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Bilirubin: A Ligand of the PPARα Nuclear Receptor

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Nuclear Receptors

Abstract

Bilirubin is the product from red blood cell lysis, which releases heme that is reduced to biliverdin by heme oxygenases (HO). Later, the biliverdin is converted to bilirubin by the biliverdin reductase (BVR) enzyme. Studies have revealed that bilirubin is significantly lower in obese patients with nonalcoholic fatty liver disease (NAFLD). While the mechanisms that reduce plasma bilirubin are unknown, it has been shown that increasing plasma bilirubin lowers body fat percentage and liver fat content in obese animal models. The bilirubin actions have been attributed to a newly revealed function that it is a hormone, which binds directly to the PPARα nuclear receptor transcription factor. PPARα regulates fatty acid oxidation (FAO) and peroxisomal function to maintain cellular homeostasis and catabolism of fatty acids. Here, we discuss the partnership of bilirubin-PPARα, along with the two other PPAR isoforms PPARβ/δ and PPARγ, and how they function to control peroxisomes and mitochondria that mediates fatty acid β-oxidation and adiposity. There may be clinical interest in bilirubin-PPARα functionality to rectify NAFLD and insulin resistance in the obese.

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References

  1. van Meer S, van Erpecum KJ, Sprengers D, Klumpen HJ, Jansen PL, Ijzermans JN, et al. Hepatocellular carcinoma in noncirrhotic livers is associated with steatosis rather than steatohepatitis: potential implications for pathogenesis. Eur J Gastroenterol Hepatol. 2016;28(8):955–62.

    Article  PubMed  Google Scholar 

  2. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114(4):842–5.

    Article  CAS  PubMed  Google Scholar 

  3. DeAngelis AM, Heinrich G, Dai T, Bowman TA, Patel PR, Lee SJ, et al. Carcinoembryonic antigen-related cell adhesion molecule 1: a link between insulin and lipid metabolism. Diabetes. 2008;57(9):2296–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schwarz JM, Linfoot P, Dare D, Aghajanian K. Hepatic de novo lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat, high-carbohydrate isoenergetic diets. Am J Clin Nutr. 2003;77(1):43–50.

    Article  CAS  PubMed  Google Scholar 

  5. Weaver L, Hamoud AA, Stec DE, Hinds TD. Biliverdin reductase and bilirubin in hepatic disease. Am J Physiol Gastrointest Liver Physiol. 2018;314(6):G668–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Romero-Gomez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol. 2017;67(4):829–46.

    Article  PubMed  Google Scholar 

  7. Fransen M, Lismont C, Walton P. The peroxisome-mitochondria connection: how and why? Int J Mol Sci. 2017;18(6):1126.

    Article  PubMed Central  CAS  Google Scholar 

  8. Alberts B, Lewis J, et al. Peroxisomes. Molecular biology of the cell. New York: Garland Sciences; 2002.

    Google Scholar 

  9. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990;347(6294):645–50.

    Article  CAS  PubMed  Google Scholar 

  10. Bougarne N, Weyers B, Desmet SJ, Deckers J, Ray DW, Staels B, et al. Molecular actions of PPARalpha in lipid metabolism and inflammation. Endocr Rev. 2018;39(5):760–802.

    Article  PubMed  Google Scholar 

  11. Stec DE, Gordon DM, Hipp JA, Hong S, Mitchell ZL, Franco NR, et al. The loss of hepatic PPARalpha promotes inflammation and serum hyperlipidemia in diet-induced obesity. Am J Physiol Regul Integr Comp Physiol. 2019;317(5):R733–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Marino JS, Stechschulte LA, Stec DE, Nestor-Kalinoski A, Coleman S, Hinds TD Jr. Glucocorticoid receptor beta induces hepatic steatosis by augmenting inflammation and inhibition of the peroxisome proliferator-activated receptor (PPAR) alpha. J Biol Chem. 2016;291(50):25776–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hinds TD Jr, Burns KA, Hosick PA, McBeth L, Nestor-Kalinoski A, Drummond HA, et al. Biliverdin reductase A attenuates hepatic steatosis by inhibition of glycogen synthase kinase (GSK) 3beta phosphorylation of serine 73 of peroxisome proliferator-activated receptor (PPAR) alpha. J Biol Chem. 2016;291(48):25179–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gordon DM, Blomquist TM, Miruzzi SA, McCullumsmith R, Stec DE, Hinds TD Jr. RNA-sequencing in human HepG2 hepatocytes reveals PPARalpha mediates transcriptome responsiveness of bilirubin. Physiol Genomics. 2019;51(6):234–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Stec DE, John K, Trabbic CJ, Luniwal A, Hankins MW, Baum J, et al. Bilirubin binding to PPARalpha inhibits lipid accumulation. PLoS One. 2016;11(4):e0153427.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Gordon DM, Neifer KL, Hamoud AA, Hawk CF, Nestor-Kalinoski AL, Miruzzi SA, et al. Bilirubin remodels murine white adipose tissue by reshaping mitochondrial activity and the coregulator profile of peroxisome proliferator-activated receptor alpha. J Biol Chem. 2020;295(29):9804–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Terry D, Hinds J, Justin F, et al. Bilirubin nanoparticles reduce diet-induced hepatic steatosis, improve fat utilization, and increase plasma β-hydroxybutyrate. Front Pharmacol. 2020;11:594574.

