Tevfik YAVUZ, Arif ARSLANER, Mevlüt PEHLİVAN, Abdurrahman COŞKUN, Ahmet ZENGİN

Does L-carnitine increase serum TNF -α and IGF-1 during liver regeneration in the rat?

Amaç: Rat deneysel parsiyel hepatektomi modelinde L-karnitin uygulamasının 72. saate kadar IGF- 1, TNF α ve lipid peroksidasyonuna etkisini araştırmayı amaçladık.Yöntem ve gereç: Atmış rat kontrol, düşük (100 mg/kg) ve yüksek doz (200 mg/kg) L-karnitin olmak üzere 3 gruba ayrıldı. Her bir grup, parsiyel hepatektomiden sonra 24 ve 72. saat olmak üzere 2 alt gruba ayrıldı. Yedi gün intra-peritoneal L-karnitin uygulamasından sonra parsiyel (% 70) hepatektomi yapıldı. L-karnitin, parsiyel hepatektomiden sonra da ratlara verilmeye devam edildi. Tüm gruplarda cerrahi operasyondan önce, 24 ve 72 saat sonra serum IGF-1, TNF-α ve doku malondialdehid düzeyleri ölçüldü.Bulgular: Kontrol grubunda, serum TNF-α düzeyleri, rejenerasyon boyunca anlamlı derecede arttı. Düşük doz (100 mg/kg) L-karnitin, TNF-α düzeylerini azaltırken yüksek doz (200 mg/kg) artırdı. IGF-1 düzeyi, kontrol grubunda cerrahi operasyondan sonra ilk 24 saate azalırken daha sonra artmaya başladı. L-karnitin gruplarında IGF-1 düzeylerinde benzer değişimler gözlendi. Malondialdehid düzeyleri kontrol grubunda ilk 24 saatte artarken daha sonra azalmaya başladı. Benzer şekilde L-karnitin gruplarında malondialdehid düzeyleri ilk 24 saatte artarken daha sonra doza bağımlı olarak azaldı.Sonuç: Karaciğer rejenerasyonunda sitokinler, büyüme faktörleri ve metabolik yollar olmak üzere üç temel unsur bulunmaktadır. Enerji metabolizmasındaki etkilerine ilaveten, yüksek doz L-karnitinin, IGF-1, TNF-α düzeyini artırarak ve malondialdehid düzeyini de azaltarak karaciğer rejenerasyonunu hızlandırabileceğini düşünmekteyiz.

L-karnitin, karaciğer rejenerasyonu sırasında serum TNF-α ve IGF-1 düzeylerini artırıyor mu?

Aim: We sought to evaluate the effect of L-carnitine administration on the levels of IGF-1, TNF-α, and lipid peroxidation during hepatic regeneration for up to 72 h in an experimental partial hepatic resection rat model. Materials and methods: Sixty rats were divided into 3 groups: control and low-dose (100 mg/kg) and high-dose (200 mg/kg) L-carnitine. Each group was divided into 2 sub groups (24 and 72 h after partial hepatectomy). Partial (70%) hepatectomy was performed after 7 days of intra-peritoneal administration of L-carnitine. After partial hepatectomy, L-carnitine was also administered to rats until sacrifice. Serum IGF-1, TNF-α, and tissue malondialdehyde levels were determined in all groups before and at 24 and 72 h after surgery. Results: Serum TNF-α increased significantly in the control group during the regeneration period. The low dose of L-carnitine (100 mg/kg) decreased the elevation of TNF-α whereas the high dose (200 mg/kg) increased it. In the control group, the IGF-1 level decreased in the first 24 h after surgery and then increased. The IGF-1 level behaved similarly in the L-carnitine groups. The malondialdehyde level in the control group increased during the first 24 h and then decreased. Similarly in the L carnitine groups, the malondialdehyde level increased during the first 24 h and then decreased significantly in a dose-dependent manner. Conclusion: Three types of biochemical pathways are essential in liver regeneration: cytokine, growth factor, and metabolic pathways. We conclude that, in addition to its effects on energy metabolism, high-dose L-carnitine may promote liver regeneration by increasing IGF-1, TNF-α, and decreasing malondialdehyde.

