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Role of Liver X Receptor, Insulin and Peroxisome Proliferator Activated Receptor α on in Vivo Desaturase Modulation of Unsaturated Fatty Acid Biosynthesis

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Lipids

Abstract

We examined the in vivo contribution of insulin, T090137 (T09), agonist of liver X receptor (LXR), fenofibrate, agonist of peroxisome proliferator activated receptor (PPAR-α) and sterol regulatory element binding protein-1c (SREBP-1c) on the unsaturated fatty acid synthesis controlled by Δ6 and Δ5 desaturases, compared with the effects on stearoylcoenzyme A desaturase-1. When possible they were checked at three levels: messenger RNA (mRNA), desaturase protein and enzymatic activity. In control rats, only fenofibrate increased the insulinemia that was maintained by the simultaneous administration of T09, but this increase has no specific effect on desaturase activity. T09 enhanced SREBP-1 in control animals and the mRNAs and activity of the three desaturases in control and type-1 diabetic rats, demonstrating a LXR/SREBP-1-mediated activation independent of insulin. However, simultaneous administration of insulin and T09 to diabetic rats led to a several-fold increase of the mRNAs of the desaturases, suggesting a strong synergic effect between insulin and LXR/retinoic X receptor (RXR). Moreover, this demonstrates the existence of an interaction between unsaturated fatty acids and cholesterol metabolism performed by the insulin/SREBP-1c system and LXR/RXR. PPAR-α also increased the expression and activity of the three desaturases independently of the insulinemia since it was equivalently evoked in streptozotocin diabetic rats. Besides, PPAR-α increased the palmitoylcoenzyme A elongase, evidencing a dual regulation in the fatty acid biosynthesis at the level of desaturases and elongases. The simultaneous administration of fenofibrate and T09 did not show additive effects on the mRNA expression and activity of the desaturases. Therefore, the results indicate a necessary sophisticated interaction of all these factors to produce the physiological effects.

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Abbreviations

CoA:

Coenzyme A

LXR:

Liver X receptor

mRNA:

Messenger RNA

PPAR-α:

Peroxisome proliferator activated receptor α

RXR:

Retinoic X receptor

SCAP:

SREBP cleavage activating protein

SCD-1:

Stearoylcoenzyme A desaturase-1

SREBP-1c:

Sterol regulatory element binding protein-1c

T09:

T0901317

References

  1. Brenner RR (2003) Hormonal modulation of Δ6 and Δ5 desaturases: case of diabetes. Prostaglandins Leukot Essent Fatty Acids 68:151–162

    Article  PubMed  CAS  Google Scholar 

  2. Gellhorn A, Benjamin W (1964) The intracellular localization of an enzymatic defect of lipid metabolism in diabetic rat. Biochim Biophys Acta 84:167–175

    PubMed  CAS  Google Scholar 

  3. Gellhorn A, Benjamin W (1964) Insulin action in alloxan diabetes modified by actinomycin D. Sciences 146:1166–1168

    CAS  Google Scholar 

  4. Mercuri O, Peluffo RO, Brenner RR (1966) Depression of microsomal desaturation of linoleic to γ-linolenic acid in the alloxan-diabetic rat. Biochim Biophys Acta 116:409–411

    PubMed  CAS  Google Scholar 

  5. Mercuri O, Peluffo RO, Brenner RR (1967) Effect of Insulin on the oxidative desaturation of α-linolenic, oleic, and palmitic acids. Lipids 2:284–285

    Article  CAS  PubMed  Google Scholar 

  6. Brenner RR, Peluffo RO, Mercuri O, Restelli MA (1968) Effect of arachidonic acid in the alloxan-diabetic rat. Am J Physiol 215:63–70

    PubMed  CAS  Google Scholar 

  7. Waters KM, Ntambi JM (1994) Insulin and dietary fructose induce stearoyl-CoA desaturase-1 gene expression in liver of diabetic mice. J Biol Chem 269:27773–27777

    PubMed  CAS  Google Scholar 

  8. Rimoldi OJ, Finarelli GS, Brenner RR (2001) Effects of diabetes and insulin on hepatic Δ6 desaturase gene expression. Biochem Biophys Res Commun 283:323–326

    Article  PubMed  CAS  Google Scholar 

  9. Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS, Goldstein JL (1999) Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci USA 96:13656–13661