    Article  CAS  Google Scholar 

  18. Hinds TD Jr, Hosick PA, Hankins MW, Nestor-Kalinoski A, Stec DE. Mice with hyperbilirubinemia due to Gilbert’s Syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARalpha. Am J Physiol Endocrinol Metab. 2017;312(4):E244–52.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Andersson C, Weeke P, Fosbol EL, Brendorp B, Kober L, Coutinho W, et al. Acute effect of weight loss on levels of total bilirubin in obese, cardiovascular high-risk patients: an analysis from the lead-in period of the Sibutramine Cardiovascular Outcome trial. Metabolism. 2009;58(8):1109–15.

    Article  CAS  PubMed  Google Scholar 

  20. O’Brien L, Hosick PA, John K, Stec DE, Hinds TD Jr. Biliverdin reductase isozymes in metabolism. Trends Endocrinol Metab. 2015;26(4):212–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Liu J, Wang L, Tian XY, Liu L, Wong WT, Zhang Y, et al. Unconjugated bilirubin mediates heme oxygenase-1-induced vascular benefits in diabetic mice. Diabetes. 2015;64(5):1564–75.

    Article  CAS  PubMed  Google Scholar 

  22. Hinds TD Jr, Sodhi K, Meadows C, Fedorova L, Puri N, Kim DH, et al. Increased HO-1 levels ameliorate fatty liver development through a reduction of heme and recruitment of FGF21. Obesity (Silver Spring). 2014;22(3):705–12.

    Article  CAS  Google Scholar 

  23. Green S. PPAR: a mediator of peroxisome proliferator action. Mutat Res. 1995;333(1–2):101–9.

    Article  CAS  PubMed  Google Scholar 

  24. Sanderson LM, Degenhardt T, Koppen A, Kalkhoven E, Desvergne B, Muller M, et al. Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) but not PPARalpha serves as a plasma free fatty acid sensor in liver. Mol Cell Biol. 2009;29(23):6257–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kim H, Haluzik M, Asghar Z, Yau D, Joseph JW, Fernandez AM, et al. Peroxisome proliferator-activated receptor-alpha agonist treatment in a transgenic model of type 2 diabetes reverses the lipotoxic state and improves glucose homeostasis. Diabetes. 2003;52(7):1770–8.

    Article  CAS  PubMed  Google Scholar 

  26. Chou CJ, Haluzik M, Gregory C, Dietz KR, Vinson C, Gavrilova O, et al. WY14,643, a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist, improves hepatic and muscle steatosis and reverses insulin resistance in lipoatrophic A-ZIP/F-1 mice. J Biol Chem. 2002;277(27):24484–9.

    Article  CAS  PubMed  Google Scholar 

  27. Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol. 2015;62(3):720–33.

    Article  CAS  PubMed  Google Scholar 

  28. Berbaum J, Harrison RK. Comparison of full-length versus ligand binding domain constructs in cell-free and cell-based peroxisome proliferator-activated receptor alpha assays. Anal Biochem. 2005;339(1):121–8.

    Article  CAS  PubMed  Google Scholar 

  29. Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature. 1992;358(6389):771–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bardot O, Aldridge TC, Latruffe N, Green S. PPAR-RXR heterodimer activates a peroxisome proliferator response element upstream of the bifunctional enzyme gene. Biochem Biophys Res Commun. 1993;192(1):37–45.

    Article  CAS  PubMed  Google Scholar 

  31. Keller H, Dreyer C, Medin J, Mahfoudi A, Ozato K, Wahli W. Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc Natl Acad Sci U S A. 1993;90(6):2160–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gray JP, Burns KA, Leas TL, Perdew GH, Vanden Heuvel JP. Regulation of peroxisome proliferator-activated receptor alpha by protein kinase C. Biochemistry. 2005;44(30):10313–21.

    Article  CAS  PubMed  Google Scholar 

  33. Dowell P, Ishmael JE, Avram D, Peterson VJ, Nevrivy DJ, Leid M. p300 functions as a coactivator for the peroxisome proliferator-activated receptor alpha. J Biol Chem. 1997;272(52):33435–43.

    Article  CAS  PubMed  Google Scholar 

  34. Pourcet B, Pineda-Torra I, Derudas B, Staels B, Glineur C. SUMOylation of human peroxisome proliferator-activated receptor alpha inhibits its trans-activity through the recruitment of the nuclear corepressor NCoR. J Biol Chem. 2010;285(9):5983–92.

    Article  CAS  PubMed  Google Scholar 

  35. Pawar A, Jump DB. Unsaturated fatty acid regulation of peroxisome proliferator-activated receptor alpha activity in rat primary hepatocytes. J Biol Chem. 2003;278(38):35931–9.

