• RAHMANIAH RAHMANIAH Department of Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
  • MELVA LOUISA Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
  • BANTARI WK WARDHANI Department of Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
  • VIVIAN SOETIKNO Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.


Objectives: In various liver disease models, including those for alcoholic liver diseases, curcumin, a polyphenolic compound derived from
Curcuma longa, is known to have an hepatoprotective effect. However, the mechanism of action underlying its effects on alcohol-induced hepatic
fibrosis remains unknown. We aimed to investigate the mechanisms of action underlying the effects of curcumin, mainly involving the transforming
growth factor (TGF)-β/Smad pathway.
Methods: Hepatic stellate cells (HSCs), LX2, were incubated with 50 mM ethanol with or without curcumin (1 and 10 μM). Viable HSCs were counted
using a LUNATM automated cell counter, whereas the expressions of TGF-β, Smad3, tissue inhibitor of metalloproteinases-1 (TIMP-1), and type 1
collagen mRNA were measured using quantitative reverse transcriptase polymerase chain reactions.
Results: Curcumin significantly suppressed ethanol-induced HSCs proliferation. The antiproliferative effect of curcumin appeared to be dose
dependent. In addition, the mRNA expressions of TGF-β, Smad3, TIMP-1, and type 1 collagen decreased in the cells treated with curcumin.
Conclusion: Curcumin seems to attenuate ethanol-induced HSCs proliferation through the suppression of TGF-β and appears to reduce the production
of extracellular matrix as shown by the decreased expression of type 1 collagen.

Keywords: Curcumin, Transforming growth factor-β, Smad, Tissue inhibitor of metalloproteinases-1, Type 1 collagen


