CC BY-NC-ND 4.0 · Rev Bras Ginecol Obstet 2018; 40(05): 251-259
DOI: 10.1055/s-0038-1666856
Original Article
Thieme Revinter Publicações Ltda Rio de Janeiro, Brazil

A Long-term Estrogen Deficiency in Ovariectomized Mice is Associated with Disturbances in Fatty Acid Oxidation and Oxidative Stress

Deficiência de estrogênio em longo prazo em camundongas ovarietcomizadas está associada a distúrbios na oxidação de ácidos graxos e estresse oxidativo
Monique Cristine de Oliveira
1   Universidade de Maringá, Maringá, PR, Brazil
2   Centro Universitário de Ingá, Maringá, PR, Brazil
,
Lilian Brites Campos-Shimada
1   Universidade de Maringá, Maringá, PR, Brazil
,
Maria Raquel Marçal-Natali
1   Universidade de Maringá, Maringá, PR, Brazil
,
Emy Luiza Ishii-Iwamoto
1   Universidade de Maringá, Maringá, PR, Brazil
,
Clairce Luzia Salgueiro-Pagadigorria
1   Universidade de Maringá, Maringá, PR, Brazil
› Author Affiliations
Further Information

Publication History

11 November 2017

06 March 2018

Publication Date:
18 June 2018 (online)

Abstract

Objective The aim of this work was to evaluate the changes caused by estrogen deficiency in lipid metabolism.

Methods This study encompassed direct measurements of plasma biochemical analyses, liver lipid contents, and assessments of the mitochondrial β-oxidation capacity as well as an evaluation of the liver redox status in an animal model of estrogen deficiency.

Results When compared with control mice, the livers of ovariectomized (OVX) mice presented considerable accretions in their lipid contents, which were accompanied by increased levels of lipid peroxidation in liver homogenates and mitochondria from OVX groups and decreased reduced glutathione (GSH) contents. In isolated mitochondria, estrogen deficiency inhibited mitochondrial β-oxidation of fatty acids irrespective of their chain length. The liver mitochondrial and peroxisomal H2O2 generations in OVX mice were increased. Additionally, the activities of all antioxidant enzymes assessed were decreased.

Conclusion These data provide one potential explanation for the increased susceptibility to metabolic diseases observed after menopause.

Resumo

Objetivo O objetivo desse trabalho foi avaliar as alterações causadas pela deficiência estrogênica no metabolismo de lipídeos.

Métodos Este estudo abrangeu análises bioquímicas plasmáticas, verificação de conteúdo lipídico do fígado e avaliações da capacidade de β-oxidação mitocondrial e do estado redox do fígado em um modelo animal de deficiência estrogênica.

Resultados Os fígados das camundongas ovariectomizadas (OVXs) apresentaram acréscimos consideráveis no conteúdo de lipídeos, que foram acompanhados por aumento de peroxidação lipídica em homogenatos e mitocôndrias de fígado e diminuição do conteúdo de glutationa reduzida (GSH) quando comparadas as camundongas do grupo controle. Nas mitocôndrias isoladas, a deficiência estrogênica causou a inibição da β-oxidação mitocondrial independentemente do comprimento da cadeia dos ácidos graxos. A geração mitocondrial e peroxissomal de H2O2 apresentou-se aumentada em camundongas OVXs. Além disso, as atividades de todas as enzimas antioxidantes avaliadas foram diminuídas.

Conclusão Esses dados fornecem uma explicação potencial para o aumento da suscetibilidade às doenças metabólicas observadas após a menopausa.

Contributions

Oliveira M. C., Shimada L. B. C., Natali M. R. M., Iwamoto E. L. I. and Pagadigorria C. Z. S. contributed to conception and design of the study and the critical review of the intellectual content of the article. All authors approved of the version to be published.