    Article  CAS  PubMed  Google Scholar 

  36. Grygiel-Gorniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications--a review. Nutr J. 2014;13:17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Xu HE, Lambert MH, Montana VG, Plunket KD, Moore LB, Collins JL, et al. Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A. 2001;98(24):13919–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hinds TD Jr, Creeden JF, Gordon DM, Spegele AC, Britton SL, Koch LG, et al. Rats genetically selected for high aerobic exercise capacity have elevated plasma bilirubin by upregulation of hepatic biliverdin reductase-A (BVRA) and suppression of UGT1A1. Antioxidants (Basel). 2020;9(9):889.

    Article  CAS  Google Scholar 

  39. Gordon DM, Adeosun SO, Ngwudike SI, Anderson CD, Hall JE, Hinds TD Jr, et al. CRISPR Cas9-mediated deletion of biliverdin reductase A (BVRA) in mouse liver cells induces oxidative stress and lipid accumulation. Arch Biochem Biophys. 2019;672:108072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cimini FA, Arena A, Barchetta I, Tramutola A, Ceccarelli V, Lanzillotta C, et al. Reduced biliverdin reductase-A levels are associated with early alterations of insulin signaling in obesity. Biochim Biophys Acta Mol Basis Dis. 2019;1865(6):1490–501.

    Article  CAS  PubMed  Google Scholar 

  41. Vanella L, Sodhi K, Kim DH, Puri N, Maheshwari M, Hinds TD Jr, et al. Increased heme-oxygenase 1 expression in mesenchymal stem cell-derived adipocytes decreases differentiation and lipid accumulation via upregulation of the canonical Wnt signaling cascade. Stem Cell Res Ther. 2013;4(2):28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tenhunen R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A. 1968;61(2):748–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rigney E, Mantle TJ. The reaction mechanism of bovine kidney biliverdin reductase. Biochim Biophys Acta. 1988;957(2):237–42.

    Article  CAS  PubMed  Google Scholar 

  44. Stec DE, Gordon DM, Nestor-Kalinoski AL, Donald MC, Mitchell ZL, Creeden JF, et al. Biliverdin reductase A (BVRA) knockout in adipocytes induces hypertrophy and reduces mitochondria in white fat of obese mice. Biomolecules. 2020;10(3):387.

    Article  CAS  PubMed Central  Google Scholar 

  45. Adeosun SO, Moore KH, Lang DM, Nwaneri AC, Hinds TD Jr, Stec DE. A novel fluorescence-based assay for the measurement of biliverdin reductase activity. React Oxyg Species (Apex). 2018;5(13):35–45.

    CAS  Google Scholar 

  46. Sundararaghavan VL, Binepal S, Stec DE, Sindhwani P, Hinds TD Jr. Bilirubin, a new therapeutic for kidney transplant? Transplant Rev (Orlando). 2018;32(4):234–40.

    Article  PubMed Central  Google Scholar 

  47. Hamoud AR, Weaver L, Stec DE, Hinds TD. Bilirubin in the liver-gut signaling axis. Trends Endocrinol Metab. 2018;29(3):140–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Holowiecki A, O’Shields B, Jenny MJ. Characterization of heme oxygenase and biliverdin reductase gene expression in zebrafish (Danio rerio): basal expression and response to pro-oxidant exposures. Toxicol Appl Pharmacol. 2016;311:74–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chen W, Maghzal GJ, Ayer A, Suarna C, Dunn LL, Stocker R. Absence of the biliverdin reductase-a gene is associated with increased endogenous oxidative stress. Free Radic Biol Med. 2018;115:156–65.

    Article  CAS  PubMed  Google Scholar 

  50. Sharma N, Tramutola A, Lanzillotta C, Arena A, Blarzino C, Cassano T, et al. Loss of biliverdin reductase-A favors tau hyper-phosphorylation in Alzheimer’s disease. Neurobiol Dis. 2019;125:176–89.

    Article  CAS  PubMed  Google Scholar 

  51. Triani F, Tramutola A, Di Domenico F, Sharma N, Butterfield DA, Head E, et al. Biliverdin reductase-A impairment links brain insulin resistance with increased Abeta production in an animal model of aging: implications for Alzheimer disease. Biochim Biophys Acta Mol basis Dis. 2018;1864(10):3181–94.

    Article  CAS  PubMed  Google Scholar 

  52. Barone E, Tramutola A, Triani F, Calcagnini S, Di Domenico F, Ripoli C, et al. Biliverdin reductase-A mediates the beneficial effects of intranasal insulin in alzheimer disease. Mol Neurobiol. 2018;56(4):2922–43.

    Article  PubMed  CAS  Google Scholar 

  53. Barone E, Di Domenico F, Cassano T, Arena A, Tramutola A, Lavecchia MA, et al. Impairment of biliverdin reductase-A promotes brain insulin resistance in Alzheimer disease: a new paradigm. Free Radic Biol Med. 2016;91:127–42.

    Article  CAS  PubMed  Google Scholar 

  54. Barone E, Di Domenico F, Mancuso C, Butterfield DA. The Janus face of the heme oxygenase/biliverdin reductase system in Alzheimer disease: it’s time for reconciliation. Neurobiol Dis. 2014;62:144–59.

