Mitochondrial Oxidative Stress Alters a Pathway in Strongly Resembling That of Bile Acid Biosynthesis and Secretion in Vertebrates
Mammalian bile acids (BAs) are oxidized metabolites of cholesterol whose amphiphilic properties serve in lipid and cholesterol uptake. BAs also act as hormone-like substances that regulate metabolism. The Caenorhabditis elegans clk-1 mutants sustain elevated mitochondrial oxidative stress and display a slow defecation phenotype that is sensitive to the level of dietary cholesterol. We found that: 1) The defecation phenotype of clk-1 mutants is suppressed by mutations in tat-2 identified in a previous unbiased screen for suppressors of clk-1. TAT-2 is homologous to ATP8B1, a flippase required for normal BA secretion in mammals. 2) The phenotype is suppressed by cholestyramine, a resin that binds BAs. 3) The phenotype is suppressed by the knock-down of C. elegans homologues of BA–biosynthetic enzymes. 4) The phenotype is enhanced by treatment with BAs. 5) Lipid extracts from C. elegans contain an activity that mimics the effect of BAs on clk-1, and the activity is more abundant in clk-1 extracts. 6) clk-1 and clk-1;tat-2 double mutants show altered cholesterol content. 7) The clk-1 phenotype is enhanced by high dietary cholesterol and this requires TAT-2. 8) Suppression of clk-1 by tat-2 is rescued by BAs, and this requires dietary cholesterol. 9) The clk-1 phenotype, including the level of activity in lipid extracts, is suppressed by antioxidants and enhanced by depletion of mitochondrial superoxide dismutases. These observations suggest that C. elegans synthesizes and secretes molecules with properties and functions resembling those of BAs. These molecules act in cholesterol uptake, and their level of synthesis is up-regulated by mitochondrial oxidative stress. Future investigations should reveal whether these molecules are in fact BAs, which would suggest the unexplored possibility that the elevated oxidative stress that characterizes the metabolic syndrome might participate in disease processes by affecting the regulation of metabolism by BAs.
Vyšlo v časopise:
Mitochondrial Oxidative Stress Alters a Pathway in Strongly Resembling That of Bile Acid Biosynthesis and Secretion in Vertebrates. PLoS Genet 8(3): e32767. doi:10.1371/journal.pgen.1002553
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002553
Souhrn
Mammalian bile acids (BAs) are oxidized metabolites of cholesterol whose amphiphilic properties serve in lipid and cholesterol uptake. BAs also act as hormone-like substances that regulate metabolism. The Caenorhabditis elegans clk-1 mutants sustain elevated mitochondrial oxidative stress and display a slow defecation phenotype that is sensitive to the level of dietary cholesterol. We found that: 1) The defecation phenotype of clk-1 mutants is suppressed by mutations in tat-2 identified in a previous unbiased screen for suppressors of clk-1. TAT-2 is homologous to ATP8B1, a flippase required for normal BA secretion in mammals. 2) The phenotype is suppressed by cholestyramine, a resin that binds BAs. 3) The phenotype is suppressed by the knock-down of C. elegans homologues of BA–biosynthetic enzymes. 4) The phenotype is enhanced by treatment with BAs. 5) Lipid extracts from C. elegans contain an activity that mimics the effect of BAs on clk-1, and the activity is more abundant in clk-1 extracts. 6) clk-1 and clk-1;tat-2 double mutants show altered cholesterol content. 7) The clk-1 phenotype is enhanced by high dietary cholesterol and this requires TAT-2. 8) Suppression of clk-1 by tat-2 is rescued by BAs, and this requires dietary cholesterol. 9) The clk-1 phenotype, including the level of activity in lipid extracts, is suppressed by antioxidants and enhanced by depletion of mitochondrial superoxide dismutases. These observations suggest that C. elegans synthesizes and secretes molecules with properties and functions resembling those of BAs. These molecules act in cholesterol uptake, and their level of synthesis is up-regulated by mitochondrial oxidative stress. Future investigations should reveal whether these molecules are in fact BAs, which would suggest the unexplored possibility that the elevated oxidative stress that characterizes the metabolic syndrome might participate in disease processes by affecting the regulation of metabolism by BAs.
