Curcumin enhances liver SIRT3 expression in the rat model of cirrhosis

Document Type : Original Article

Authors

1 Department of Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran

2 Department of Physiology, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran

Abstract

Objective(s): Bill duct ligation (BDL) is a representative model of biliary cholestasis in animals. Curcumin has a protective effect on the liver; however, its underlying mechanisms are not completely known. This study explored the hepatoprotective activity of curcumin on hepatic damage via measuring the expression of sirtuin3 (SIRT3), AMP-activated protein kinase (AMPK), carnitine palmitoyltransferase 1A (CPT-1A), isocitrate dehydrogenase2 (IDH2) and manganese superoxide dismutase (MnSOD) as well as the level of serum lipid profile in the BDL fibrotic rat model.
Materials and Methods: The study consisted of four groups (n=8 for each of Wistar rats): sham group, sham+curcumin (sham+Cur) group (received curcumin 100 mg/kg/day), BDL+Cur group, and BDL group. Transcription levels of SIRT3, AMPK, CPT-1A, IDH2, MnSOD and protein expression level of SIRT3 were measured by real-time PCR and Western blotting, respectively.
Results: It was identified that SIRT3, AMPK, CPT-1A, IDH2 and MnSOD expression significantly decreased in BDL rats compared to sham rats; however, in the curcumin treatment of BDL rats, the expression of these factors increased significantly compared to BDL (P-value <0.05). It was, moreover, observed that treatment of BDL rats with curcumin reduced liver injury as verified by a reduction in the levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) and increase in high-density lipoprotein (HDL)(P-value <0.05).
Conclusion: Curcumin reduced liver damage and oxidative stress in the liver tissue of BDL rats through up-regulation of SIRT3, AMPK, CPT-1A, IDH2 and MnSOD as well as changing the level of serum lipid profile.