    Article  CAS  PubMed  Google Scholar 

  55. Barone E, Mancuso C, Di Domenico F, Sultana R, Murphy MP, Head E, et al. Biliverdin reductase-A: a novel drug target for atorvastatin in a dog pre-clinical model of Alzheimer disease. J Neurochem. 2012;120(1):135–46.

    Article  CAS  PubMed  Google Scholar 

  56. Barone E, Di Domenico F, Cenini G, Sultana R, Coccia R, Preziosi P, et al. Oxidative and nitrosative modifications of biliverdin reductase-A in the brain of subjects with Alzheimer’s disease and amnestic mild cognitive impairment. J Alzheimers Dis. 2011;25(4):623–33.

    Article  CAS  PubMed  Google Scholar 

  57. Vitek L, Jirsa M, Brodanova M, Kalab M, Marecek Z, Danzig V, et al. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis. 2002;160(2):449–56.

    Article  CAS  PubMed  Google Scholar 

  58. Hinds TD Jr, Hosick PA, Chen S, Tukey RH, Hankins MW, Nestor-Kalinoski A, et al. Mice with hyperbilirubinemia due to Gilbert’s syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARalpha. Am J Physiol Endocrinol Metab. 2017;312(4):E244–E52.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Simpson AE. The cytochrome P450 4 (CYP4) family. Gen Pharmacol. 1997;28(3):351–9.

    Article  CAS  PubMed  Google Scholar 

  60. Fruchart JC. Selective peroxisome proliferator-activated receptor alpha modulators (SPPARMalpha): the next generation of peroxisome proliferator-activated receptor alpha-agonists. Cardiovasc Diabetol. 2013;12:82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gonzalez Mdel C, Corton JC, Acero N, Munoz-Mingarro D, Quiros Y, Alvarez-Millan JJ, et al. Peroxisome proliferator-activated receptoralpha agonists differentially regulate inhibitor of DNA binding expression in rodents and human cells. PPAR Res. 2012;2012:483536.

    PubMed  Google Scholar 

  62. Ren H, Vallanat B, Brown-Borg HM, Currie R, Corton JC. Regulation of proteome maintenance gene expression by activators of peroxisome proliferator-activated receptor alpha. PPAR Res. 2010;2010:727194.

    Article  PubMed  CAS  Google Scholar 

  63. Hinds TD Jr, Stec DE. Bilirubin, a cardiometabolic signaling molecule. Hypertension. 2018;72(4):788–95.

    Article  CAS  PubMed  Google Scholar 

  64. Zhou JA, Jiang M, Yang X, Liu Y, Guo J, Zheng J, et al. Unconjugated bilirubin ameliorates the inflammation and digestive protease increase in TNBS-induced colitis. Mol Med Rep. 2017;16(2):1779–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lee Y, Kim H, Kang S, Lee J, Park J, Jon S. Bilirubin nanoparticles as a nanomedicine for anti-inflammation therapy. Angew Chem Int Ed Engl. 2016;55(26):7460–3.

    Article  CAS  PubMed  Google Scholar 

  66. Hinds TD Jr, Stec DE. Bilirubin safeguards cardiorenal and metabolic diseases: a protective role in health. Curr Hypertens Rep. 2019;21(11):87.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Hinds TD Jr, Adeosun SO, Alamodi AA, Stec DE. Does bilirubin prevent hepatic steatosis through activation of the PPARalpha nuclear receptor? Med Hypotheses. 2016;95:54–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6(11):1123–32.

    Article  CAS  PubMed  Google Scholar 

  69. Chang H, Zhao F, Xie X, Liao Y, Song Y, Liu C, et al. PPARalpha suppresses Th17 cell differentiation through IL-6/STAT3/RORgammat pathway in experimental autoimmune myocarditis. Exp Cell Res. 2019;375(1):22–30.

    Article  CAS  PubMed  Google Scholar 

  70. Longhi MS, Vuerich M, Kalbasi A, Kenison JE, Yeste A, Csizmadia E, et al. Bilirubin suppresses Th17 immunity in colitis by upregulating CD39. JCI Insight. 2017;2(9):e92791.

    Article  PubMed Central  Google Scholar 

  71. Chalmin F, Mignot G, Bruchard M, Chevriaux A, Vegran F, Hichami A, et al. Stat3 and Gfi-1 transcription factors control Th17 cell immunosuppressive activity via the regulation of ectonucleotidase expression. Immunity. 2012;36(3):362–73.

    Article  CAS  PubMed  Google Scholar 

  72. Cherkaoui-Malki M, Meyer K, Cao WQ, Latruffe N, Yeldandi AV, Rao MS, et al. Identification of novel peroxisome proliferator-activated receptor alpha (PPARalpha) target genes in mouse liver using cDNA microarray analysis. Gene Expr. 2001;9(6):291–304.

    Article  CAS  PubMed  Google Scholar 

  73. Woods CG, Heuvel JP, Rusyn I. Genomic profiling in nuclear receptor-mediated toxicity. Toxicol Pathol. 2007;35(4):474–94.