 
  • References

  • 1 Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab 2003; 88 (06) 2404-2411 . Doi: 10.1210/jc.2003-030242
  • 2 Day CP, James OF. Steatohepatitis: a tale of two “hits”?. Gastroenterology 1998; 114 (04) 842-845 . Doi: 10.1016/S0016-5085(98)70599-2
  • 3 Paquette A, Wang D, Jankowski M, Gutkowska J, Lavoie JM. Effects of ovariectomy on PPAR α, SREBP-1c, and SCD-1 gene expression in the rat liver. Menopause 2008; 15 (06) 1169-1175 . Doi: 10.1097/gme.0b013e31817b8159
  • 4 Völzke H, Schwarz S, Baumeister SE. , et al. Menopausal status and hepatic steatosis in a general female population. Gut 2007; 56 (04) 594-595 . Doi: 10.1136/gut.2006.115345
  • 5 Borrás C, Gambini J, López-Grueso R, Pallardó FV, Viña J. Direct antioxidant and protective effect of estradiol on isolated mitochondria. Biochim Biophys Acta 2010; 1802 (01) 205-211
  • 6 Campos LB, Gilglioni EH, Garcia RF. , et al. Cimicifuga racemosa impairs fatty acid β-oxidation and induces oxidative stress in livers of ovariectomized rats with renovascular hypertension. Free Radic Biol Med 2012; 53 (04) 680-689 . Doi: 10.1016/j.freeradbiomed.2012.05.043
  • 7 Gilglioni EH, Campos LB, Oliveira MC. , et al. Beneficial effects of tibolone on blood pressure and liver redox status in ovariectomized rats with renovascular hypertension. J Gerontol A Biol Sci Med Sci 2013; 68 (05) 510-520 . Doi: 10.1093/gerona/gls210
  • 8 Sankar P, Zachariah B, Vickneshwaran V, Jacob SE, Sridhar MG. Amelioration of oxidative stress and insulin resistance by soy isoflavones (from Glycine max) in ovariectomized Wistar rats fed with high fat diet: the molecular mechanisms. Exp Gerontol 2015; 63: 67-75 . Doi: 10.1016/j.exger.2015.02.001
  • 9 Marí M, Morales A, Colell A, García-Ruiz C, Fernández-Checa JC. Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal 2009; 11 (11) 2685-2700 . Doi: 10.1089/ARS.2009.2695
  • 10 Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 1957; 226 (01) 497-509
  • 11 Bracht A, Ishii-Iwamoto EL, Salgueiro-Pagadigorria CL. Técnicas de centrifugação e de fracionamento celular. In: Bracht A, Ishii-Iwamoto EL. , orgs. Métodos de Laboratório em Bioquímica . São Paulo, SP: Manole; 2003: 77-101
  • 12 Natarajan SK, Eapen CE, Pullimood AB, Balasubramanian KA. Oxidative stress in experimental liver microvesicular steatosis: role of mitochondria and peroxisomes. J Gastroenterol Hepatol 2006; 21 (08) 1240-1249 . Doi: 10.1111/j.1440-1746.2006.04313.x
  • 13 Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193 (01) 265-275
  • 14 Garland PB, Shepherd D, Nicholls DG, Yates DW, Light PA. Interactions between fatty acid oxidation and the tricarboxylic acid cycle. In: Lowestein JM. , ed. Citric Acid Cycle: Control and Compartmentation . New York, NY: Marcel Dekker; 1969: 163-212
  • 15 Scholz R, Bucher T. Hemoglobin-free perfusion of rat liver. In: Chance B, Estabrook RW, Williamson JR. , eds. Control of Energy Metabolism . New York, NY: Academic Press; 1965: 393-414
  • 16 Mellanby J, Williamson DH. Acetoacetate. In: Bergmeyer HU. , ed. Methods of Enzymatic Analysis . New York, NY: Academic Press; 1974: 1840-1843
  • 17 Hissin PJ, Hilf R. A fluorometric method for determination of oxidized and reduced glutathione in tissues. Anal Biochem 1976; 74 (01) 214-226 . Doi: 10.1016/0003-2697(76)90326-2
  • 18 Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95 (02) 351-358 . Doi: 10.1016/0003-2697(79)90738-3
  • 19 Berson A, De Beco V, Lettéron P. , et al. Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes. Gastroenterology 1998; 114 (04) 764-774 . Doi: 10.1016/S0016-5085(98)70590-6