1. Ghosh Dastidar S, Warner JB, Warner DR, McClain CJ,
Kirpich IA. Rodent models of alcoholic liver disease: Role of binge
ethanol administration. Biomolecules 2018;8:E3.
2. Singal AK, Kamath PS, Gores GJ, Shah VH. Alcoholic hepatitis: Current
challenges and future directions. Clin Gastroenterol Hepatol 2014;
3. Gaitantzi H, Meyer C, Rakoczy P, Thomas M, Wahl K, Wandrer F, et al.
Ethanol sensitizes hepatocytes for TGF-?-triggered apoptosis. Cell
Death Dis 2018;9:51.
4. Liu H, Dong F, Li G, Niu M, Zhang C, Han Y, et al. Liuweiwuling tablets
attenuate BDL-induced hepatic fibrosis via modulation of TGF-?/Smad
and NF-?B signaling pathways. J Ethnopharmacol 2018;210:232-41.
5. Del Campo JA, Gallego P, Grande L. Role of inflammatory response in
liver diseases: Therapeutic strategies. World J Hepatol 2018;10:1-7.
6. Wang Y, Shen RW, Han B, Li Z, Xiong L, Zhang FY, et al. Notch
signaling mediated by TGF-?/Smad pathway in concanavalin
A-induced liver fibrosis in rats. World J Gastroenterol 2017;23:2330-6.
7. Fabregat I, Moreno-Càceres J, Sánchez A, Dooley S, Dewidar B,
Giannelli G, et al. TGF-? signalling and liver disease. FEBS J 2016;
8. Walton KL, Johnson KE, Harrison CA. Targeting TGF-? mediated
SMAD signaling for the prevention of fibrosis. Front Pharmacol 2017;
9. Leivonen SK, Lazaridis K, Decock J, Chantry A, Edwards DR,
Kähäri VM, et al. TGF-?-elicited induction of tissue inhibitor of
metalloproteinases (TIMP)-3 expression in fibroblasts involves
complex interplay between smad3, p38?, and ERK1/2. PLoS One 2013;
10. Zhu Y, Gu J, Zhu T, Jin C, Hu X, Wang X, et al. Crosstalk between
smad2/3 and specific isoforms of ERK in TGF-?1-induced TIMP-3
expression in rat chondrocytes. J Cell Mol Med 2017;21:1781-90.
11. Lin PS, Chang HH, Yeh CY, Chang MC, Chan CP, Kuo HY, et al.
Transforming growth factor beta 1 increases collagen content, and
stimulates procollagen I and tissue inhibitor of metalloproteinase-1
production of dental pulp cells: Role of MEK/ERK and activin receptorlike
kinase-5/smad signaling. J Formos Med Assoc 2017;116:351-8.
12. Hu RW, Carey EJ, Lindor KD, Tabibian JH. Curcumin in hepatobiliary
disease: Pharmacotherapeutic properties and emerging potential clinical
applications. Ann Hepatol 2017;16:835-41.
13. Lin J, Tang Y, Kang Q, Feng Y, Chen A. Curcumin inhibits gene
expression of receptor for advanced glycation end-products (RAGE)
in hepatic stellate cells in vitro by elevating PPAR? activity and
attenuating oxidative stress. Br J Pharmacol 2012;166:2212-27.
14. Bruck R, Ashkenazi M, Weiss S, Goldiner I, Shapiro H, Aeed H,
et al. Prevention of liver cirrhosis in rats by curcumin. Liver Int 2007;
15. Kabirifar R, Ghoreshi Z, Rezaifar A, Binesh F, Bamdad K,
Moradi A. Curcumin, quercetin and atorvastatin protected against the
hepatic fibrosis by activating AMP-activated protein kinase. J Funct
Foods 2018;40:341-8.
16. Guo C, Ma J, Zhong Q, Zhao M, Hu T, Chen T, et al. Curcumin
improves alcoholic fatty liver by inhibiting fatty acid biosynthesis.
Toxicol Appl Pharmacol 2017;328:1-9.
17. Ghorbani Z, Hajizadeh M, Hekmatdoost A. Dietary supplementation
in patients with alcoholic liver disease: A review on current evidence.
Hepatobiliary Pancreat Dis Int 2016;15:348-60.
18. Xu F, Liu C, Zhou D, Zhang L. TGF-?/SMAD pathway and its
regulation in hepatic fibrosis. J Histochem Cytochem 2016;64:157-67.
19. Reeves HL, Friedman SL. Activation of hepatic stellate cells-a key
issue in liver fibrosis. Front Biosci 2002;7:d808-26.
20. Dooley S, Delvoux B, Lahme B, Mangasser-Stephan K, Gressner AM.
Modulation of transforming growth factor beta response and signaling
during transdifferentiation of rat hepatic stellate cells to myofibroblasts.
Hepatology 2000;31:1094-106.
21. Dooley S, ten Dijke P. TGF-? in progression of liver disease. Cell
Tissue Res 2012;347:245-56.
22. Zheng J, Ma LT, Ren QY, Li L, Zhang Y, Shi HJ, et al. The influence
of astragalus polysaccharide and ?-elemene on LX-2 cell growth,
apoptosis and activation. BMC Gastroenterol 2014;14:224.
23. Odile S, Fatiha DA, Dominique LG. Up-to-date insight about membrane
remodeling as a mechanism of action for ethanol-induced liver toxicity.
In: Shimizu I, editor. Trends in Alcoholic Liver Disease Research-
Clinical and Scientific Aspects. Croatia: InTech; 2012. p. 159-78.
24. Gressner AM, Weiskirchen R. Modern pathogenetic concepts of liver
fibrosis suggest stellate cells and TGF-beta as major players and
therapeutic targets. J Cell Mol Med 2006;10:76-99.
25. Chen L, Charrier AL, Leask A, French SW, Brigstock DR. Ethanolstimulated
differentiated functions of human or mouse hepatic stellate
cells are mediated by connective tissue growth factor. J Hepatol 2011;
26. Liu M, Xu Y, Han X, Yin L, Xu L, Qi Y, et al. Dioscin alleviates
alcoholic liver fibrosis by attenuating hepatic stellate cell activation via
the TLR4/MyD88/NF-?B signaling pathway. Sci Rep 2015;5:18038.
27. Yao QY, Xu BL, Wang JY, Liu HC, Zhang SC, Tu CT, et al. Inhibition
by curcumin of multiple sites of the transforming growth factor-beta1
signalling pathway ameliorates the progression of liver fibrosis induced
by carbon tetrachloride in rats. BMC Complement Altern Med 2012;
28. Thompson KJ, McKillop IH, Schrum LW. Targeting collagen expression
in alcoholic liver disease. World J Gastroenterol 2011;17:2473-81.
29. Hackler L Jr., Ózsvári B, Gyuris M, Sipos P, Fábián G, Molnár E, et al.
The curcumin analog C-150, influencing NF-?B, UPR and akt/notch
pathways has potent anticancer activity in vitro and in vivo. PLoS One 2016;
30. Chung SS, Vadgama JV. Curcumin and epigallocatechin gallate inhibit
the cancer stem cell phenotype via down-regulation of STAT3-NF?B
signaling. Anticancer Res 2015;35:39-46.
31. Lubbad A, Oriowo MA, Khan I. Curcumin attenuates inflammation
through inhibition of TLR-4 receptor in experimental colitis. Mol Cell
Biochem 2009;322:127-
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