    Article  CAS  PubMed  Google Scholar 

  74. Lin H, Yu CH, Jen CY, Cheng CF, Chou Y, Chang CC, et al. Adiponectin-mediated heme oxygenase-1 induction protects against iron-induced liver injury via a PPARalpha dependent mechanism. Am J Pathol. 2010;177(4):1697–709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ndisang JF. Cross-talk between heme oxygenase and peroxisome proliferator-activated receptors in the regulation of physiological functions. Front Biosci (Landmark Ed). 2014;19:916–35.

    Article  Google Scholar 

  76. Kronke G, Kadl A, Ikonomu E, Bluml S, Furnkranz A, Sarembock IJ, et al. Expression of heme oxygenase-1 in human vascular cells is regulated by peroxisome proliferator-activated receptors. Arterioscler Thromb Vasc Biol. 2007;27(6):1276–82.

    Article  PubMed  CAS  Google Scholar 

  77. Li M, Li Z, Sun X, Yang L, Fang P, Liu Y, et al. Heme oxygenase-1/p21WAF1 mediates peroxisome proliferator-activated receptor-gamma signaling inhibition of proliferation of rat pulmonary artery smooth muscle cells. FEBS J. 2010;277(6):1543–50.

    Article  CAS  PubMed  Google Scholar 

  78. Ali F, Ali NS, Bauer A, Boyle JJ, Hamdulay SS, Haskard DO, et al. PPARdelta and PGC1alpha act cooperatively to induce haem oxygenase-1 and enhance vascular endothelial cell resistance to stress. Cardiovasc Res. 2010;85(4):701–10.

    Article  CAS  PubMed  Google Scholar 

  79. Bigo C, Kaeding J, El Husseini D, Rudkowska I, Verreault M, Vohl MC, et al. PPARalpha: a master regulator of bilirubin homeostasis. PPAR Res. 2014;2014:747014.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Hasegawa Y, Kishimoto S, Takahashi H, Inotsume N, Takeuchi Y, Fukushima S. Altered expression of nuclear receptors affects the expression of metabolic enzymes and transporters in a rat model of cholestasis. Biol Pharm Bull. 2009;32(12):2046–52.

    Article  PubMed  Google Scholar 

  81. Sundararaghavan VL, Sindhwani P, Hinds TD Jr. Glucuronidation and UGT isozymes in bladder: new targets for the treatment of uroepithelial carcinomas? Oncotarget. 2016;8(2):3640.

    Article  PubMed Central  Google Scholar 

  82. Dai F, Jiang T, Bao YY, Chen GJ, Chen L, Zhang Q, et al. Fenofibrate improves high-fat diet-induced and palmitate-induced endoplasmic reticulum stress and inflammation in skeletal muscle. Life Sci. 2016;157:158–67.

    Article  CAS  PubMed  Google Scholar 

  83. Boyle KE, Friedman JE, Janssen RC, Underkofler C, Houmard JA, Rasouli N. Metabolic inflexibility with obesity and the effects of fenofibrate on skeletal muscle fatty acid oxidation. Horm Metab Res. 2017;49(1):50–7.

    CAS  PubMed  Google Scholar 

  84. Gabaldon T. Peroxisome diversity and evolution. Philos Trans R Soc Lond Ser B Biol Sci. 2010;365(1541):765–73.

    Article  CAS  Google Scholar 

  85. Bonekamp NA, Volkl A, Fahimi HD, Schrader M. Reactive oxygen species and peroxisomes: struggling for balance. Biofactors. 2009;35(4):346–55.

    Article  CAS  PubMed  Google Scholar 

  86. Wanders RJ, Waterham HR. Biochemistry of mammalian peroxisomes revisited. Annu Rev Biochem. 2006;75:295–332.

    Article  CAS  PubMed  Google Scholar 

  87. Violante S, Ijlst L, Te Brinke H, Koster J, Tavares de Almeida I, Wanders RJ, et al. Peroxisomes contribute to the acylcarnitine production when the carnitine shuttle is deficient. Biochim Biophys Acta. 2013;1831(9):1467–74.

    Article  CAS  PubMed  Google Scholar 

  88. Schrader M, Grille S, Fahimi HD, Islinger M. Peroxisome interactions and cross-talk with other subcellular compartments in animal cells. Subcell Biochem. 2013;69:1–22.

    Article  CAS  PubMed  Google Scholar 

  89. Lodhi IJ, Semenkovich CF. Peroxisomes: a nexus for lipid metabolism and cellular signaling. Cell Metab. 2014;19(3):380–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Huang TY, Zheng D, Houmard JA, Brault JJ, Hickner RC, Cortright RN. Overexpression of PGC-1alpha increases peroxisomal activity and mitochondrial fatty acid oxidation in human primary myotubes. Am J Physiol Endocrinol Metab. 2017;312(4):E253–e63.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol. 2003;552(Pt 2):335–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cadet J, Wagner JR. DNA base damage by reactive oxygen species, oxidizing agents, and UV radiation. Cold Spring Harb Perspect Biol. 2013;5(2):a012559.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Nassir F, Ibdah JA. Role of mitochondria in nonalcoholic fatty liver disease. Int J Mol Sci. 2014;15(5):8713–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Distel B, Erdmann R, Gould SJ, Blobel G, Crane DI, Cregg JM, et al. A unified nomenclature for peroxisome biogenesis factors. J Cell Biol. 1996;135(1):1–3.