Zdroje
1. RussellDW 2003 The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 72 137 174
2. ChiangJY 2009 Bile acids: regulation of synthesis. J Lipid Res
3. LefebvrePCariouBLienFKuipersFStaelsB 2009 Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 89 147 191
4. TangXHalleckMSSchlegelRAWilliamsonP 1996 A subfamily of P-type ATPases with aminophospholipid transporting activity. Science 272 1495 1497
5. PaulusmaCCGroenAKunneCHo-MokKSSpijkerboerAL 2006 Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport. Hepatology 44 195 204
6. BullLNvan EijkMJPawlikowskaLDeYoungJAJuijnJA 1998 A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet 18 219 224
7. SeamenEBlanchetteJMHanM 2009 P-type ATPase TAT-2 negatively regulates monomethyl branched-chain fatty acid mediated function in post-embryonic growth and development in C. elegans. PLoS Genet 5 e1000589 doi:10.1371/journal.pgen.1000589
8. LyssenkoNNMitevaYGilroySHanna-RoseWSchlegelRA 2008 An unexpectedly high degree of specialization and a widespread involvement in sterol metabolism among the C. elegans putative aminophospholipid translocases. BMC Dev Biol 8 96
9. EntchevEVKurzchaliaTV 2005 Requirement of sterols in the life cycle of the nematode Caenorhabditis elegans. Semin Cell Dev Biol 16 175 182
10. MotolaDLCumminsCLRottiersVSharmaKKLiT 2006 Identification of ligands for DAF-12 that govern dauer formation and reproduction in C. elegans. Cell 124 1209 1223
11. SmolenaarsMMMadsenORodenburgKWVan der HorstDJ 2007 Molecular diversity and evolution of the large lipid transfer protein superfamily. J Lipid Res 48 489 502
12. GrantBHirshD 1999 Receptor-mediated endocytosis in the Caenorhabditis elegans oocyte. Mol Biol Cell 10 4311 4326
13. MatyashVGeierCHenskeAMukherjeeSHirshD 2001 Distribution and transport of cholesterol in Caenorhabditis elegans. Mol Biol Cell 12 1725 1736
14. BranickyRDesjardinsDLiuJLHekimiS 2010 Lipid transport and signaling in Caenorhabditis elegans. Dev Dyn 239 1365 1377
15. ShibataYBranickyRLandaverdeIOHekimiS 2003 Redox regulation of germline and vulval development in Caenorhabditis elegans. Science 302 1779 1782
16. FelkaiSEwbankJJLemieuxJLabbeJCBrownGG 1999 CLK-1 controls respiration, behavior and aging in the nematode Caenorhabditis elegans. EMBO J 18 1783 1792
17. LevavasseurFMiyaderaHSiroisJTremblayMLKitaK 2001 Ubiquinone is necessary for mouse embryonic development but is not essential for mitochondrial respiration. J Biol Chem 276 46160 46164
18. YangWHekimiS 2010 A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans. PLoS Biol 8 e1000556 doi:10.1371/journal.pbio.1000556
19. LapointeJHekimiS 2008 Early mitochondrial dysfunction in long-lived Mclk1+/− mice. J Biol Chem 283 26217 26227
20. WongABoutisPHekimiS 1995 Mutations in the clk-1 gene of Caenorhabditis elegans affect developmental and behavioral timing. Genetics 139 1247 1259
21. BranickyRHekimiS 2006 What keeps C. elegans regular: the genetics of defecation. Trends Genet 22 571 579
22. BranickyRShibataYFengJHekimiS 2001 Phenotypic and suppressor analysis of defecation in clk-1 mutants reveals that reaction to changes in temperature is an active process in Caenorhabditis elegans. Genetics 159 997 1006
23. HihiAKBeauchampMCBranickyRDesjardinsACasanovaI 2008 Evolutionary conservation of drug action on lipoprotein metabolism-related targets. J Lipid Res 49 74 83
24. NielandTJShawJTJaipuriFAMaligaZDuffnerJL 2007 Influence of HDL-cholesterol-elevating drugs on the in vitro activity of the HDL receptor SR-BI. J Lipid Res 48 1832 1845
