Effect of malondialdehyde-acetaldehyde-protein adducts on the protein kinase C-dependent secretion of urokinase-type plasminogen activator in hepatic stellate cells

Kusum Kharbanda, Kris A. Shubert, Todd A Wyatt, Michael Floyd Sorrell, Dean J. Tuma

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Previous studies from our laboratory have shown that malondialdehyde-acetaldehyde-protein adducts (MAA adducts) are formed in hepatocytes of ethanol-fed rats and directly influence the hepatic stellate cells (HSCs) to induce their secretion of chemokines and to up-regulate their expression of adhesion molecules. Since protein kinase C (PKC) is known to play a major role in many diverse intracellular signal transduction processes, we investigated whether MAA adducts influence the function of HSCs via a PKC-dependent pathway. HSCs in culture were exposed to MAA adducts, and PKC activity was determined. We observed a time- and concentration-dependent activation of PKC when cultures were exposed to BSA-MAA as compared with unmodified BSA. Using PKC isoform-specific inhibitors, we also showed that BSA-MAA induces the activation of a specific isoform of PKC, PKC-α, in HSCs. No activation of PKC was observed when HSCs were exposed to other aldehyde adducts such as BSA-acetaldehyde or BSA-malondialdehyde, indicating that the effects of MAA adducts on HSCs were somewhat specific. We further examined whether the observed increase in PKC activation induced by MAA adducts in HSCs, in turn, causes a functional effect. We observed that BSA-MAA induces the increased secretion of urokinase-type plasminogen activator, a key component of the plasmin-generating system, and that PKC activation is necessary for this enhanced urokinase-type plasminogen activator secretion. These results indicate that MAA adducts via a PKC-mediated pathway may regulate plasmin-mediated matrix degradation in the liver, thereby contributing to the progression of hepatic fibrosis.

Original languageEnglish (US)
Pages (from-to)553-562
Number of pages10
JournalBiochemical Pharmacology
Volume63
Issue number3
DOIs
StatePublished - Feb 1 2002

Fingerprint

Hepatic Stellate Cells
Acetaldehyde
Urokinase-Type Plasminogen Activator
Malondialdehyde
Protein Kinase C
Proteins
Chemical activation
Fibrinolysin
Protein Isoforms
Signal transduction
Liver
Chemokines
Aldehydes
Hepatocytes
Signal Transduction
Fibrosis
Ethanol
Up-Regulation
Rats
Cell Culture Techniques

Keywords

  • Alcoholic liver disease
  • Hepatic stellate cells
  • MAA aducts
  • PKC
  • Urokinase-type plasminogen activator

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

@article{cc17b6b106f746abba81730a99bbcafe,
title = "Effect of malondialdehyde-acetaldehyde-protein adducts on the protein kinase C-dependent secretion of urokinase-type plasminogen activator in hepatic stellate cells",
abstract = "Previous studies from our laboratory have shown that malondialdehyde-acetaldehyde-protein adducts (MAA adducts) are formed in hepatocytes of ethanol-fed rats and directly influence the hepatic stellate cells (HSCs) to induce their secretion of chemokines and to up-regulate their expression of adhesion molecules. Since protein kinase C (PKC) is known to play a major role in many diverse intracellular signal transduction processes, we investigated whether MAA adducts influence the function of HSCs via a PKC-dependent pathway. HSCs in culture were exposed to MAA adducts, and PKC activity was determined. We observed a time- and concentration-dependent activation of PKC when cultures were exposed to BSA-MAA as compared with unmodified BSA. Using PKC isoform-specific inhibitors, we also showed that BSA-MAA induces the activation of a specific isoform of PKC, PKC-α, in HSCs. No activation of PKC was observed when HSCs were exposed to other aldehyde adducts such as BSA-acetaldehyde or BSA-malondialdehyde, indicating that the effects of MAA adducts on HSCs were somewhat specific. We further examined whether the observed increase in PKC activation induced by MAA adducts in HSCs, in turn, causes a functional effect. We observed that BSA-MAA induces the increased secretion of urokinase-type plasminogen activator, a key component of the plasmin-generating system, and that PKC activation is necessary for this enhanced urokinase-type plasminogen activator secretion. These results indicate that MAA adducts via a PKC-mediated pathway may regulate plasmin-mediated matrix degradation in the liver, thereby contributing to the progression of hepatic fibrosis.",
keywords = "Alcoholic liver disease, Hepatic stellate cells, MAA aducts, PKC, Urokinase-type plasminogen activator",
author = "Kusum Kharbanda and Shubert, {Kris A.} and Wyatt, {Todd A} and Sorrell, {Michael Floyd} and Tuma, {Dean J.}",
year = "2002",
month = "2",
day = "1",
doi = "10.1016/S0006-2952(01)00883-8",
language = "English (US)",
volume = "63",
pages = "553--562",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - Effect of malondialdehyde-acetaldehyde-protein adducts on the protein kinase C-dependent secretion of urokinase-type plasminogen activator in hepatic stellate cells