    Article  CAS  PubMed  Google Scholar 

  95. Martens K, Bottelbergs A, Peeters A, Jacobs F, Espeel M, Carmeliet P, et al. Peroxisome deficient aP2-Pex5 knockout mice display impaired white adipocyte and muscle function concomitant with reduced adrenergic tone. Mol Genet Metab. 2012;107(4):735–47.

    Article  CAS  PubMed  Google Scholar 

  96. Weng H, Ji X, Endo K, Iwai N. Pex11a deficiency is associated with a reduced abundance of functional peroxisomes and aggravated renal interstitial lesions. Hypertension. 2014;64(5):1054–60.

    Article  CAS  PubMed  Google Scholar 

  97. Chen C, Wang H, Chen B, Chen D, Lu C, Li H, et al. Pex11a deficiency causes dyslipidaemia and obesity in mice. J Cell Mol Med. 2019;23(3):2020–31.

    Article  CAS  PubMed  Google Scholar 

  98. Weng H, Ji X, Naito Y, Endo K, Ma X, Takahashi R, et al. Pex11alpha deficiency impairs peroxisome elongation and division and contributes to nonalcoholic fatty liver in mice. Am J Physiol Endocrinol Metab. 2013;304(2):E187–96.

    Article  CAS  PubMed  Google Scholar 

  99. Violante S, Achetib N, van Roermund CWT, Hagen J, Dodatko T, Vaz FM, et al. Peroxisomes can oxidize medium- and long-chain fatty acids through a pathway involving ABCD3 and HSD17B4. FASEB J. 2019;33(3):4355–64.

    Article  CAS  PubMed  Google Scholar 

  100. Silveira LS, Pimentel GD, Souza CO, Biondo LA, Teixeira AAS, Lima EA, et al. Effect of an acute moderate-exercise session on metabolic and inflammatory profile of PPAR-alpha knockout mice. Cell Biochem Funct. 2017;35(8):510–7.

    Article  CAS  PubMed  Google Scholar 

  101. Shiomi Y, Yamauchi T, Iwabu M, Okada-Iwabu M, Nakayama R, Orikawa Y, et al. A novel peroxisome proliferator-activated receptor (PPAR)alpha agonist and PPARgamma antagonist, Z-551, ameliorates high-fat diet-induced obesity and metabolic disorders in mice. J Biol Chem. 2015;290(23):14567–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Honsho M, Yamashita S, Fujiki Y. Peroxisome homeostasis: mechanisms of division and selective degradation of peroxisomes in mammals. Biochim Biophys Acta. 2016;1863(5):984–91.

    Article  CAS  PubMed  Google Scholar 

  103. Tabak HF, Braakman I, van der Zand A. Peroxisome formation and maintenance are dependent on the endoplasmic reticulum. Annu Rev Biochem. 2013;82:723–44.

    Article  CAS  PubMed  Google Scholar 

  104. Fransen M, Lismont C. Peroxisomes and cellular oxidant/antioxidant balance: protein redox modifications and impact on inter-organelle communication. Subcell Biochem. 2018;89:435–61.

    Article  CAS  PubMed  Google Scholar 

  105. Walton PA, Brees C, Lismont C, Apanasets O, Fransen M. The peroxisomal import receptor PEX5 functions as a stress sensor, retaining catalase in the cytosol in times of oxidative stress. Biochim Biophys Acta, Mol Cell Res. 2017;1864(10):1833–43.

    Article  CAS  Google Scholar 

  106. Netto LE, Antunes F. The roles of peroxiredoxin and thioredoxin in hydrogen peroxide sensing and in signal transduction. Mol Cells. 2016;39(1):65–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lismont C, Revenco I, Fransen M. Peroxisomal hydrogen peroxide metabolism and signaling in health and disease. Int J Mol Sci. 2019;20(15):3673.

    Article  CAS  PubMed Central  Google Scholar 

  108. Fransen M, Nordgren M, Wang B, Apanasets O. Role of peroxisomes in ROS/RNS-metabolism: implications for human disease. Biochim Biophys Acta. 2012;1822(9):1363–73.

    Article  CAS  PubMed  Google Scholar 

  109. O’Brien ML, Twaroski TP, Cunningham ML, Glauert HP, Spear BT. Effects of peroxisome proliferators on antioxidant enzymes and antioxidant vitamins in rats and hamsters. Toxicol Sci. 2001;60(2):271–8.

    Article  PubMed  Google Scholar 

  110. Geillon F, Gondcaille C, Raas Q, Dias AMM, Pecqueur D, Truntzer C, et al. Peroxisomal ATP-binding cassette transporters form mainly tetramers. J Biol Chem. 2017;292(17):6965–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Berger J, Albet S, Bentejac M, Netik A, Holzinger A, Roscher AA, et al. The four murine peroxisomal ABC-transporter genes differ in constitutive, inducible and developmental expression. Eur J Biochem. 1999;265(2):719–27.

    Article  CAS  PubMed  Google Scholar 

  112. Fourcade S, Savary S, Albet S, Gauthe D, Gondcaille C, Pineau T, et al. Fibrate induction of the adrenoleukodystrophy-related gene (ABCD2): promoter analysis and role of the peroxisome proliferator-activated receptor PPARalpha. Eur J Biochem. 2001;268(12):3490–500.

