High fat diet-induced non alcoholic fatty liver disease in rats is associated with hyperhomocysteinemia caused by down regulation of the transsulphuration pathway

Lipids in Health and Disease

Kathleen M Botham⁴  Begoña Ochoa³  Mariarosaria Napolitano¹  Ainara Cano³  Barbara Rossi²  Xabier Buqué³  Patricia Aspichueta³  Simonetta Palleschi²  Elena Bravo¹ 

[1] Department of Cellular Biology and Neuroscience, Istituto Superiore Sanità, Rome, Italy;Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore Sanità, Rome, Italy;Department of Physiology, University of the Basque Country Faculty of Medicine and Dentistry, Sarriena s/n, 48940 Leioa, Spain. Rome, Italy;Department of Veterinary Basic Sciences, the Royal Veterinary College, Royal College St., London NW1 0TU, UK

关键词: transsulphuration pathway;    non alcoholic fatty liver disease;    hyperhomocysteinemia;    Homocysteine;   

Others  :  1212680
DOI  :  10.1186/1476-511X-10-60

 received in 2011-03-03, accepted in 2011-04-19,  发布年份 2011

【 摘 要 】

Background

Hyperhomocysteinemia (HHcy) causes increased oxidative stress and is an independent risk factor for cardiovascular disease. Oxidative stress is now believed to be a major contributory factor in the development of non alcoholic fatty liver disease, the most common liver disorder worldwide. In this study, the changes which occur in homocysteine (Hcy) metabolism in high fat-diet induced non alcoholic fatty liver disease (NAFLD) in rats were investigated.

Methods and results

After feeding rats a standard low fat diet (control) or a high fat diet (57% metabolisable energy as fat) for 18 weeks, the concentration of homocysteine in the plasma was significantly raised while that of cysteine was lowered in the high fat as compared to the control diet fed animals. The hepatic activities of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CGS), the enzymes responsible for the breakdown of homocysteine to cysteine via the transsulphuration pathway in the liver, were also significantly reduced in the high fat-fed group.

Conclusions

These results indicate that high fat diet-induced NAFLD in rats is associated with increased plasma Hcy levels caused by down-regulation of hepatic CBS and CGL activity. Thus, HHcy occurs at an early stage in high fat diet-induced NAFLD and is likely to contribute to the increased risk of cardiovascular disease associated with the condition.

