID LIVER LEVEL; LIPID METABOLISM; LIPOGENESIS; LIVER CELL; METABOLIC REGULATION; NONHUMAN; RAT; TRANSCRIPTION REGULATION; UPREGULATION; ANIMAL; BIOSYNTHESIS; CELL LINE; CHEMISTRY; CYTOLOGY; DIET RESTRICTION; DNA RESPONSIVE ELEMENT; DRUG POTENTIATION; GENETIC TRANSCRIPTION; GENETICS; LIVER; METABOLISM; OXIDATION REDUCTION REACTION;

CITRUS X PARADISI; HEPATITIS C VIRUS; RATTUS;

ANIMALS; BILE ACIDS AND SALTS; CELL LINE; CHOLESTEROL; CITRUS PARADISI; DOWN-REGULATION; FASTING; FATTY ACIDS; FLAVANONES; HEPATOCYTES; HUMANS; KETONE BODIES; LIPID METABOLISM; LIVER; ORPHAN NUCLEAR RECEPTORS; OXIDATION-REDUCTION; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS; PPAR ALPHA; PPAR GAMMA; RATS; RESPONSE ELEMENTS; TRANSCRIPTION, GENETIC; TRIGLYCERIDES; UP-REGULATION;

EID: 77957871769     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0012399     Document Type: Article

References (64)