    Article  CAS  PubMed  Google Scholar 

  113. Siong Tan HW, Anjum B, Shen HM, Ghosh S, Yen PM, Sinha RA. Lysosomal inhibition attenuates peroxisomal gene transcription via suppression of PPARA and PPARGC1A levels. Autophagy. 2019;15(8):1455–9.

    Article  CAS  PubMed Central  Google Scholar 

  114. Tang Y, et al. Role of peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARalpha-mediated species differences in triclosan-induced liver toxicity. Arch Toxicol. 2018;92(11):3391–402.

    Article  CAS  PubMed  Google Scholar 

  115. Wang D, Tosevska A, Heiss EH, Ladurner A, Molzer C, Wallner M, et al. Bilirubin decreases macrophage cholesterol efflux and ATP-binding cassette transporter A1 protein expression. J Am Heart Assoc. 2017;6(5):e005520.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Wang S, Smith JD. ABCA1 and nascent HDL biogenesis. Biofactors. 2014;40(6):547–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Röhrl C, Eigner K, Fruhwürth S, Stangl H. Bile acids reduce endocytosis of high-density lipoprotein (HDL) in HepG2 cells. PLoS One. 2014;9(7):e102026.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Kim CS, Choi HS, Joe Y, Chung HT, Yu R. Induction of heme oxygenase-1 with dietary quercetin reduces obesity-induced hepatic inflammation through macrophage phenotype switching. Nutr Res Pract. 2016;10(6):623–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Penas F, Mirkin GA, Vera M, Cevey A, Gonzalez CD, Gomez MI, et al. Treatment in vitro with PPARalpha and PPARgamma ligands drives M1-to-M2 polarization of macrophages from T. cruzi-infected mice. Biochim Biophys Acta. 2015;1852(5):893–904.

    Article  CAS  PubMed  Google Scholar 

  120. Kelly B, O’Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 2015;25(7):771–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Hesketh M, Sahin KB, West ZE, Murray RZ. Macrophage phenotypes regulate scar formation and chronic wound healing. Int J Mol Sci. 2017;18(7):1545.

    Article  CAS  PubMed Central  Google Scholar 

  122. Wicks SE, Vandanmagsar B, Haynie KR, Fuller SE, Warfel JD, Stephens JM, et al. Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism. Proc Natl Acad Sci U S A. 2015;112(25):E3300–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Noland RC, Worsham EA, Simon J, Fuller SE, Baes M, Ghosh S, et al. Peroxisomes in skeletal muscle protect against lipid-induced insulin resistance. FASEB J. 2016;30(1_supplement):1246.

    Google Scholar 

  124. Shin MH, Lee SR, Kim MK, Shin CY, Lee DH, Chung JH. Activation of peroxisome proliferator-activated receptor alpha improves aged and UV-irradiated skin by catalase induction. PLoS One. 2016;11(9):e0162628.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Esmaeili MA, Yadav S, Gupta RK, Waggoner GR, Deloach A, Calingasan NY, et al. Preferential PPAR-α activation reduces neuroinflammation, and blocks neurodegeneration in vivo. Hum Mol Genet. 2016;25(2):317–27.

    Article  CAS  PubMed  Google Scholar 

  126. Mihailovic-Stanojevic N, Miloradović Z, Ivanov M, Bugarski B, Jovović Đ, Karanović D, et al. Upregulation of Heme Oxygenase-1 in response to wild thyme treatment protects against hypertension and oxidative stress. Oxidative Med Cell Longev. 2016;2016:1458793.

    Article  CAS  Google Scholar 

  127. Barañano DE, Rao M, Ferris CD, Snyder SH. Biliverdin reductase: a major physiologic cytoprotectant. Proc Natl Acad Sci. 2002;99(25):16093–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Rakhshandehroo M, Hooiveld G, Müller M, Kersten S. Comparative analysis of gene regulation by the transcription factor PPARα between mouse and human. PLoS One. 2009;4(8):e6796.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Guo XY, Sun F, Chen JN, Wang YQ, Pan Q, Fan JG. circRNA_0046366 inhibits hepatocellular steatosis by normalization of PPAR signaling. World J Gastroenterol. 2018;24(3):323–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Frohnert BI, Hui TY, Bernlohr DA. Identification of a functional peroxisome proliferator-responsive element in the murine fatty acid transport protein gene. J Biol Chem. 1999;274(7):3970–7.

    Article  CAS  PubMed  Google Scholar 

  131. Edvardsson U, Ljungberg A, Linden D, William-Olsson L, Peilot-Sjogren H, Ahnmark A, et al. PPARalpha activation increases triglyceride mass and adipose differentiation-related protein in hepatocytes. J Lipid Res. 2006;47(2):329–40.

