Paraoxonase 1 and dietary hyperhomocysteinemia modulate the expression of mouse proteins involved in liver homeostasis

• Authors: Joanna Suszyńska-Zajczyk , Hieronim Jakubowski
• Languages of publication: EN

Abstracts

EN

Homocysteine (Hcy), a product of methionine metabolism, is elevated by the consumption of a high-methionine diet that can cause fatty liver disease. Paraoxonase 1 (Pon1), a hydrolase expressed mainly in the liver and carried in the circulation on high-density lipoprotein, participates in Hcy metabolism. Low Pon1 activity is linked to fatty liver disease. We hypothesize that hyperhomocysteinemia and low Pon1 induce changes in gene expression that could impair liver homeostasis. To test this hypothesis, we analyzed the liver proteome of Pon1-/- and Pon1+/+ mice fed a high methionine diet (1% methionine in the drinking water) for 8 weeks using 2D IEF/SDS-PAGE gel electrophoresis and MALDI-TOF mass spectrometry. We identified seven liver proteins whose expression was significantly altered in Pon1-/- mice. In animals fed with a control diet, the expression of three liver proteins involved in lipoprotein metabolism (ApoE), iron metabolism (Ftl), and regulation of nitric oxide generation (Ddah1) was up-regulated by the Pon1-/- genotype. In mice fed with a high-methionine diet, expression of four liver proteins was up-regulated and of three proteins was down-regulated by the Pon1-/- genotype. The up-regulated proteins are involved in lipoprotein metabolism (ApoE), energy metabolism (Atp5h), oxidative stress response (Prdx2), and nitric oxide regulation (Ddah1). The down-regulated proteins are involved in energy metabolism (Gamt), iron metabolism (Ftl), and catechol metabolism (Comt). Expression of one protein (Ftl) was up-regulated both by the Pon1-/- genotype and a high-methionine diet. Our findings suggest that Pon1 interacts with diverse cellular processes - from lipoprotein metabolism, nitric oxide regulation, and energy metabolism to iron transport and antioxidant defenses - that are essential for normal liver homeostasis and modulation of these interactions by a high-methionine diet may contribute to fatty liver disease.

Keywords

EN

Pon1; high-methionine diet; hyperhomocysteinemia; mouse liver proteome

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2014
• Volume: 61
• Issue: 4
• Pages: 815-823

Dates

published

2014

received

2014-07-17

revised

2014-09-29

accepted

2014-10-07

(unknown)

2014-10-28

Contributors

author

Joanna Suszyńska-Zajczyk

• Institute of Bioorganic Chemistry, Poznań, Poland

author

Hieronim Jakubowski

• Institute of Bioorganic Chemistry, and Department of Biochemistry and Biotechnology, University of Life Sciences, Poznań, Poland nd Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers-New Jersey Medical School, International Center for Public Health, Newark, NJ, USA