【 授权许可】

   
2011 Bravo et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Adams LA, Angulo P: Recent concepts in non-alcoholic fatty liver disease. Diabetic Med 2005, 22:1129-1133.
• [2]Svegliati-Baroni G, Candelaresi C, Saccomanno S, Ferretti G, Bachetti T, Marzioni M, De Minicis S, Nobili L, Salzano R, Omenetti A, Pacetti D, Sigmund S, Benedetti A, Casini AA: A model of insulin resistance and nonalcoholic steatohepatitis in rats. Am J Pathol 2006, 169:846-860.
• [3]Videla LA, Rodrigo R, Araya J, Ponichik J: Insulin resistance and oxidative stress interdependency in non-alcoholic fatty liver disease. Trends Mol Med 2006, 12:555-558.
• [4]Grattagliano I, Palmieri VO, Portincasa P, Moschetta A, Palasciano G: Oxidative stress-induced risk factors associated with the metabolic syndrome: a unifying hypothesis. J Nutr Biochem 2008, 19:491-504.
• [5]Videla LA, Rodrigo R, Araya J, Poniachik J: Oxidative stress and depletion of hepatic long-chain polyunsaturated fatty acids may contribute to nonalcoholic fatty liver disease. Free Radic Biol Med 2004, 37:1499-1507.
• [6]Videla LA, Rodrigo RN, Orellana M, Fernandez V, Tapia G, Quiñones L, Varela N, Contreras J, Lazarte R, Csendes A, Rojas J, Maluenda F, Burdiles P, Diaz JC, Smok G, Thielemann L, Poniachik J: Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients. Clin Sci 2004, 106:261-268.
• [7]Araya J, Rodrigo RN, Videla LA, Thielemann L, Orellana M, Pettinelli P, Poniachik J: Increase in long-chain polyunsaturated fatty acid n - 6/n - 3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. Clin Sci 2004, 106:635-643.
• [8]Tessari P, Coracina A, Cosma A, Tiengo A: Hepatic lipid metabolism and non-alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2009, 19:291-302.
• [9]Buque X, Martinez MJ, Cano A, Miquilena ME, Garcia-Monzon C, Aspichueta P, Ochoa B: A subset of dysregulated metabolic and survival genes is associated with severity of hepatic steatosis in obese Zucker rats. J Lipid Res 2009, 51:500-513.
• [10]Targher G, Arcaro G: Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis 2007, 191:235-240.
• [11]Zhou J, Austin RC: Contributions of hyperhomocysteinemia to atherosclerosis: Causal relationship and potential mechanisms. BioFactors 2009, 35:120-129.
• [12]Wijekoon EP, Brosnan ME, Brosnan JT: Homocysteine metabolism in diabetes. Biochem Soc Trans 2007, 35:1175-1179.
• [13]Jhee KH, Kruger WD: The Role of Cystathionine beta-synthase in homocysteine metabolism. Antioxid Redox Signal 2005, 7:813-822.
• [14]Gaull G, Starman JA, Schaffner N: Homocystinuria due to cystathionine synthase deficiency: enzymatic and ultrastructural studies. J Pediatr 1974, 84:381-390.
• [15]Namekata K, Enokido Y, Ishii I, Nagai Y, Harada T, Kimura H: Abnormal lipid metabolism in cystathionine β-synthase-deficient mice, an animal model for hyperhomocysteinemia. J Biol Chem 2004, 279:52961-52969.
• [16]Gulsen M, Yesilova Z, Bagci S, Uygun A, Ozcan A, Ercin CN, Erdil A, Sanisoglu SY, Cakir E, Ates Y, Erbil MK, Karaeren N, Dagalp K: Elevated plasma homocysteine concentrations as a predictor of steatohepatitis in patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2005, 20:1448-1455.
• [17]Safwat GM, Pisanò S, D'Amore E, Borioni G, Napolitano M, Kamal AA, Ballanti P, Botham KM, Bravo E: Induction of non-alcoholic fatty liver disease and insulin resistance by feeding a high-fat diet in rats: does coenzyme Q monomethyl ether have a modulatory effect? Nutrition 2009, 25:1157-1168.
• [18]Cano A, Ciaffoni F, Safwa GM, Aspichueta P, Ochoa B, Bravo E, Botham KM: Hepatic very low density lipoprotein assembly is disturbed in a rat model of non alcoholic fatty liver disease: Is there a role for dietary Coenzyme Q? J Applied Physiol 2009, 107:707-717.
• [19]Folch J, Lees N, Sloane-Stanley GH: A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 1957, 226:497-509.
• [20]Mudd S, Finkelstein HDJ, Irreverre F, Laster L: Transsulfuration in mammals. Microassays and tissue distributions of three enzymes of the pathway. J Biol Chem 1965, 240:4382-4392.
• [21]Heinonen K: Studies on cystathionase activity in rat liver and brain during development. Effects of hormones and amino acids in vivo. Biochem J 1973, 136:1011-1015.
• [22]Vandesompele J, Preter KD, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F: Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. [http://genomebiology.com/2002/3/7/research/0034] webciteGenome Biol 2002. 18
• [23]Bradford M: A sensitive method for quantitation of microgram quantities of protein utilizing the principle of dye-binding. Anal Biochem 1976, 72:248-254.
• [24]Pfeiffer CM, Huff DL, Gunter EW: Rapid and Accurate HPLC Assay for Plasma Total Homocysteine and Cysteine in a Clinical Laboratory Setting. Clin Chem 1999, 45:290-292.
• [25]Houstis N, Rosen ED, Lander ES: Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 2006, 440:944-948.
• [26]Cravo M, Gloria L, Selhub J, Nadeau M, Camilo M, Resende M, Cardoso J, Leitao C, Mira F: Hyperhomocysteinemia in chronic alcoholism: correlation with folate, vitamin B-12, and vitamin B-6 status. Am J Clin Nutr 1996, 63:220-224.
• [27]Watanabe M, Osada J, Aratani Y, Kluckman K, Reddick R, Malinow MR, Maeda N: Mice deficient in cystathionine β-synthase: animal models for mild and severe homocyst(e)inemia. Proc Natl Acad Sci USA 1995, 92:1585-1589.
• [28]Hirsch S, Poniachick J, Avendaño M, Csendes A, Burdiles P, Smok G, Diaz JC, de la Maza MP: Serum folate and homocysteine levels in obese females with non-alcoholic fatty liver. Nutrition 2005, 21:137-141.
• [29]Gil B, Casado M, Pajares MA: Differential expression pattern of S-adenosylmethionine synthetase isoenzymes during rat liver development. Hepatology 1996, 24:876-881.
• [30]Kwon DY, Jung YS, Kim SJ, Park HK, Park JH, Kim YC: Impaired Sulfur-Amino Acid Metabolism and Oxidative Stress in Nonalcoholic Fatty Liver Are Alleviated by Betaine Supplementation in Rats. J Nutr 2009, 139:63-68.
• [31]Meister A, Anderson ME: Glutathione. Annu Rev Biochem 1983, 52:711-760.