    Article  PubMed  CAS  Google Scholar 

  10. Matsuzaka T, Shimano H, Yahagi N, Amemiya-Kudo M, Yoshikawa T, Hasty AH, Tamura Y, Osuga J, Okazaki H, Iizuka Y, Takahashi A, Sone H, Gotoda T, Ishibashi S, Yamada N (2002) Dual regulation of mouse Δ5 and Δ6 desaturase gene expression by SREBP-1 and PPARα. J Lipid Res 43:107–114

    PubMed  CAS  Google Scholar 

  11. Montanaro MA, Bernasconi AM, González MS, Rimoldi OJ, Brenner RR (2005) Effect of fenofibrate and insulin on the biosynthesis of unsaturated fatty acids in streptozotocin diabetic rats. Prostaglandins Leukot Essent Fatty Acids 73:369–378

    Article  PubMed  CAS  Google Scholar 

  12. Repa JJ, Liang G, Ou J, Bashmako WJ, Lobaccaro JMA, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ (2000) Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ. Genes Dev 14:2819–2830

    Article  PubMed  CAS  Google Scholar 

  13. Yoshikawa T, Shimano H, Yahagi N, Ide T, Amemiya-Kudo M, Matsuzaka T, Nakakuki M, Tomita S, Okazaki H, Tamusa Y, Izuka Y, Ohashi K, Takahashi A, Sone H, Osaga J, Gotoda T, Ishibashi S, Yamada N (2002) Polyunsaturated fatty acid suppress sterol regulatory element binding protein 1c promoter activity by inhibition of liver X receptor (LXR) binding to LXR response elements. J Biol Chem 277:1705–1711

    Article  PubMed  CAS  Google Scholar 

  14. Chen G, Liang G, Ou J, Goldstein JL, Brown MS (2004) Central role for liver X receptor in insulin mediated activation of SREBP-1c transcription and stimulation of fatty synthesis in liver. Proc Natl Acad Sci USA 101:11245–11250

    Article  PubMed  CAS  Google Scholar 

  15. Shulz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD, Shan B (2000) Role of LXR in control of lipogenesis. Genes Dev 14:2831–2838

    Article  Google Scholar 

  16. Herbert V, Lau KS, Gottlieb CH, Bleicher S (1965) Coated charcoal immunoassay of insulin. J Clin Endocrinol Metab 25:1375–1384

    Article  PubMed  CAS  Google Scholar 

  17. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  18. Folch J, Lees M, Sloane-Stanley GH (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226:497–509

    PubMed  CAS  Google Scholar 

  19. Small GM, Burdedt K, Connock MJ (1985) A sensitive spectrophotometric assay for peroxisomal acyl-CoA oxidase. Biochem J 227:205–210

    PubMed  CAS  Google Scholar 

  20. Kudo N, Toyama T, Mitsumoto A, Kawashima Y (2003) Regulation by carbohydrate and clofibric acid of palmitoyl-CoA chain elongation in the liver of rats. Lipids 38:531–537

    Article  PubMed  CAS  Google Scholar 

  21. Sambrook J, Frithch EF, Mamatis T (1989) Molecular cloning, a laboratory manual. Cold Spring Harbor Laboratory Press, New York, pp 938–957

    Google Scholar 

  22. D´Andrea S, Guillou H, Jan S, Catheline D, Thibault JN, Bouriel M, Legrand P (2002) The same rat Δ6 desaturase acts not only on 18- but also on 24-carbon fatty acids in very long chain polyunsaturated fatty acid biosynthesis. Biochem J 364:49–55

    CAS  Google Scholar 

  23. Hegarty BD, Bobard A, Hainarelt I, Ferre P, Bossard P, Foufelle F (2005) Distinct roles of insulin and liver X receptor in the induction and cleavage of sterol regulatory element binding protein-C. Proc Natl Acad Sci USA 102:791–796

    Article  PubMed  CAS  Google Scholar 

  24. Hu R, Iskü E, Nakagawa Y (1994) Differential changes in relative levels of arachidonic acid in major phospholipids from rat tissues during progression of diabetes. J Biochem 115:405–408

    PubMed  CAS  Google Scholar 

  25. Brenner RR (2006) Antagonism between Type 1 and Type 2 diabetes in unsaturated fatty acid biosynthesis. Future Lipidol (in press)

  26. Zhou YT, Shimabujuro M, Wang MY, Lee Y, Higa M, Milburn JL, Newgard CB, Unger RH (1998) Role of peroxisome proliferator-activated receptor-α in disease of pancreatic β-cells. Proc Natl Acad Sci USA 95:8898–8903