References

• Bayrak A, Bayrak T, Tokgozoglu SL, Volkan-Salanci B, Deniz A, Yavuz B, Alikasifoglu M, Demirpence E (2012) Serum PON-1 activity but not Q192R polymorphism is related to the extent of atherosclerosis. J Atheroscler Thromb 19: 376-384.
• Bhattacharyya T, Nicholls SJ, Topol EJ, Zhang RL, Yang X, Schmitt D, Fu XM, Shao MY, Brennan DM, Ellis SG, Brennan ML, Allayee H, Lusis AJ, Hazen SL (2008) Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA 299: 1265-1276.
• Borowczyk K, Shih DM, Jakubowski H (2012a) Metabolism and neurotoxicity of homocysteine thiolactone in mice: evidence for a protective role of paraoxonase 1. J Alzheimers Dis 30: 225-231.
• Borowczyk K, Tisonczyk J, Jakubowski H (2012b) Metabolism and neurotoxicity of homocysteine thiolactone in mice: protective role of bleomycin hydrolase. Amino Acids 43: 1339-1348.
• Brosnan JT, Jacobs RL, Stead LM, Brosnan ME (2004) Methylation demand: a key determinant of homocysteine metabolism. Acta Biochim Pol 51: 405-413.
• Candiano G, Bruschi M, Musante L, Santucci L, Ghiggeri GM, Carnemolla B, Orecchia P, Zardi L, Righetti PG (2004) Blue silver: a very sensitive colloidal Coomassie G-250 staining for proteome analysis. Electrophoresis 25: 1327-1333.
• Costa LG, Giordano G, Cole TB, Marsillach J, Furlong CE (2013) Paraoxonase 1 (PON1) as a genetic determinant of susceptibility to organophosphate toxicity. Toxicology 307: 115-122.
• Das AM (2003) Regulation of the mitochondrial ATP-synthase in health and disease. Mol Genet Metab 79: 71-82.
• De Bonis ML, Tessitore A, Pellecchia MT, Longo K, Salvatore A, Russo A, Ingrosso D, Zappia V, Barone P, Galletti P, Tedeschi G (2010) Impaired transmethylation potential in Parkinson's disease patients treated with L-Dopa. Neurosci Lett 468: 287-291.
• DiBello PM, Dayal S, Kaveti S, Zhang D, Kinter M, Lentz SR, Jacobsen DW (2010) The nutrigenetics of hyperhomocysteinemia: quantitative proteomics reveals differences in the methionine cycle enzymes of gene-induced versus diet-induced hyperhomocysteinemia. Mol Cell Proteomics 9: 471-485.
• Domagala TB, Lacinski M, Trzeciak WH, Mackness B, Mackness MI, Jakubowski H (2006) The correlation of homocysteine-thiolactonase activity of the paraoxonase (PON1) protein with coronary heart disease status. Cell Mol Biol 52: 4-10.
• Farid AS, Honkawa K, Fath EM, Nonaka N, Horii Y (2013) Serum paraoxonase-1 as biomarker for improved diagnosis of fatty liver in dairy cows. BMC Vet Res 9: 73.
• Faurobert M, Pelpoir E, Chaib J (2007) Phenol extraction of proteins for proteomic studies of recalcitrant plant tissues. Methods Mol Biol 355: 9-14.
• Ferre N, Camps J, Cabre M, Paul A, Joven J (2001) Hepatic paraoxonase activity alterations and free radical production in rats with experimental cirrhosis. Metabolism 50: 997-1000.
• Ferre N, Camps J, Prats E, Vilella E, Paul A, Figuera L, Joven J (2002) Serum paraoxonase activity: a new additional test for the improved evaluation of chronic liver damage. Clin Chem 48: 261-268.
• Ferretti G, Bacchetti T, Marotti E, Curatola G (2003) Effect of homocysteinylation on human high-density lipoproteins: a correlation with paraoxonase activity. Metabolism 52: 146-151.
• Garcia-Heredia A, Kensicki E, Mohney RP, Rull A, Triguero I, Marsillach J, Tormos C, Mackness B, Mackness M, Shih DM, Pedro-Botet J, Joven J, Saez G, Camps J (2013) Paraoxonase-1 Deficiency Is Associated with Severe Liver Steatosis in Mice Fed a High-fat High-cholesterol Diet: A Metabolomic Approach. J Proteome Res 12: 1946-1955.
• Glowacki R, Bald E, Jakubowski H (2010) Identification and origin of Nepsilon-homocysteinyl-lysine isopeptide in humans and mice. Amino Acids 39: 1563-1569.
• Glowacki R, Jakubowski H (2004) Cross-talk between Cys34 and lysine residues in human serum albumin revealed by N-homocysteinylation. J Biol Chem 279: 10864-10871.