1. McGarry JD, Foster DW (1980) Regulation of hepatic fatty acid oxidation and ketone body production. Annu Rev Biochem 49: 395-420.
2. Gastaldelli A, Kozakova M, Hojlund K, Flyvbjerg A, Favuzzi A, et al. (2009) Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population. Hepatology 49: 1537-1544.
3. Buchman A, Korenblatt K, Klein S (2006) Nutrition and the Liver. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff's diseases of the liver. Philadelphia: Lippincott, Wiliams, and Wilkins Co.
4. Hogan P, Dall T, Nikolov P, Association AD (2003) Economic costs of diabetes in the US in 2002. Diabetes Care 26: 917-932.
5. Wilcox LJ, Borradaile NM, Huff MW (1999) Antiatherogenic Properties of Naringenin, a Citrus Flavonoid. Cardiovascular Drug Reviews 17: 160-178.
6. Crozier A, Jaganath IB, Clifford MN (2009) Dietary phenolics: chemistry, bioavailability and effects on health. Natural product reports 26: 1001-1043.
7. Jung UJ, Kim HJ, Lee JS, Lee MK, Kim HO, et al. (2003) Naringin supplementation lowers plasma lipids and enhances erythrocyte antioxidant enzyme activities in hypercholesterolemic subjects. Clinical Nutrition 22: 561-568.
8. Kurowska E, Borradaile N, Spence JD, Carroll KK (2000) Hypocholesterolemic effects of dietary citrus juices in rabbits. Nutr Res 20: 121-129.
9. Lee C-H, Jeong T-S, Choi Y-K, Hyun B-H, Oh G-T, et al. (2001) Antiatherogenic effect of citrus flavonoids, naringin and naringenin, associated with hepatic ACAT and aortic VCAM-1 and MCP-1 in high cholesterol-fed rabbits. Biochem Biophys Res Commun 284: 681-688.
10. Kim S-Y, Kim H-J, Lee M-K, Jeon S-M, Do G-M, et al. (2006) Naringin timedependently lowers hepatic cholesterol biosynthesis and plasma cholesterol in rats fed high-fat and high-cholesterol diet. J Med Food 9: 582-586.
11. Wilcox LJ, Borradaile NM, Dreu LEd, Huff MW (2001) Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP. Journal of Lipid Research 42: 725-734.
12. Kurowska EM, Manthey JA, Casaschi A, Theriault AG (2004) Modulation of HepG2 Cell Net Apolipoprotein B Secretion by the Citrus Polymethoxyflavone, Tangeretin. Lipids 39: 143-151.
13. Borradaile NM, Dreu LEd, Barrett PHR, Huff MW (2002) Inhibition of hepatocyte apoB secretion by naringenin: enhanced rapid intracellular degradation independent of reduced microsomal cholesteryl esters. Journal of Lipid Research 43: 1544-1554.
14. Borradaile NM, Dreu LEd, Huff MW (2003) Inhibition of Net HepG2 Cell Apolipoprotein B Secretion by the Citrus Flavonoid Naringenin Involves Activation of Phosphatidylinositol 3-Kinase, Independent of Insulin Receptor Substrate-1 Phosphorylation. Diabetes 52: 2554-2561.
15. Huong DT, Takahashi Y, Ide T (2006) Activity and mRNA levels of enzymes involved in hepatic fatty acid oxidation in mice fed citrus flavonoids. Nutrition 22: 546-552.
16. Liu L, Shan S, Zhang K, Ning Z-Q, Lu X-P, et al. (2008) Naringenin and Hesperetin, Two Flavonoids Derived from Citrus aurantium Up-regulate Transcription of Adiponectin. Phytotherapy Research 22: 1400-1403.
17. Mulvihill EE, Allister EM, Sutherland BG, Telford DE, Sawyez CG, et al. (2009) Naringenin prevents dyslipidemia, apoB overproduction and hyperinsulinemia in LDL-receptor null mice with diet-induced insulin resistance. Diabetes.
18. Lee C-H, Olson P, Evans RM (2003) Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology 144: 2201-2207.
19. Gervois P, Fruchart J, Staels B (2007) Drug Insight: mechanisms of action and therapeutic applications for agonists of peroxisome proliferator-activated receptors. Nature clinical practice Endocrinology & metabolism 3: 145-156.
20. Seimandi M, Lemaire G, Pillon A, Perrin A, Carlavan I, et al. (2005) Differential responses of PPARalpha, PPARdelta, and PPARgamma reporter cell lines to selective PPAR synthetic ligands. Anal Biochem 344: 8-15.
21. Nahmias Y, Goldwasser J, Casali M, van Poll D, Wakita T, et al. (2008) Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin. Hepatology 47: 1437-1445.
22. Lee SH, Park YB, Bae KH, Bok SH, Kwon YK, et al. (1999) Cholesterollowering activity of naringenin via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase and acyl coenzyme A:cholesterol acyltransferase in rats. Ann Nutr Metab 43: 173-180.
23. Borradaile NM, de Dreu LE, Huff MW (2003) Inhibition of net HepG2 cell apolipoprotein B secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation. Diabetes 52: 2554-2561.
24. Gupta S, Pandak WM, Hylemon PB (2002) LXR alpha is the dominant regulator of CYP7A1 transcription. Biochem Biophys Res Commun 293: 338-343.
25. di Fabiani E, Crestani M, Mitro N (2004) Lipid-activated nuclear receptors: from gene transcription to the control of cellular metabolism. Eur J Lipid Sci Technol 106: 432-450.
26. Mittra S, Bansal VS, Bhatnagar PK (2008) From a glucocentric to a lipocentric approach towards metabolic syndrome. Drug Discovery Today 13: 211-218.
27. Gronemeyer H, Gustafsson JA, Laudet V (2004) Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3: 950-964.
28. Ory DS (2004) Nuclear receptor signaling in the control of cholesterol homeostasis: have the orphans found a home? Circulation Research 95: 660-670.
29. Mitro N, Mak PA, Vargas L, Godio C, Hampton E, et al. (2007) The nuclear receptor LXR is a glucose sensor. Nature 445: 219-223.
30. Edwards PA, Kennedy MA, Mak PA (2002) LXRs; oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis. Vascul Pharmacol 38: 249-256.
31. Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, et al. (2000) Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102: 731-744.
32. Gottlicher M, Widmark E, Li Q, Gustafsson JA (1992) Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc Natl Acad Sci U S A 89: 4653-4657.
33. Martin PGP, Guillou H, Lasserre F, Déjean S, Lan A, et al. (2007) Novel aspects of PPARalpha-mediated regulation of lipid and xenobiotic metabolism revealed through a nutrigenomic study. Hepatology 45: 767-777.
34. Van Raalte DH, Min L, Pritchard PH, Wasan KM (2004) Peroxisome proliferator-activated receptor (PPAR)-alpha: a pharmacological target with a promising future. Pharm Res 21: 1531-1538.