    Article  PubMed  CAS  Google Scholar 

  27. Gremlich S, Nolan C, Rodiut R, Buealen R, Peyot ML, Delghingaro-Augusto V, Desvergne B, Michalik L, Prentki M, Wahli W (2005) Pancreatic islet adaptation to fasting is dependent on peroxisome proliferator-activated receptor (alpha) transcriptional up-regulation of fatty acid oxidation. Endocrinology 146:375–382

    Article  PubMed  CAS  Google Scholar 

  28. Bihan H, Rouault Ch, Reach G, Poitout V, Staels B, Guerre-Millo M (2005) Pancreatic islet response to hyperglycemia is dependent on peroxisome proliferator-activated receptor alpha (PPAR-α). FEBS Lett 579:2284–2288

    Article  PubMed  CAS  Google Scholar 

  29. Ravnskjaer K, Boergesen M, Rubi B, Larsen JK, Nielsen T, Fridriksson J, Maechler P, Mandrup S (2005) Peroxisome proliferator-activated receptor-α (PPAR-α) potentiates whereas PPAR-γ attenuates glucose-stimulated insulin secretion in pancreatic β-cells. Endocrinology 146:3266–3276

    Article  PubMed  CAS  Google Scholar 

  30. Tordzman K, Stanley KN, Bernal-Mizrachi C, Leone TS, Coleman T, Kelly DP, Semenkovich CF (2002) PPAR-α suppresses insulin secretion and induces UCP2 in insulinoma cells. J Lipid Res 43:936–943

    Google Scholar 

  31. Anderson SP, Dunn C, Laughter A, Yoon J, Swanson C, Stulnig TM, Steffensen KR, Chandraratna RAS, Gustafsson JA, Corton JCh (2004) Overlapping transcriptional programs regulated by the nuclear receptors peroxisome proliferator activated receptor α, retinoic X receptor, and liver X receptor in mouse liver. Mol Pharmacol 66:1440–1452

    Article  PubMed  CAS  Google Scholar 

  32. Ide T, Shimano H, Yoshikawa T, Yahagi N, Amemiya-Kudo M, Matzuzaka T, Nakakuki M, Yatoh S, Iizuka Y, Tomita S, Ohashi K, Takahashi A, Sone H, Gotoda T, Osuga J, Ishibashi S, Yamada N (2003) Cross-talk between peroxisome proliferator-activated receptor (PPAR) α and the liver X receptor (LXR) in nutritional regulation of fatty acid metabolism II LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling. Mol Endocrinol 17:1255–1267

    Article  PubMed  CAS  Google Scholar 

  33. Cao G, Liang Y, Broderick CL, Oldham BA, Beyer TP, Schmidt RJ, Zhang Y, Stayrook KR, Suen Ch, Otto KA, Miller AR, Dai J, Foxworthy P, Gao H, Ryan TP, Jiang X, Burris TP, Eacho PI, Etgen GJ (2003) Antidiabetic action of a liver X receptor agonist mediated by inhibition of hepatic gluconeogenesis. J Biol Chem 278:1131–1136

    Article  PubMed  CAS  Google Scholar 

  34. Chinetti G, Lestavel S, Bocher V, Remaley AT, Neve B, Torra IP, Teissier E, Minnich A, Jaye M, Duverger N, Brewer HB, Fruchart JC, Clavey V, Setaels B (2001) PPAR-α and PPAR-γ activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABC A-1 pathway. Nat Med 7:53–58

    Article  PubMed  CAS  Google Scholar 

  35. Guan JZ, Tamasawa N, Murakami H, Matsui J, Yamato K, Suda T (2003) Clofibrate, a peroxisome proliferator enhances reverse cholesterol transport through cytochrome P450 activation and oxysterol generation. Tohaku J Exp Med 201:251–259

    Article  CAS  Google Scholar 

  36. Li AC, Glass CK (2004) PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis. J Lipid Res 45:2161–2173

    Article  PubMed  CAS  Google Scholar 

  37. Brenner RR, Bernasconi AM, González MS, Rimoldi OJ (2002) Dietary cholesterol modulates Δ6 and Δ5 desaturase mRNAs and enzymatic activity in rats fed a low-EFA diet. Lipids 37:375–383

    Article  PubMed  CAS  Google Scholar 

  38. Chisholm JW, Hong J, Mills SA, Lacon RM (2003) The LXR ligand T0901317 induces severe lipogenesis in db/db diabetic mouse. J Lipid Res 44:2039–2048