  • 20 Taguchi H, Ogura Y, Takanashi T, Hashizoe M, Honda Y. In vivo quantitation of peroxides in the vitreous humor by fluorophotometry. Invest Ophthalmol Vis Sci 1996; 37 (07) 1444-1450
  • 21 Aebi H. Catalase. In: Bergmeyer HU. , ed. Methods of Enzymatic Analysis . New York, NY: Academic Press; 1974: 673-690
  • 22 Marklund S, Marklund G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 1974; 47 (03) 469-474 . Doi: 10.1111/j.1432-1033.1974.tb03714.x
  • 23 Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 1967; 70 (01) 158-169
  • 24 Mize CE, Langdon RG. Hepatic glutathione reductase. I. Purification and general kinetic properties. J Biol Chem 1962; 237: 1589-1595
  • 25 Tian WN, Pignatare JN, Stanton RC. Signal transduction proteins that associate with the platelet-derived growth factor (PDGF) receptor mediate the PDGF-induced release of glucose-6-phosphate dehydrogenase from permeabilized cells. J Biol Chem 1994; 269 (20) 14798-14805
  • 26 Adams LA, Angulo P. Recent concepts in non-alcoholic fatty liver disease. Diabet Med 2005; 22 (09) 1129-1133 . Doi: 10.1111/j.1464-5491.2005.01748
  • 27 Martins-Maciel ER, Campos LB, Salgueiro-Pagadigorria CL, Bracht A, Ishii-Iwamoto EL. Raloxifene affects fatty acid oxidation in livers from ovariectomized rats by acting as a pro-oxidant agent. Toxicol Lett 2013; 217 (01) 82-89 . Doi: 10.1016/j.toxlet.2012.11.021
  • 28 Franzoni AC, Amorim AM, Silva JVM, Storti JAP, Oliveira MC. Use of ursodeoxycholic acid on post-menopausal obesity, hepatic steatosis and plasma profile as an alternative treatment for hormone replacement therapy. Braz Arch Biol Technol 2015; 58: 898-904 . Doi: 10.1590/S1516-89132015060310
  • 29 de Oliveira MC, Gilglioni EH, de Boer BA. , et al. Bile acid receptor agonists INT747 and INT777 decrease oestrogen deficiency-related postmenopausal obesity and hepatic steatosis in mice. Biochim Biophys Acta 2016; 1862 (11) 2054-2062
  • 30 Rogers NH, Perfield II JW, Strissel KJ, Obin MS, Greenberg AS. Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity. Endocrinology 2009; 150 (05) 2161-2168 . Doi: 10.1210/en.2008-1405
  • 31 Villanova N, Moscatiello S, Ramilli S. , et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology 2005; 42 (02) 473-480
  • 32 Veech RL, Raijman L, Krebs HA. Equilibrium relations between the cytoplasmic adenine nucleotide system and nicotinamide-adenine nucleotide system in rat liver. Biochem J 1970; 117 (03) 499-503 . Doi: 10.1042/bj1170499
  • 33 Mannaerts GP, Debeer LJ, Thomas J, De Schepper PJ. Mitochondrial and peroxisomal fatty acid oxidation in liver homogenates and isolated hepatocytes from control and clofibrate-treated rats. J Biol Chem 1979; 254 (11) 4585-4595
  • 34 Kim YY, Kim SH, Oh S. , et al. Increased fat due to estrogen deficiency induces bone loss by elevating monocyte chemoattractant protein-1 (MCP-1) production. Mol Cells 2010; 29 (03) 277-282 . Doi: 10.1007/s10059-010-0027-x
  • 35 Sanyal AJ, Campbell-Sargent C, Mirshahi F. , et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001; 120 (05) 1183-1192 . Doi: 10.1053/gast.2001.23256
  • 36 Kowaltowski AJ, de Souza-Pinto NC, Castilho RF, Vercesi AE. Mitochondria and reactive oxygen species. Free Radic Biol Med 2009; 47 (04) 333-343 . Doi: 10.1016/j.freeradbiomed.2009.05.004
  • 37 Mohamed Sadek K. Antioxidant and immunostimulant effect of carica papaya linn. Aqueous extract in acrylamide intoxicated rats. Acta Inform Med 2012; 20 (03) 180-185 . Doi: 10.5455/aim.2012.20.180-185
  • 38 Ibim SEM, Randall R, Han P, Musey PI. Modulation of hepatic glucose-6-phosphate dehydrogenase activity in male and female rats by estrogen. Life Sci 1989; 45 (17) 1559-1565 . Doi: 10.1016/0024-3205(89)90422-0