Down Regulation of a Matrix Degrading Cysteine Protease Cathepsin L, by Acetaldehyde: Role of C/EBPα

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2011 Jun 21

PMID 21687683

Citations 4

Authors

Riyaz A Mir

Shyam S Chauhan

Affiliations

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Abstract

Background: The imbalance between extra cellular matrix (ECM) synthesis and degradation is critical aspect of various hepatic pathologies including alcohol induced liver fibrosis. This study was carried out to investigate the effect of acetaldehyde on expression of an extra cellular matrix degrading protease cathepsin L (CTSL) in HepG2 cells.

Methodology And Results: We measured the enzymatic activity, protein and, mRNA levels of CTSL in acetaldehyde treated and untreated cells. The binding of CAAT enhancer binding protein α (C/EBP α) to CTSL promoter and its key role in the transcription from this promoter and conferring responsiveness to acetaldehyde was established by site directed mutagenesis, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) assays and siRNA technology. Acetaldehyde treatment significantly decreased CTSL activity and protein levels in HepG2 cells. A similar decrease in the mRNA levels and promoter activity was also observed. This decrease by acetaldehyde was attributed to the fall in the liver enriched transcription factor C/EBP α levels and it's binding to the CTSL promoter. Mutagenesis of C/EBP α binding motifs revealed the key role of this factor in CTSL transcription as well as conferring responsiveness to acetaldehyde. The siRNA mediated silencing of the C/EBP α expression mimicked the effect of acetaldehyde on CTSL levels and its promoter activity. It also abolished the responsiveness of this promoter to acetaldehyde.

Conclusion: Acetaldehyde down regulates the C/EBP α mediated CTSL expression in hepatic cell lines. The decreased expression of CTSL may at least in part contribute to ECM deposition in liver which is a hallmark of alcoholic liver fibrosis.

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References

Rousselet N, Mills L, Jean D, Tellez C, Bar-Eli M, Frade R . Inhibition of tumorigenicity and metastasis of human melanoma cells by anti-cathepsin L single chain variable fragment. Cancer Res. 2004; 64(1):146-51. DOI: 10.1158/0008-5472.can-03-1717. View

Iredale J, Benyon R, Arthur M, Ferris W, Alcolado R, Winwood P . Tissue inhibitor of metalloproteinase-1 messenger RNA expression is enhanced relative to interstitial collagenase messenger RNA in experimental liver injury and fibrosis. Hepatology. 1996; 24(1):176-84. DOI: 10.1002/hep.510240129. View

Ishak K, ZIMMERMAN H, Ray M . Alcoholic liver disease: pathologic, pathogenetic and clinical aspects. Alcohol Clin Exp Res. 1991; 15(1):45-66. DOI: 10.1111/j.1530-0277.1991.tb00518.x. View

Niemela O, Parkkila S, Yla-Herttuala S, Villanueva J, RUEBNER B, Halsted C . Sequential acetaldehyde production, lipid peroxidation, and fibrogenesis in micropig model of alcohol-induced liver disease. Hepatology. 1995; 22(4 Pt 1):1208-14. View

Fibbi G, Pucci M, Grappone C, Pellegrini G, Salzano R, Casini A . Functions of the fibrinolytic system in human Ito cells and its control by basic fibroblast and platelet-derived growth factor. Hepatology. 1999; 29(3):868-78. DOI: 10.1002/hep.510290343. View

Keerthivasan S, Keerthivasan G, Mittal S, Chauhan S . Transcriptional upregulation of human cathepsin L by VEGF in glioblastoma cells. Gene. 2007; 399(2):129-36. DOI: 10.1016/j.gene.2007.05.002. View

Ishidoh K, Kominami E . Gene regulation and extracellular functions of procathepsin L. Biol Chem. 1998; 379(2):131-5. DOI: 10.1515/bchm.1998.379.2.131. View

Rojkind M . Role of metalloproteinases in liver fibrosis. Alcohol Clin Exp Res. 1999; 23(5):934-9. View

Fernandez M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J . Angiogenesis in liver disease. J Hepatol. 2009; 50(3):604-20. DOI: 10.1016/j.jhep.2008.12.011. View

10.

Shaw S, Jayatilleke E, Ross W, GORDON E, Leiber C . Ethanol-induced lipid peroxidation: potentiation by long-term alcohol feeding and attenuation by methionine. J Lab Clin Med. 1981; 98(3):417-24. View

11.

Arora S, Chauhan S . Identification and characterization of a novel human cathepsin L splice variant. Gene. 2002; 293(1-2):123-31. DOI: 10.1016/s0378-1119(02)00700-x. View

12.

Niemela O, Juvonen T, Parkkila S . Immunohistochemical demonstration of acetaldehyde-modified epitopes in human liver after alcohol consumption. J Clin Invest. 1991; 87(4):1367-74. PMC: 295176. DOI: 10.1172/JCI115141. View

13.

Ryvnyak V, Ryvnyak E, Tudos R . Electron histochemical localization of cathepsin L in the liver. Bull Exp Biol Med. 2004; 137(1):90-1. DOI: 10.1023/b:bebm.0000024396.17895.77. View

14.

Dehrmann F, Coetzer T, Pike R, Dennison C . Mature cathepsin L is substantially active in the ionic milieu of the extracellular medium. Arch Biochem Biophys. 1995; 324(1):93-8. DOI: 10.1006/abbi.1995.9924. View

15.

Lieber C . Alcohol and the liver: 1994 update. Gastroenterology. 1994; 106(4):1085-105. DOI: 10.1016/0016-5085(94)90772-2. View

16.

Arthur M . Collagenases and liver fibrosis. J Hepatol. 1995; 22(2 Suppl):43-8. View

17.

Mello T, Ceni E, Surrenti C, Galli A . Alcohol induced hepatic fibrosis: role of acetaldehyde. Mol Aspects Med. 2008; 29(1-2):17-21. DOI: 10.1016/j.mam.2007.10.001. View

18.

Rodriguez-Antona C, Bort R, Jover R, Tindberg N, Ingelman-Sundberg M, Gomez-Lechon M . Transcriptional regulation of human CYP3A4 basal expression by CCAAT enhancer-binding protein alpha and hepatocyte nuclear factor-3 gamma. Mol Pharmacol. 2003; 63(5):1180-9. DOI: 10.1124/mol.63.5.1180. View

19.

Carter E, Wands J . Ethanol-induced inhibition of liver cell function: I. Effect of ethanol on hormone stimulated hepatocyte DNA synthesis and the role of ethanol metabolism. Alcohol Clin Exp Res. 1988; 12(4):555-62. DOI: 10.1111/j.1530-0277.1988.tb00241.x. View

20.

Milani S, Herbst H, Schuppan D, Grappone C, Pellegrini G, Pinzani M . Differential expression of matrix-metalloproteinase-1 and -2 genes in normal and fibrotic human liver. Am J Pathol. 1994; 144(3):528-37. PMC: 1887080. View