    Article  PubMed  CAS  Google Scholar 

  39. Wang Y, Kurdi-Haidar B, Oram JF (2004) LXR-mediated activation of macrophage stearoyl-CoA desaturase generates unsaturated fatty acids that destabilize ABCA1. J Lipid Res 45:972–980

    Article  PubMed  CAS  Google Scholar 

  40. Tang Ch, Cho HP, Nakamura MT, Clarke SD (2003) Regulation of human Δ6 desaturase gene transcription: identification of a functional direct repeat-1 element. J Lipid Res 44:686–695

    Article  CAS  Google Scholar 

  41. He WS, Nara TY, Nakamura MT (2002) Delayed induction of Δ6 and Δ5 desaturases by peroxisome proliferator. Biochem Biophys Res Commun 299:832–838

    Article  CAS  Google Scholar 

  42. Leonard AE, Pereira SL, Sprecher H, Huang Y-Sh (2004) Elongation of long-chain fatty acids. Prog Lipid Res 43:36–54

    Article  PubMed  CAS  Google Scholar 

  43. Inagaki K, Aki T, Fukuda Y, Kawamoto S, Shigeta S, Ono K, Suzuki O (2002) Identification and expression of a rat fatty acid elongase involved in the biosynthesis of C18 fatty acids. Biosci Biotechnol Biochem 66:613–621

    Article  PubMed  CAS  Google Scholar 

  44. Matsuzaka T, Shimano H, Yahagi N, Yoshikawa T, Amemiya-Kudo M, Hasty AH, Okasaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Takahashi A, Nato S, Sone H, Ishibashi S, Yamada N (2002) Cloning and characterization of a mammalian fatty acyl-CoA elongase as a lipogenic enzyme regulated by SREBPs. J Lipid Res 43:911–920

    PubMed  CAS  Google Scholar 

  45. Miller CW, Ntambi JM (1996) Peroxisome proliferator induce mouse liver stearoyl-CoA desaturase 1 gene expression. Proc Natl Acad Sci USA 93:9443–9448

    Article  PubMed  CAS  Google Scholar 

  46. Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20:649–698

    Article  PubMed  CAS  Google Scholar 

  47. Sampath H, Ntambi JM (2005) Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu Rev Nutr 23:317–340

    Article  CAS  Google Scholar 

  48. Botolin D, Wang Y, Christian B, Jump DB (2006) Docosahexaenoic acid (22:6n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk- and 26S proteasome-dependent pathways. J Lipid Res 47:181–192

    Article  PubMed  CAS  Google Scholar 

  49. Tobin AKR, Steineger HH, Alberti HH, Spydevold S, Auwerx Ø, Gustafsson JÅ, Nebb HI (2000) Cross-talk between fatty acid and cholesterol metabolism mediated by liver X receptor-α. Mol Endocrinol 14:741–752

    Article  PubMed  CAS  Google Scholar 

  50. Brenner RR (1974) The oxidative desaturation of unsaturated fatty acids in animals. Mol Cell Biochem 3:41–52

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This research is published in honor of the coauthor María S. González who passed away in October 2006. The gifts of T0901317 from Amgen and the SCD-1, Δ6 desaturase and Δ5 desaturase complementary DNA from J. Ozols, T. Aki and R. Zolfaghari and C. Ross, respectively, are greatly acknowledged. This work was partially supported by grant PIP 5724 from CONICET, Argentina.

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Authors and Affiliations

  1. Instituto de Investigaciones Bioquímicas de La Plata (UNLP-CONICET), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 60 y 120, 1900, La Plata, Argentina

    Mauro A. Montanaro, María S. González, Ana M. Bernasconi & Rodolfo R. Brenner

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  1. Mauro A. Montanaro
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  2. María S. González
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  3. Ana M. Bernasconi
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  4. Rodolfo R. Brenner
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Correspondence to Rodolfo R. Brenner.

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Montanaro, M.A., González, M.S., Bernasconi, A.M. et al. Role of Liver X Receptor, Insulin and Peroxisome Proliferator Activated Receptor α on in Vivo Desaturase Modulation of Unsaturated Fatty Acid Biosynthesis. Lipids 42, 197–210 (2007). https://doi.org/10.1007/s11745-006-3006-4

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  • DOI: https://doi.org/10.1007/s11745-006-3006-4

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