35. Vuppalanchi R, Chalasani N (2009) Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: Selected practical issues in their evaluation and management. Hepatology 49: 306-317.
36. Millatt LJ, Bocher V, Fruchart J-C, Staels B (2003) Liver X receptors and the control of cholesterol homeostasis: potential therapeutic targets for the treatment of atherosclerosis. Biochim Biophys Acta 1631: 107-118.
37. Forman, Ruan, Chen, Schroepfer, Evans (1997) The orphan nuclear receptor LXRalpha is positively and negatively regulated by distinct products of mevalonate metabolism. Proc Natl Acad Sci USA 94: 10588-10593.
38. Yoshikawa T, Shimano H, Amemiya-Kudo M, Yahagi N, Hasty A, et al. (2001) Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Molecular and Cellular Biology 21: 2991-3000.
39. Pawar, Botolin, Mangelsdorf, Jump (2003) The Role of Liver X Receptor-a in the Fatty Acid Regulation of Hepatic Gene Expression. Journal of Biological Chemistry.
40. Vega RB, Huss JM, Kelly DP (2000) The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Molecular and Cellular Biology 20: 1868-1876.
41. Son YL, Lee YC (2009) Molecular determinants of the interactions between LXR/RXR heterodimers and TRAP220. Biochem Biophys Res Commun 384: 389-393.
42. Ide T, Shimano H, Yoshikawa T, Yahagi N, Amemiya-Kudo M, et al. (2003) Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. II. LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling. Molecular Endocrinology 17: 1255-1267.
43. Yoshikawa T, Ide T, Shimano H, Yahagi N, Amemiya-Kudo M, et al. (2003) Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha andliver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling. Molecular Endocrinology 17: 1240-1254.
44. Miyata KS, McCaw SE, Patel HV, Rachubinski RA, Capone JP (1996) The orphan nuclear hormone receptor LXR alpha interacts with the peroxisome proliferator-activated receptor and inhibits peroxisome proliferator signaling. J Biol Chem 271: 9189-9192.
45. Laffitte BA, Joseph SB, Walczak R, Pei L, Wilpitz DC, et al. (2001) Autoregulation of the human liver X receptor alpha promoter. Molecular and Cellular Biology 21: 7558-7568.
46. Tobin KA, Steineger HH, Alberti S, Spydevold O, Auwerx J, et al. (2000) Crosstalk between fatty acid and cholesterol metabolism mediated by liver X receptoralpha. Molecular Endocrinology 14: 741-752.
47. Hu X, Li S, Wu J, Xia C, Lala D (2003) Liver X receptors interact with corepressors to regulate gene expression. Molecular Endocrinology 17: 1019-1026.
48. Rochette-Egly C (2003) Nuclear receptors: integration of multiple signalling pathways through phosphorylation. Cellular Signal 15: 355-356.
49. McKenna NJ, O'Malley BW (2002) Combinatorial Control of Gene Expression by Nuclear Receptors and Coregulators. Cell 108: 465-474.
50. Wilcox LJ, Borradaile NM, de Dreu LE, Huff MW (2001) Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP. J Lipid Res 42: 725-734.
51. Borradaile NM, de Dreu LE, Barrett PH, Huff MW (2002) Inhibition of hepatocyte apoB secretion by naringenin: enhanced rapid intracellular degradation independent of reduced microsomal cholesteryl esters. J Lipid Res 43: 1544-1554.
52. Allister EM, Borradaile NM, Edwards JY, Huff MW (2005) Inhibition of microsomal triglyceride transfer protein expression and apolipoprotein B100 secretion by the citrus flavonoid naringenin and by insulin involves activation of the mitogen-activated protein kinase pathway in hepatocytes. Diabetes 54: 1676-1683.
53. Jeon SM, Kim HK, Kim HJ, Do GM, Jeong TS, et al. (2007) Hypocholesterolemic and antioxidative effects of naringenin and its two metabolites in highcholesterol fed rats. Transl Res 149: 15-21.
54. Huong DT, Takahashi Y, Ide T (2006) Activity and mRNA levels of enzymes involved in hepatic fatty acid oxidation in mice fed citrus flavonoids. Nutrition (Burbank, Los Angeles County, Calif) 22: 546-552.
55. Liu L, Shan S, Zhang K, Ning Z-Q, Lu X-P, et al. (2008) Naringenin and hesperetin, two flavonoids derived from Citrus aurantium up-regulate transcription of adiponectin. Phytotherapy research: PTR 22: 1400-1403.
56. Chang F, Jaber LA, Berlie HD, O'Connell MB (2007) Evolution of peroxisome proliferator-activated receptor agonists. Ann Pharmacother 41: 973-983.
57. Gastaminza P, Cheng G, Wieland S, Zhong J, Liao W, et al. (2008) Cellular determinants of hepatitis C virus assembly, maturation, degradation, and secretion. Journal of Virology 82: 2120-2129.
58. Huang H, Sun F, Owen DM, Li W, Chen Y, et al. (2007) Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins. Proc Natl Acad Sci USA 104: 5848-5853.
59. Kim K, Kim, Kim KH, Cheong J (2008) Hepatitis B virus X protein induces lipogenic transcription factor SREBP1 and fatty acid synthase through the activation of nuclear receptor LXRalpha. Biochem J 416: 219-230.
60. Na T-A, Shin YK, Roh KJ, Kang SA, Hong I, et al. (2008) Liver X receptor mediates hepatitis B virus X protein-induced lipogenesis in hepatitis B virusassociated hepatocellular carcinoma. Hepatology 49: 1122-1131.
61. Mahmood S, Togawa K, Kawanaka M, Niiyama G, Yamada G (2008) An Analysis of Risk Factors for Developing Hepatocellular Carcinoma in a Group of Hepatitis C Patients with Stage 3 Fibrosis following Interferon Therapy. Cancer Inform 6: 381-387.
62. Noguchi-Yachide T, Miyachi H, Aoyama H, Aoyama A, Makishima, et al. (2007) Structural development of liver X receptor (LXR) antagonists derived from thalidomide-related glucosidase inhibitors. Chem Pharm Bull 55: 1750-1754.
63. Marcus SL, Miyata KS, Zhang B, Subramani S, Rachubinski RA, et al. (1993) Diverse peroxisome proliferator-activated receptors bind to the peroxisome proliferator-responsive elements of the rat hydratase/dehydrogenase and fatty acyl-CoA oxidase genes but differentially induce expression. Proc Natl Acad Sci USA 90: 5723-5727.
64. Kidambi S, Yarmush RS, Novik E, Chao P, Yarmush ML, et al. (2009) Oxygenmediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance. Proc Natl Acad Sci U S A 106: 15714-15719.