• Hirsch S, Poniachick J, Avendano M, Csendes A, Burdiles P, Smok G, Diaz JC, de la Maza MP (2005) Serum folate and homocysteine levels in obese females with non-alcoholic fatty liver. Nutrition 21: 137-141.
• Hu XW, Qin SM, Li D, Hu LF, Liu CF (2013) Elevated homocysteine levels in levodopa-treated idiopathic Parkinson's disease: a meta-analysis. Acta Neurol Scand 128: 73-82.
• Ishimine N, Usami Y, Nogi S, Sumida T, Kurihara Y, Matsuda K, Nakamura K, Yamauchi K, Okumura N, Tozuka M (2010) Identification of N-homocysteinylated apolipoprotein AI in normal human serum. Ann Clin Biochem 47: 453-459.
• Jakubowski H (1999) Protein homocysteinylation: possible mechanism underlying pathological consequences of elevated homocysteine levels. FASEB J 13: 2277-2283.
• Jakubowski H (2000) Calcium-dependent human serum homocysteine thiolactone hydrolase. A protective mechanism against protein N-homocysteinylation. J Biol Chem 275: 3957-3962.
• Jakubowski H (2002) Homocysteine is a protein amino acid in humans. Implications for homocysteine-linked disease. J Biol Chem 277: 30425-30428.
• Jakubowski H (2008a) New method for the determination of protein N-linked homocysteine. Anal Biochem 380: 257-261.
• Jakubowski H (2008b) Paraoxonase 1 (PON1), a junction between the metabolisms of homocysteine and lipids. Proteins Cell Regul 6: 87-102.
• Jakubowski H, Boers GH, Strauss KA (2008) Mutations in cystathionine beta-synthase or methylenetetrahydrofolate reductase gene increase N-homocysteinylated protein levels in humans. FASEB J 22: 4071-4076.
• Jakubowski H, Perla-Kajan J, Finnell RH, Cabrera RM, Wang H, Gupta S, Kruger WD, Kraus JP, Shih DM (2009) Genetic or nutritional disorders in homocysteine or folate metabolism increase protein N-homocysteinylation in mice. FASEB J 23: 1721-1727.
• Jakubowski H, Zhang L, Bardeguez A, Aviv A (2000) Homocysteine thiolactone and protein homocysteinylation in human endothelial cells: implications for atherosclerosis. Circ Res 87: 45-51.
• Jiang H, Stabler SP, Allen RH, Maclean KN (2012) Altered expression of apoA-I, apoA-IV and PON-1 activity in CBS deficient homocystinuria in the presence and absence of treatment: possible implications for cardiovascular outcomes. Mol Genet Metab 107: 55-65.
• Kaplowitz N, Than TA, Shinohara M, Ji C (2007) Endoplasmic reticulum stress and liver injury. Semin Liver Dis 27: 367-377.
• Lacinski M, Skorupski W, Cieslinski A, Sokolowska J, Trzeciak WH, Jakubowski H (2004) Determinants of homocysteine-thiolactonase activity of the paraoxonase-1 (PON1) protein in humans. Cell Mol Biol 50: 885-893.
• Liao D, Tan H, Hui R, Li Z, Jiang X, Gaubatz J, Yang F, Durante W, Chan L, Schafer AI, Pownall HJ, Yang X, Wang H (2006) Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I Protein synthesis and enhancing HDL cholesterol clearance. Circ Res 99: 598-606.
• Luczak M, Formanowicz D, Pawliczak E, Wanic-Kossowska M, Wykretowicz A, Figlerowicz M (2011) Chronic kidney disease-related atherosclerosis - proteomic studies of blood plasma. Proteome Sci 9: 25.
• Mackness B, Beltran-Debon R, Aragones G, Joven J, Camps J, Mackness M (2010) Human tissue distribution of paraoxonases 1 and 2 mRNA. IUBMB Life 62: 480-482.
• Marsillach J, Ferre N, Vila MC, Lligona A, Mackness B, Mackness M, Deulofeu R, Sola R, Pares A, Pedro-Botet J, Joven J, Caballeria J, Camps J (2007) Serum paraoxonase-1 in chronic alcoholics: relationship with liver disease. Clin Biochem 40: 645-650.
• Marsillach J, Mackness B, Mackness M, Riu F, Beltran R, Joven J, Camps J (2008) Immunohistochemical analysis of paraoxonases-1, 2, and 3 expression in normal mouse tissues. Free Radic Biol Med 45: 146-157.
• Mudd SH, Ebert MH, Scriver CR (1980) Labile methyl group balances in the human: the role of sarcosine. Metabolism 29: 707-720.
• Ogawa T, Kimoto M, Sasaoka K (1987) Occurrence of a new enzyme catalyzing the direct conversion of NG,NG-dimethyl-L-arginine to L-citrulline in rats. Biochem Biophys Res Commun 148: 671-677.