25. CunninghamMLCollinsBJHejtmancikMRHerbertRATravlosGS 2010 Effects of the PPARalpha Agonist and Widely Used Antihyperlipidemic Drug Gemfibrozil on Hepatic Toxicity and Lipid Metabolism. PPAR Res 2010
26. ShepherdJPackardCJBickerSLawrieTDMorganHG 1980 Cholestyramine promotes receptor-mediated low-density-lipoprotein catabolism. N Engl J Med 302 1219 1222
27. FengJBussiereFHekimiS 2001 Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans. Dev Cell 1 633 644
28. WollamJMagomedovaLMagnerDBShenYRottiersV 2011 The Rieske oxygenase DAF-36 functions as a cholesterol 7-desaturase in steroidogenic pathways governing longevity. Aging Cell 10 879 884
29. Yoshiyama-YanagawaTEnyaSShimada-NiwaYYaguchiSHaramotoY 2011 The conserved Rieske oxygenase DAF-36/Neverland is a novel cholesterol-metabolizing enzyme. J Biol Chem 286 25756 25762
30. WangDQTazumaSCohenDECareyMC 2003 Feeding natural hydrophilic bile acids inhibits intestinal cholesterol absorption: studies in the gallstone-susceptible mouse. Am J Physiol Gastrointest Liver Physiol 285 G494 502
31. GillMSHeldJMFisherALGibsonBWLithgowGJ 2004 Lipophilic regulator of a developmental switch in Caenorhabditis elegans. Aging Cell 3 413 421
32. YangWLiJHekimiS 2007 A Measurable increase in oxidative damage due to reduction in superoxide detoxification fails to shorten the life span of long-lived mitochondrial mutants of Caenorhabditis elegans. Genetics 177 2063 2074
33. Van RaamsdonkJMHekimiS 2009 Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLoS Genet 5 e1000361 doi:10.1371/journal.pgen.1000361
34. Van RaamsdonkJMMengYCampDYangWJiaX 2010 Decreased Energy Metabolism Extends Lifespan in Caenorhabditis elegans Without Reducing Oxidative Damage. Genetics
35. GerischBRottiersVLiDMotolaDLCumminsCL 2007 A bile acid-like steroid modulates Caenorhabditis elegans lifespan through nuclear receptor signaling. Proc Natl Acad Sci U S A 104 5014 5019
36. Li-HawkinsJGafvelsMOlinMLundEGAnderssonU 2002 Cholic acid mediates negative feedback regulation of bile acid synthesis in mice. J Clin Invest 110 1191 1200
37. FurukawaSFujitaTShimabukuroMIwakiMYamadaY 2004 Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114 1752 1761
38. AndoKFujitaT 2009 Metabolic syndrome and oxidative stress. Free Radic Biol Med 47 213 218
39. GrattaglianoIPalmieriVOPortincasaPMoschettaAPalascianoG 2008 Oxidative stress-induced risk factors associated with the metabolic syndrome: a unifying hypothesis. J Nutr Biochem 19 491 504
40. RobertsCKSindhuKK 2009 Oxidative stress and metabolic syndrome. Life Sci 84 705 712
41. BrockTJBrowseJWattsJL 2006 Genetic regulation of unsaturated fatty acid composition in C. elegans. PLoS Genet 2 e108 doi:10.1371/journal.pgen.0020108
42. YangWHekimiS 2010 Two modes of mitochondrial dysfunction lead independently to lifespan extension in Caenorhabditis elegans. Aging Cell 9 433 447
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 3
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- PIF4–Mediated Activation of Expression Integrates Temperature into the Auxin Pathway in Regulating Hypocotyl Growth
- Metabolic Profiling of a Mapping Population Exposes New Insights in the Regulation of Seed Metabolism and Seed, Fruit, and Plant Relations
- A Splice Site Variant in the Bovine Gene Compromises Growth and Regulation of the Inflammatory Response
- Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database