L-carnitine ameliorated fatty liver in high-calorie diet/STZ-induced type 2 diabetic mice by improving mitochondrial function

Diabetology & Metabolic Syndrome

Chunbo Wang²  Zhulin Wang¹  Jing Dong³  Weizhen Zhong²  Qing Li¹  Yunqiu Xia² 

[1] Class 5, Grade 2007, Medical College, Qingdao University, Ningxia Road, Qingdao, China;Center for Human Functional Experiment, Medical College, Qingdao University, Ningxia Road, Qingdao, China;Physiology Department of the Medical College, Qingdao University, Ningxia Road, Qingdao, China

关键词: Mitochondria;    Nonalcoholic Fatty Liver Disease (NAFLD);    Carnitine;    Type 2 Diabetes Mellitus;   

Others  :  817524
DOI  :  10.1186/1758-5996-3-31

 received in 2011-09-22, accepted in 2011-11-15,  发布年份 2011

【 摘 要 】

Background

There are an increasing number of patients suffering from fatty liver caused by type 2 diabetes. We intended to study the preventive and therapeutic effect of L-carnitine (LC) on nonalcoholic fatty liver disease (NAFLD) in streptozotocin (STZ)-induced type 2 diabetic mice and to explore its possible mechanism.

Methods

Thirty male Kungming mice were randomly divided into five groups: control group, diabetic group, pre-treatment group (125 mg/kg BW), low-dose (125 mg/kg BW) therapeutic group and high-dose (250 mg/kg BW) therapeutic group. The morphology of hepatocytes was observed by light and electron microscopy. LC and ALC (acetyl L-carnitine) concentrations in the liver were determined by high-performance liquid chromatography (HPLC). Moreover, liver weight, insulin levels and free fatty acid (FFA) and triglyceride (TG) levels in the liver and plasma were measured.

Results

Average liver LC and ALC levels were 33.7% and 20% lower, respectively, in diabetic mice compared to control mice (P < 0.05). After preventive and therapeutic treatment with LC, less hepatocyte steatosis, clearer crista and fewer glycogen granules in the mitochondria were observed. Decreased liver weight, TG levels, and FFA concentrations (P < 0.05) in the liver were also observed after treatment with LC in diabetic mice. Moreover, liver LC and ALC levels increased upon treatment with LC, whereas the ratio of LC and ALC decreased significantly (P < 0.01).

Conclusion

LC supplements ameliorated fatty liver in type 2 diabetic mice by increasing fatty acid oxidation and decreasing the LC/ALC ratio in the liver. Therefore, oral administration of LC protected mitochondrial function in liver.

