Effect of pioglitazone, quercetin and hydroxy citric acid on extracellular matrix components in experimentally induced non-alcoholic steatohepatitis


1 Department of Biochemistry, Saveetha Medical College and Hospital, Faculty of Medicine, Saveetha University, Saveetha Nagar, Thandalam, Chennai – 602 105, Tamilnadu, India

2 Department of Biochemistry, Saveetha Dental College and Hospital, Saveetha University, 162, P.H.Road, Chennai – 600 077, Tamilnadu, India

3 Department of Biomedical Engineering, SSN Engineering College, OMR, Klavakkam, Chennai – 603 110, Tamilnadu, India


Objective(s):Non-alcoholic steatohepatitis (NASH), is an important component of Non-alcoholic fatty liver disease (NAFLD) spectrum, which progresses to the end stage liver disease, if not diagnosed and treated properly. The disproportionate production of pro- and anti-inflammatory adipokines secreted from fat contributes to the pathogenesis of NASH. In this study, the comparative effect of pioglitazone, quercetin and hydroxy citric acid on extracellular matrix (ECM) component levels were studied in experimentally induced NASH.
Materials and Methods: The experimental protocol consists of using 48 male Wister rats, which were divided into 8 groups. The levels of hyaluronic acid, leptin and adiponectin were monitored in experimental NASH.
Results:The experimental NASH rats treated with pioglitazone showed significant decrease in the levels of hyaluronic acid and significant increase in adiponectin levels when compared to experimentally induced NASH group, but did not show any effect on the levels of leptin. Contrary to these two drugs, viz. pioglitazone and hydroxy citric acid, the group treated with quercetin showedsignificant decrease in the levels of hyaluronic acid and leptin and significant decrease in adiponectin levels compared with that of experimentally induced NASH NASH group, offering maximum protection against NASH. Conclusion: Considering our findings, it could be concluded that quercetin may offer maximum protection against NASH by significantly increasing the levels of adiponectin, when compared to pioglitazone and hydroxy citric acid.


1. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980; 55:434–438.
2. Ahmed MH, Byrne CD. Non-alcoholic steatohepatitis. In Byrne CD, D Wild S, editors. Metabolic syndrome. Chichester: John Wiley & Sons; 2005. p. 279-305.
3. Liou I, Kowdley KV. Natural history of nonalcoholic-steatohepatitis. J Clin Gastroenterol 2006; 40: S11–16.
4. Charlton M. Nonalcoholic fatty liver disease: a review of current understanding and future impact. Clin Gastroenterol Hepatol 2004; 2:1048–1058.
5. Wei Y, Clark SE, Thyfault JP, Uptergrove GM, Li W, Whaley-Connell AT, et al.  Oxidative stress-mediated mitochondrial dysfunction contributes to angiotensin II-induced nonalcoholic fatty liver disease in transgenic Ren2 rats. Am J Pathol 2009; 174:1329–1337.
6. Tilg H, Diehl AM. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med 2000; 343:1467–1476.
7. Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, et al. Leptin regulates proinflammatory immune responses. FASEB J 1998; 12:57–65.
8. Bouloumie A, Marumo T, Lafontan M, Busse R. Leptin induces oxidative stress in human endothelial cells. FASEB J 1999; 13:1231–1238.
9. Chitturi S, Farrell G, Frost L, Kriketos A, Lin R, Fung C, et al. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology 2002; 36:403–409.
10. Tilg H, Hotamisligil GS. Nonalcoholic fatty liver disease: Cytokine- adipokine interplay and regulation of insulin resistance. Gastroenterology 2006; 131:934-945.
11. Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell 2001; 104:531-143.
12. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395:6763-6770.
13. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372:6425-6532.
14. Halaas JL, Friedman JM. Leptin and its receptor. J Endocrinol 1997: 155:215-156.
15. Surapaneni KM, Jainu M. Pioglitazone, quercetin and hydroxy citric acid effect on hepatic biomarkers in Non Alcoholic Steatohepatitis. Pharmacogn Res 2014; 6:153-162.
16. Surapaneni KM, Jainu M. Effect of pioglitazone, quercetin, and hydroxy citric acid on the lipid profile and lipoproteins in experimentally induced non-alcoholicsteatohepatitis (NASH). Indian J Pharm Educ Res 2014; 48:32-38.
17. Surapaneni KM, Priya VV, Mallika J. Pioglitazone, quercetin and hydroxy citric acid effect on cytochrome P450 2E1 (CYP2E1) enzyme levels in experimentally induced non alcoholic steatohepatitis (NASH). Eur Rev Med Pharmacol Sci 2014; 18:2736-2741.
18. Surapaneni KM, Jainu M. Comparative effect of pioglitazone, quercetin and hydroxy citric acid on the status of lipid peroxidation and antioxidants in experimental non-alcoholic steatohepatitis. J Phyiol Pharmacol 2014; 65:67-74.
19. Surapaneni KM, Saraswathi P, Jainu M. Non alcoholic steatohepatitis (NASH) experimental model induction in rats. Int J Pharm Bio Sci 2012; 3:1085 – 1090.
20. Surapaneni KM, Sarswathi P, Jainu M. Role of pioglitazone, quercetin and hydroxy citric acid against non alcoholic steatohepatitis (NASH) - histological and scanning electron microscopy (SEM) studies in an experimental model of NASH. Asian J Pharm Clin Res 2012; 5:244-247.
21. Stryer L, Biochemistry. 3 rd ed. New York: W. H. Freedman and Company. 1988.p.275 - 277.
22. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995; 1:1151-1161.
23. Tsao TS, Murrey HE, Hug C, Lee DH, Lodish HF. Oligomerization state-dependent activation of NF-kappa B signaling pathway by adipocyte complement-related protein of 30 kDa (Acrp30). J Biol Chem 2002; 277:29359-29362.
24. Suzuki A, Angulo P, Lymp J, Li D, Satomura S, Lindor K. Hyaluronic acid, an accurate serum marker for severe hepatic fibrosis in patients with non-alcoholic fatty liver disease. Liver Int 2005; 25:779–786.
25. Oh MK, Winn J,Poordad F. Review article: diagnosis and treatment of non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2008; 28:503–522.
26. Miele L, Forgione A, La Torre G, Vero V, Cefalo C, Racco S, et al. Serum levels of HA and tissue metalloproteinase inhibitor-1 combined with age predict the presence of nonalcoholic steatohepatitis in a pilot cohort of subjects with nonalcoholic fatty liver disease. Transl Res 2009; 154:194-201.
27. Haukeland JW, Dam°as JK, Konopski Z, Løberg EM, Haaland T, Goverud I, et al. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCl2. J Hepatol 2006; 44:1167–1174.
28. Kamada Y, Takehara T, Hayashi N. Adipocytokines  and liver disease. J Gastroenterol 2008; 43:811-822.
29. Huang XD, Fan Y, Zhang H, Gifford-Moore D, Huang XD, Christie D, et al. Serum leptin and soluble leptin receptor in non-alcoholic fatty liver disease. World J Gastroenterol 2008; 14:2888- 2893.
30. Tsochatzis EA, Manolakopoulos S, Papatheodo-ridis GV, Archimandritis AJ. Insulin resistance and metabolic syndrome in chronic liver diseases: old entities with new implications. Scand J Gastroenterol 2009; 44:6–14.
31. Pellme F, Smith U, Funahashi T, Matsuzawa Y, Brekke H, Wiklund O, et al. Circulating adiponectin levels are reduced in nonobese but insulin-resistant first-degree relatives of type 2 diabetic patients. Diabetes 2003; 52:1182–1186.
32. Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein (Acrp30) increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A 2001; 98:2005–2010.
33. Berg AH, Combs TP, Scherer PE. ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab 2002; 13:84–89.
34. Yokota, T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N et al. Adiponectin new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 2000; 96: 1723-1732.
35. Gastaldelli A, Harrison S, Belfort-Aguiar R, Hardies J, Balas B,  Schenker S, et al. Pioglitazone in the treatment of NASH: the role of adiponectin. Aliment Pharmacol Ther 2010; 32:769-775.
36. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7:941–946.
37. Wellen KE, Uysal KT, Wiesbrock S, Yang Q, Chen H, Hotamisligil GS.  Interaction of tumor necrosis factor-alpha- and thiazolidinedione-regulated pathways. Endocrinology 2004; 145:2214–2220.
38. Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, et al. Disruption of adiponectin causes insulin resistance and neointimal formation. Biol Chem 2002; 277:25863–25866.
39. Xu A, Wang Y, Keshaw H, Xu LY, Lam KSL, Cooper GJS. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. Clin Invest 2003; 112:91–100.
40. Masaki T, Chiba S, Tatsukawa H, Yasuda T, Noguchi H, Seike M, et al. Adiponectin protects LPS- induced liver injury through modulation of TNF- alpha in KK-Ay obese mice. Hepatology 2004; 40:177-184.