Keywords

References

1.Teixeira C, Franco E, Oliveira PA, Colaco B, Gama A, Carrola J, et al. Effects of nebivolol on liver fibrosis induced by bile duct ligation in Wistar rats. In Vivo 2013; 27:635-640.
2.Ji H, Jiang JY, Xu Z, Kroeger EA, Lee SS, Liu H, et al. Change in lipid profile and impairment of endothelium-dependent relaxation of blood vessels in rats after bile duct ligation. Life Sci 2003; 73:1253-1263.
3.Longo M, Crosignani A, Podda M. Hyperlipidemia in chronic cholestatic liver disease. Curr Treat Options Gastroenterol 2001; 4:111-114.
4.George J. Ascorbic acid concentrations in dimethylnitrosamine-induced hepatic fibrosis in rats. Clin Chim Acta 2003; 335:39-47.
5.Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115:209-218.
6.Halliwell B. Oxidative stress and cancer: have we moved forward? Biochem J 2007; 401:1-11.
7.Aoyama T, Paik YH, Watanabe S, Laleu B, Gaggini F, Fioraso‐Cartier L, et al. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology 2012; 56:2316-2327.
8.Poli G. Pathogenesis of liver fibrosis: role of oxidative stress. Mol Aspects Med 2000; 21:49-98.
9.Natarajan SK, Thomas S, Ramamoorthy P, Basivireddy J, Pulimood AB, Ramachandran A, et al. Oxidative stress in the development of liver cirrhosis: a comparison of two different experimental models J Gastroenterol Hepatol 2006; 21:947-957.
10.Liu Q, Bengmark S, Qu S. The role of hepatic fat accumulation in pathogenesis of non-alcoholic fatty liver disease (NAFLD). Lipids Health Dis 2010; 9:1.
11.Kincaid B, Bossy-Wetzel E. Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration. Front Aging Neurosci 2013; 5:48.
12.Palacios OM, Carmona JJ, Michan S, Chen KY, Manabe Y, Ward Jr, et al. Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle. Aging (Albany NY) 2009; 1:771-783.
13.Klishadi MS, Zarei F, Hejazian SH, Moradi A, Hemati M, Safari F. Losartan protects the heart against ischemia reperfusion injury: sirtuin3 involvement. J Pharm Pharm Sci 2015; 18:112-123.
14.Giralt A, Villarroya F. SIRT3, a pivotal actor in mitochondrial functions: metabolism, cell death and aging. Biochem J 2012; 444:1-10.
15.Shi T, Fan GQ, Xiao SD. SIRT3 reduces lipid accumulation via AMPK activation in human hepatic cells. J Dig Dis  2010; 11:55-62.
16.You M, Jogasuria A, Taylor C, Wu J. Sirtuin 1 signaling and alcoholic fatty liver disease. Hepatobiliary Surg Nutr 2014; 4:88-100.
17.Ghoreshi ZA, Kabirifar R, Safari F, Karimollah A, Moradi A, Eskandari-Nasab E. Hepatoprotective effects of curcumin in rats after bile duct ligation via downregulation of Rac1 and NOX1. Nutrition 2017; 36:72-78.
18.Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab 2010; 12:662-667.
19.Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A, Gupta MP. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest 2009; 119:2758-2771.
20.Choudhury M, Jonscher KR, Friedman JE. Reduced mitochondrial function in obesity-associated fatty liver: SIRT3 takes on the fat. Aging (Albany NY) 2011; 3:175-178.
21.Gupta A, Rath PC. Curcumin, a natural antioxidant, acts as a noncompetitive inhibitor of human RNase L in presence of its cofactor 2-5A in vitro. BioMed Res Int 2014; 2014.
22.Wang M-E, Chen Y-C, Chen I-S, Hsieh S-C, Chen S-S, Chiu C-H. Curcumin protects against thioacetamide-induced hepatic fibrosis by attenuating the inflammatory response and inducing apoptosis of damaged hepatocytes. J Nutr Biochem 2012; 23:1352-1366.
23.Zheng J, Wu C, Lin Z, Guo Y, Shi L, Dong P, et al. Curcumin up‐regulates phosphatase and tensin homologue deleted on chromosome 10 through microRNA‐mediated control of DNA methylation–a novel mechanism suppressing liver fibrosis. FEBS J 2014; 281:88-103.
24.Park EJ, Jeon CH, Ko G, Kim J, Sohn DH. Protective effect of curcumin in rat liver injury induced by carbon tetrachloride. J Pharm Pharmacol 2000; 52:437-440.
25.Reyes-Gordillo K, Segovia J, Shibayama M, Tsutsumi V, Vergara P, Moreno MG, et al. Curcumin prevents and reverses cirrhosis induced by bile duct obstruction or CCl4 in rats: role of TGF-beta modulation and oxidative stress. Fundam Clin Pharmacol 2008; 22:417-427.
26.Onyango P, Celic I, McCaffery JM, Boeke JD, Feinberg AP. SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. Proc Natl Acad Sci  2002; 99:13653-13658.
27.Schwer B, North BJ, Frye RA, Ott M, Verdin E. The human silent information regulator (Sir) 2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide–dependent deacetylase. J Cell Biol 2002; 158:647-657.
28.Grabowska W, Suszek M, Wnuk M, Lewinska A, Wasiak E, Sikora E, et al. Curcumin elevates sirtuin level but does not postpone in vitro senescence of human cells building the vasculature. Oncotarget 2016.
29.Chen Y, Qing W, Sun M, Lv L, Guo D, Jiang Y. Melatonin protects hepatocytes against bile acid-induced mitochondrial oxidative stress via the AMPK-SIRT3-SOD2 pathway. Free Radic Res  2015; 49:1275-1284.
30.Um MY, Hwang KH, Ahn J, Ha TY. Curcumin Attenuates Diet‐Induced Hepatic Steatosis by Activating AMP‐Activated Protein Kinase. Basic Clin Pharmacol Toxicol 2013; 113:152-157.
31.Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, et al. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci 2002; 99:15983-15987.
32.Song S, Attia RR, Connaughton S, Niesen MI, Ness GC, Elam MB, et al. Peroxisome proliferator activated receptor α (PPARα) and PPAR gamma coactivator (PGC-1α) induce carnitine palmitoyltransferase IA (CPT-1A) via independent gene elements. Mol Cell Endocrinol 2010; 325:54-63.
33.Serviddio G, Bellanti F, Stanca E, Lunetti P, Blonda M, Tamborra R, et al. Silybin exerts antioxidant effects and induces mitochondrial biogenesis in liver of rat with secondary biliary cirrhosis. Free Radic Biol Med 2014; 73:117-126.
34.GHADA Z. Effect of curcumin, mixture of curcumin and piperine and curcum (turmeric) on lipid profile of normal and hyperlipidemic rats. EJHM 2005; 21:145-161.
35.Tseilikman V, Pankov N, Pankova N, Filimonova T, Sinitskii A, Kozochkin D, et al. Correlation between circulating corticosterone and protein carbonylation in the liver after short-term hypokinesia. Bull Exp Biol Med 2013; 156:188.
36.De Waal EM, Liang H, Pierce A, Hamilton RT, Buffenstein R, Chaudhuri AR. Elevated protein carbonylation and oxidative stress do not affect protein structure and function in the long-living naked-mole rat: a proteomic approach. Biochem Biophys Res Commun 2013; 434:815-819.
37.Serviddio G, Pereda J, Pallardó FV, Carretero J, Borras C, Cutrin J, et al. Ursodeoxycholic acid protects against secondary biliary cirrhosis in rats by preventing mitochondrial oxidative stress. Hepatology 2004; 39:711-720.
38.Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 2010; 143:802-812.
39.Zhong Z, Froh M, Wheeler MD, Smutney O, Lehmann TG, Thurman RG. Viral gene delivery of superoxide dismutase attenuates experimental cholestasis-induced liver fibrosis in the rat. Gene Ther 2002; 9:183-191.
40.Schiffman SC, Li Y, Martin RC. The association of manganese superoxide dismutase expression in barrett's esophageal progression with MnTBAP and curcumin oil therapy. J Surg Res 2012; 176:535-541.
Iranian Journal of Basic Medical Sciences
Volume 20, Issue 12
December 2017
Pages 1306-1311

Files

Share

How to cite

Statistics