【 授权许可】

   
2011 Xia et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N: Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001, 50:1844-1850.
• [2]Bloomgarden ZT: Second World Congress on the Insulin Resistance Syndrome: insulin resistance syndrome and nonalcoholic fatty liver disease. Diabetes Care 2005, 28:1518-1523.
• [3]Reaven GM: Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988, 37:1595-1607.
• [4]Sheth SG, Gordon FD, Chopra S: Nonalcoholic steatohepatitis. Ann Intern Med 1997, 126:137-145.
• [5]Lupi R, Dotta F, Marselli L, Del GS, Masini M, Santangelo C, Patane G, Boggi U, Piro S, Anello M, et al.: Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 2002, 51:1437-1442.
• [6]Bak M, Kicinska-Krogulska M, Czerniak P, Michowicz A, Krakowiak A: [Toxic liver injuries--a current view on pathogenesis. Part II]. Med Pr 2011, 62:203-210.
• [7]Wang S, Kamat A, Pergola P, Swamy A, Tio F, Cusi K: Metabolic factors in the development of hepatic steatosis and altered mitochondrial gene expression in vivo. Metabolism 2011.
• [8]Mingrone G: Carnitine in type 2 diabetes. Ann N Y Acad Sci 2004, 1033:99-107.
• [9]Cave MC, Hurt RT, Frazier TH, Matheson PJ, Garrison RN, McClain CJ, McClave SA: Obesity, inflammation, and the potential application of pharmaconutrition. Nutr Clin Pract 2008, 23:16-34.
• [10]Broquist HP, Borum PR: Carnitine biosynthesis: nutritional implications. Adv Nutr Res 1982, 4:181-204.
• [11]Kerner J, Bieber L: Isolation of a malonyl-CoA-sensitive CPT/beta-oxidation enzyme complex from heart mitochondria. Biochemistry 1990, 29:4326-4334.
• [12]Pearson DJ, Tubbs PK: Carnitine and derivatives in rat tissues. Biochem J 1967, 105:953-963.
• [13]Calabrese V, Cornelius C, Dinkova-Kostova AT, Calabrese EJ, Mattson MP: Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid Redox Signal 2010, 13:1763-1811.
• [14]Rebouche CJ, Seim H: Carnitine metabolism and its regulation in microorganisms and mammals. Annu Rev Nutr 1998, 18:39-61.
• [15]Broderick TL, Quinney HA, Lopaschuk GD: Carnitine stimulation of glucose oxidation in the fatty acid perfused isolated working rat heart. J Biol Chem 1992, 267:3758-3763.
• [16]Gramignano G, Lusso MR, Madeddu C, Massa E, Serpe R, Deiana L, Lamonica G, Dessi M, Spiga C, Astara G, et al.: Efficacy of l-carnitine administration on fatigue, nutritional status, oxidative stress, and related quality of life in 12 advanced cancer patients undergoing anticancer therapy. Nutrition 2006, 22:136-145.
• [17]Mingrone G, Greco AV, Capristo E, Benedetti G, Giancaterini A, De GA, Gasbarrini G: L-carnitine improves glucose disposal in type 2 diabetic patients. J Am Coll Nutr 1999, 18:77-82.
• [18]Beck-Nielsen H: Insulin resistance in skeletal muscles of patients with diabetes mellitus. Diabetes Metab Rev 1989, 5:487-493.
• [19]Lysiak W, Lilly K, DiLisa F, Toth PP, Bieber LL: Quantitation of the effect of L-carnitine on the levels of acid-soluble short-chain acyl-CoA and CoASH in rat heart and liver mitochondria. J Biol Chem 1988, 263:1151-1156.
• [20]Rossignol DA, Frye RE: Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry 2011.
• [21]Hao J, Shen W, Sun L, Long J, Sharman E, Shi X, Liu J: Mitochondrial dysfunction in the liver of type 2 diabetic Goto-Kakizaki rats: improvement by a combination of nutrients. Br J Nutr 2011, 1-8.
• [22]Karanth J, Jeevaratnam K: Effect of carnitine supplementation on mitochondrial enzymes in liver and skeletal muscle of rat after dietary lipid manipulation and physical activity. Indian J Exp Biol 2010, 48:503-510.
• [23]Bowyer BA, Miles JM, Haymond MW, Fleming CR: L-carnitine therapy in home parenteral nutrition patients with abnormal liver tests and low plasma carnitine concentrations. Gastroenterology 1988, 94:434-438.
• [24]Romano M, Vacante M, Cristaldi E, Colonna V, Gargante MP, Cammalleri L, Malaguarnera M: L-carnitine treatment reduces steatosis in patients with chronic hepatitis C treated with alpha-interferon and ribavirin. Dig Dis Sci 2008, 53:1114-1121.
• [25]Malaguarnera M, Gargante MP, Russo C, Antic T, Vacante M, Malaguarnera M, Avitabile T, Li VG, Galvano F: L-carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis--a randomized and controlled clinical trial. Am J Gastroenterol 2010, 105:1338-1345.
• [26]Tisi A, Federico R, Moreno S, Lucretti S, Moschou PN, Roubelakis-Angelakis KA, Angelini R, Cona A: Perturbation of polyamine catabolism can strongly affect root development and xylem differentiation. Plant Physiol 2011, 157:200-215.
• [27]Cao Y, Wang YX, Liu CJ, Wang LX, Han ZW, Wang CB: Comparison of pharmacokinetics of L-carnitine, acetyl-L-carnitine and propionyl-L-carnitine after single oral administration of L-carnitine in healthy volunteers. Clin Invest Med 2009, 32:E13-E19.
• [28]Brunt EM, Tiniakos DG: Histopathology of nonalcoholic fatty liver disease. World J Gastroenterol 2010, 16:5286-5296.
• [29]Luo J, Quan J, Tsai J, Hobensack CK, Sullivan C, Hector R, Reaven GM: Nongenetic mouse models of non-insulin-dependent diabetes mellitus. Metabolism 1998, 47:663-668.
• [30]James O, Day C: Non-alcoholic steatohepatitis: another disease of affluence. Lancet 1999, 353:1634-1636.
• [31]Kiens B, Essen-Gustavsson B, Gad P, Lithell H: Lipoprotein lipase activity and intramuscular triglyceride stores after long-term high-fat and high-carbohydrate diets in physically trained men. Clin Physiol 1987, 7:1-9.
• [32]RANDLE PJ, GARLAND PB, HALES CN, NEWSHOLME EA: The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963, 1:785-789.
• [33]Bloomgarden ZT: Second World Congress on the Insulin Resistance Syndrome: insulin resistance syndrome and nonalcoholic fatty liver disease. Diabetes Care 2005, 28:1518-1523.
• [34]Purohit V, Rapaka R, Shurtleff D: Role of cannabinoids in the development of fatty liver (steatosis). AAPS J 2010, 12:233-237.
• [35]Lupi R, Dotta F, Marselli L, Del GS, Masini M, Santangelo C, Patane G, Boggi U, Piro S, Anello M, et al.: Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 2002, 51:1437-1442.
• [36]Ahmad S: L-carnitine in dialysis patients. Semin Dial 2001, 14:209-217.
• [37]Srinivas SR, Prasad PD, Umapathy NS, Ganapathy V, Shekhawat PS: Transport of butyryl-L-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB(0,+). Am J Physiol Gastrointest Liver Physiol 2007, 293:G1046-G1053.
• [38]Cha YS: Effects of L-carnitine on obesity, diabetes, and as an ergogenic aid. Asia Pac J Clin Nutr 2008, 17(Suppl 1):306-308.
• [39]McGarry JD, Robles-Valdes C, Foster DW: Role of carnitine in hepatic ketogenesis. Proc Natl Acad Sci USA 1975, 72:4385-4388.
• [40]Coleman RA, Lee DP: Enzymes of triacylglycerol synthesis and their regulation. Prog Lipid Res 2004, 43:134-176.
• [41]Pons R, De Vivo DC: Primary and secondary carnitine deficiency syndromes. J Child Neurol 1995, 10(Suppl 2):S8-24.
• [42]Scholte HR, Rodrigues PR, de Jonge PC, Luyt-Houwen IE, Hedwig M, Verduin M, Ross JD: Primary carnitine deficiency. J Clin Chem Clin Biochem 1990, 28:351-357.
• [43]Ames BN: Delaying the mitochondrial decay of aging. Ann N Y Acad Sci 2004, 1019:406-411.