    Article  CAS  PubMed  Google Scholar 

  132. Rakhshandehroo M, Knoch B, Muller M, Kersten S. Peroxisome proliferator-activated receptor alpha target genes. PPAR Res. 2010;2010:612089.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Maher JM, Aleksunes LM, Dieter MZ, Tanaka Y, Peters JM, Manautou JE, et al. Nrf2- and PPAR alpha-mediated regulation of hepatic Mrp transporters after exposure to perfluorooctanoic acid and perfluorodecanoic acid. Toxicol Sci. 2008;106(2):319–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Sharma RK, Doig MV, Lewis DF, Gibson GG. Role of hepatic and renal cytochrome P-450 IVA1 in the metabolism of lipid substrates. Biochem Pharmacol. 1989;38(20):3621–9.

    Article  CAS  PubMed  Google Scholar 

  135. Prorok T, Jana M, Patel D, Pahan K. Cinnamic acid protects the nigrostriatum in a mouse model of Parkinson’s disease via peroxisome proliferator-activated receptoralpha. Neurochem Res. 2019;44(4):751–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Di Cara F, Sheshachalam A, Braverman NE, Rachubinski RA, Simmonds AJ. Peroxisome-mediated metabolism is required for immune response to microbial infection. Immunity. 2017;47(1):93–106, e7.

    Article  PubMed  CAS  Google Scholar 

  137. Hinds TD, John K, McBeth L, Trabbic CJ, Sanchez ER. Timcodar (VX-853) is a non-FKBP12 binding macrolide derivative that inhibits PPARγand suppresses adipogenesis. PPAR Res. 2016;2016:1–10.

    Article  CAS  Google Scholar 

  138. Hinds TD Jr, Stechschulte LA, Cash HA, Whisler D, Banerjee A, Yong W, et al. Protein phosphatase 5 mediates lipid metabolism through reciprocal control of glucocorticoid receptor and peroxisome proliferator-activated receptor-gamma (PPARgamma). J Biol Chem. 2011;286(50):42911–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Jones JR, Barrick C, Kim KA, Lindner J, Blondeau B, Fujimoto Y, et al. Deletion of PPARgamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance. Proc Natl Acad Sci U S A. 2005;102(17):6207–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem. 2008;77:289–312.

    Article  CAS  PubMed  Google Scholar 

  141. Natali A, Ferrannini E. Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia. 2006;49(3):434–41.

    Article  CAS  PubMed  Google Scholar 

  142. Fonseca V. Effect of thiazolidinediones on body weight in patients with diabetes mellitus. Am J Med. 2003;115(Suppl 8A):42s–8s.

    Article  CAS  PubMed  Google Scholar 

  143. Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, et al. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008;134(3):405–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Fedorova LV, Sodhi K, Gatto-Weis C, Puri N, Hinds TD Jr, Shapiro JI, et al. Peroxisome proliferator-activated receptor delta agonist, HPP593, prevents renal necrosis under chronic ischemia. PLoS One. 2013;8(5):e64436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, et al. AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem. 2004;279(13):12005–8.

    Article  CAS  PubMed  Google Scholar 

  146. Sodhi K, Puri N, Kim DH, Hinds TD, Stechschulte LA, Favero G, et al. PPARdelta binding to heme oxygenase 1 promoter prevents angiotensin II-induced adipocyte dysfunction in Goldblatt hypertensive rats. Int J Obes. 2005;38(3):456–65.

    Article  CAS  Google Scholar 

  147. Giordano Attianese GM, Desvergne B. Integrative and systemic approaches for evaluating PPARβ/δ (PPARD) function. Nucl Recept Signal. 2015;13:e001.

    PubMed  PubMed Central  Google Scholar 

  148. Liu Y, Colby JK, Zuo X, Jaoude J, Wei D, Shureiqi I. The role of PPAR-δ in metabolism, inflammation, and cancer: many characters of a critical transcription factor. Int J Mol Sci. 2018;19(11):3339.

    Article  PubMed Central  CAS  Google Scholar 

  149. Cheang WS, Wong WT, Zhao L, Xu J, Wang L, Lau CW, et al. PPARdelta is required for exercise to attenuate endoplasmic reticulum stress and endothelial dysfunction in diabetic mice. Diabetes. 2017;66(2):519–28.

    Article  CAS  PubMed  Google Scholar 

  150. Romanowska M, Reilly L, Palmer CN, Gustafsson MC, Foerster J. Activation of PPARbeta/delta causes a psoriasis-like skin disease in vivo. PLoS One. 2010;5(3):e9701.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgments

This work was supported by the National Institutes of Health 1R01DK121797 (T.D.H.) and 1R01DK126884 (D.E.S.); the National Heart, Lung, and Blood Institute K01HL125445 (T.D.H.) and P01HL05197 (D.E.S.); and the National Institute of General Medical Sciences P20GM104357 (D.E.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

    Stephen Hong & Darren Gordon

  2. Center for Excellence in Cardiovascular-Renal Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA

    David E. Stec

  3. Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA

    Terry D. Hinds Jr

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  1. School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA

    Mostafa Z. Badr

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Hong, S., Gordon, D., Stec, D.E., Hinds, T.D. (2021). Bilirubin: A Ligand of the PPARα Nuclear Receptor. In: Badr, M.Z. (eds) Nuclear Receptors. Springer, Cham. https://doi.org/10.1007/978-3-030-78315-0_17

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