• Oppenheim EW, Adelman C, Liu X, Stover PJ (2001) Heavy chain ferritin enhances serine hydroxymethyltransferase expression and de novo thymidine biosynthesis. J Biol Chem 276: 19855-19861.
• Perla-Kajan J, Jakubowski H (2010) Paraoxonase 1 protects against protein N-homocysteinylation in humans. FASEB J 24: 931-936.
• Perla-Kajan J, Jakubowski H (2012) Paraoxonase 1 and homocysteine metabolism. Amino Acids 43: 1405-1417.
• Perla-Kajan J, Stanger O, Luczak M, Ziolkowska A, Malendowicz LK, Twardowski T, Lhotak S, Austin RC, Jakubowski H (2008) Immunohistochemical detection of N-homocysteinylated proteins in humans and mice. Biomed Pharmacother 62: 473-479.
• Rauh M, Verwied S, Knerr I, Dorr HG, Sonnichsen A, Koletzko B (2001) Homocysteine concentrations in a German cohort of 500 individuals: reference ranges and determinants of plasma levels in healthy children and their parents. Amino Acids 20: 409-418.
• Robert K, Chasse JF, Santiard-Baron D, Vayssettes C, Chabli A, Aupetit J, Maeda N, Kamoun P, London J, Janel N (2003) Altered gene expression in liver from a murine model of hyperhomocysteinemia. J Biol Chem 278: 31504-31511.
• Shevchenko A, Shevchenko A (2001) Evaluation of the efficiency of in-gel digestion of proteins by peptide isotopic labeling and MALDI mass spectrometry. Anal Biochem 296: 279-283.
• Shih DM, Gu L, Xia YR, Navab M, Li WF, Hama S, Castellani LW, Furlong CE, Costa LG, Fogelman AM, Lusis AJ (1998) Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature 394: 284-287.
• Stuhlinger MC, Stanger O (2005) Asymmetric dimethyl-L-arginine (ADMA): a possible link between homocyst(e)ine and endothelial dysfunction. Curr Drug Metab 6: 3-14.
• Suh JR, Oppenheim EW, Girgis S, Stover PJ (2000) Purification and properties of a folate-catabolizing enzyme. J Biol Chem 275: 35646-35655.
• Suszynska-Zajczyk J, Wroblewski J, Utyro O, Luczak M, Marczak L, Jakubowski H (2014a) Bleomycin hydrolase and hyperhomocysteinemia modulate the expression of mouse proteins involved in liver homeostasis. Amino Acids 46: 1471-1480.
• Suszyńska-Zajczyk J, Łuczak M, Marczak Ł, Jakubowski H (2014b) Inactivation of the paraoxonase 1 gene affects the expression of mouse brain proteins involved in neurodegeneration. J Alzheimers Dis 42: 247-260.
• Undas A, Jankowski M, Twardowska M, Padjas A, Jakubowski H, Szczeklik A (2005) Antibodies to N-homocysteinylated albumin as a marker for early-onset coronary artery disease in men. Thromb Haemost 93: 346-350.
• Undas A, Perla J, Lacinski M, Trzeciak W, Kazmierski R, Jakubowski H (2004) Autoantibodies against N-homocysteinylated proteins in humans: implications for atherosclerosis. Stroke 35: 1299-1304.
• Velez-Carrasco W, Merkel M, Twiss CO, Smith JD (2008) Dietary methionine effects on plasma homocysteine and HDL metabolism in mice. J Nutr Biochem 19: 362-370.
• Wehr H, Bednarska-Makaruk M, Graban A, Lipczynska-Lojkowska W, Rodo M, Bochynska A, Ryglewicz D (2009) Paraoxonase activity and dementia. J Neurol Sci 283: 107-108.
• Werstuck GH, Lentz SR, Dayal S, Hossain GS, Sood SK, Shi YY, Zhou J, Maeda N, Krisans SK, Malinow MR, Austin RC (2001) Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest 107: 1263-1273.
• Woeller CF, Fox JT, Perry C, Stover PJ (2007) A ferritin-responsive internal ribosome entry site regulates folate metabolism. J Biol Chem 282: 29927-29935.
• Zaabczyk M, Glowacki R, Machnik A, Herod P, Kazek G, Jakubowski H, Undas A (2011) Elevated concentrations of Nε-homocysteinyl-lysine isopeptide in acute myocardial infarction: links with ADMA formation. Clin Chem Lab Med 49: 729-735.
• Zhang C, Peng W, Jiang X, Chen B, Zhu J, Zang Y, Zhang J, Zhu T, Qin J (2008) Transgene expression of human PON1 Q in mice protected the liver against CCl4-induced injury. J Gene Med 10: 94-100.
• Zhou J, Moller J, Danielsen CC, Bentzon J, Ravn HB, Austin RC, Falk E (2001) Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 21: 1470-1476.