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1. Rigotti P, Peters JC, Tranberg KG, Fischer JE. Efects of amino acid infusions on liver regeneration ater partial hepatectomy in the rat. J Parent Ent Nutr 1986;10:17-20.
2. Ellis LM, Bryant MS, Copeland EM 3rd, Bland KI, Baumgartner TG, Kao KJ et al. Postoperative enteral versus total parenteral nutrition immediately ater partial hepatectomy: efects on hepatic regeneration and function. Curr Surg 1987;44:470-472.
3. Lai HS, Chen WJ, Chen KM. Energy substrate for liver regeneration ater partial hepatectomy in rats: efects of glucose vs fat. J Parent Ent Nutr 1992;16:152-156.
4. Blaha V, Simek J, Zivny P, Sobotka L, Zadak Z. Efect of parenteral administration of carnitine on liver regeneration in partially hepatectomized rats. Physiol Bohemoslov 1990;39:233-242.
5. Lai HS, Chen Y, Chen WJ. Carnitine contents in remnant liver, kidney, and skeletal muscle ater partial hepatectomy in rats: randomized trial. World J Surg 1998;22:42–47.
6. Bremer J. Carnitine--metabolism and functions. Physiol Rev 1983;63:1420-1480.
7. Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology 2006;43:S45-S53.
8. Higgins GM, Anderson RM. Experimental pathology of the liver. Restoration oh the liver of the white rat following surgical removal. Arch Pathol 1931;12:186-206.
9. Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 1978;86:271–278.
10. Spector AA, Yorek MA. Membrane lipid composition and cellular function. J Lipid Res 1985;26:1015-1035.
11. Arduini A, Holme S, Sweeney JD, Dottori S, Sciarroni AF, Calvani M. Addition of L-carnitine to additive solution- suspended red cells stored at 4oC reduces in vitro hemolysis and improves in vivo viability. Transfusion 1997;37:166-174.
12. Veldee MS. Nutritional assessment, therapy, and monitoring. In: Burtis CA, Ashwood ER. Tietz textbook of clinical chemistry, 3rd edn. Philadelphia: W.B. Saunders Company, 1999:1359-94.
13. Akerman P, Cote P, Yang SQ, McClain C, Nelson S, Bagby GJ et al. Antibodies to tumor necrosis factor-alpha inhibit liver regeneration ater partial hepatectomy. Am J Physiol 1992;263:G579–585.
14. Trautwein C, Rakemann T, Niehof M, Rose-John S, Manns MP. Acute phase response factor, increased binding, and target gene transcription during liver regeneration. Gastroenterology 1996;110:1854-1862.
15. Iwai M, Cui TX, Kitamura H, Saito M, Shimazu T. Increased secretion of tumour necrosis factor and interleukin 6 from isolated, perfused liver of rats ater partial hepatectomy. Cytokine 2001;13: 60-64.
16. Kim TH, Mars WM, Stolz DB, Michalopoulos GK. Expression and activation of pro-MMP-2 and pro-MMP-9 during rat liver regeneration. Hepatology 2000;31:75-82.
17. Argast GM, Campbell JS, Brooling JT, Fausto N. Epidermal growth factor receptor transactivation mediates tumor necrosis factor-induced hepatocyte replication. J Biol Chem 2004;279:34530-34536.
18. Matsumoto K, Nakamura T. Hepatocyte growth factor: molecular structure, roles in liver regeneration, and other biological functions. Crit Rev Oncogene 1992;3:27-54.
19. Michalopoulos GK, Khan Z. Liver regeneration, growth factors, and amphiregulin. Gastroenterology 2005;128:503-506.
20. Borowiak M, Garratt AN, Wustefeld T, Strehle M, Trautwein C, Birchmeier C. Met provides essential signals for liver regeneration. Proc Natl Acad Sci USA 2004;101:10608-10613.
21. Huh CG, Factor VM, Sanchez A, Uchida K, Conner EA, horgeirsson SS. Hepatocyte growth factor/c-met signaling pathway is required for eicient liver regeneration and repair. Proc Natl Acad Sci USA 2004;101:4477-4482.
22. Fausto N, Laird AD, Webber EM. Liver regeneration. II. Role of growth factors and cytokines in hepatic regeneration. FASEB J 1995;9:1527–1536.
23. Yamada Y, Kirillova I, Peschon JJ, Fausto N. Initiation of liver growth by tumor necrosis factor: deicient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc Natl Acad Sci USA 1997;94:1441–1446.
24. McElduf A, Poronnik P, Baxter RC, Williams P. A comparison of the insulin and insulin-like growth factor I receptors from rat brain and liver. Endocrinology 1988;122:1933–1939.
25. Zindy F, Lamas E, Schmidt S, Kirn A, Brechot C. Expression of insulinlike growth factor II (IGF-II) and IGF-II, IGF-I and insulin receptors mRNAs in isolated non-parenchymal rat liver cells. J Hepatol 1992;14:30–34.
26. Pennisi PA, Kopchick JJ, horgeirsson S, LeRoith D, Yakar S. Role of growth hormone (GH) in liver regeneration. Endocrinology 2004;145:4748-4755
27. Derin N, Izgut-Uysal VN, Agac A, Aliciguzel Y, demir N. L- Carnitine protects gastric mucosa by decreasing ischemiareperfusion induced lipid peroxidation. J Physiol Pharmacol 2004;55:595-606.
28. Reznick AZ, Kagan VE, Ramsey R, Tsuchiya M, Khwaja S, Serbinova EA, Packer L. Antiradical efects in L-propionyl carnitine protection of the heart against ischemia-reperfusion injury: the possible role of iron chelation. Arch Biochem Biophys 1992;296:394-401.