AU - Kharbanda, Kusum

AU - Shubert, Kris A.

AU - Wyatt, Todd A

AU - Sorrell, Michael Floyd

AU - Tuma, Dean J.

PY - 2002/2/1

Y1 - 2002/2/1

N2 - Previous studies from our laboratory have shown that malondialdehyde-acetaldehyde-protein adducts (MAA adducts) are formed in hepatocytes of ethanol-fed rats and directly influence the hepatic stellate cells (HSCs) to induce their secretion of chemokines and to up-regulate their expression of adhesion molecules. Since protein kinase C (PKC) is known to play a major role in many diverse intracellular signal transduction processes, we investigated whether MAA adducts influence the function of HSCs via a PKC-dependent pathway. HSCs in culture were exposed to MAA adducts, and PKC activity was determined. We observed a time- and concentration-dependent activation of PKC when cultures were exposed to BSA-MAA as compared with unmodified BSA. Using PKC isoform-specific inhibitors, we also showed that BSA-MAA induces the activation of a specific isoform of PKC, PKC-α, in HSCs. No activation of PKC was observed when HSCs were exposed to other aldehyde adducts such as BSA-acetaldehyde or BSA-malondialdehyde, indicating that the effects of MAA adducts on HSCs were somewhat specific. We further examined whether the observed increase in PKC activation induced by MAA adducts in HSCs, in turn, causes a functional effect. We observed that BSA-MAA induces the increased secretion of urokinase-type plasminogen activator, a key component of the plasmin-generating system, and that PKC activation is necessary for this enhanced urokinase-type plasminogen activator secretion. These results indicate that MAA adducts via a PKC-mediated pathway may regulate plasmin-mediated matrix degradation in the liver, thereby contributing to the progression of hepatic fibrosis.

AB - Previous studies from our laboratory have shown that malondialdehyde-acetaldehyde-protein adducts (MAA adducts) are formed in hepatocytes of ethanol-fed rats and directly influence the hepatic stellate cells (HSCs) to induce their secretion of chemokines and to up-regulate their expression of adhesion molecules. Since protein kinase C (PKC) is known to play a major role in many diverse intracellular signal transduction processes, we investigated whether MAA adducts influence the function of HSCs via a PKC-dependent pathway. HSCs in culture were exposed to MAA adducts, and PKC activity was determined. We observed a time- and concentration-dependent activation of PKC when cultures were exposed to BSA-MAA as compared with unmodified BSA. Using PKC isoform-specific inhibitors, we also showed that BSA-MAA induces the activation of a specific isoform of PKC, PKC-α, in HSCs. No activation of PKC was observed when HSCs were exposed to other aldehyde adducts such as BSA-acetaldehyde or BSA-malondialdehyde, indicating that the effects of MAA adducts on HSCs were somewhat specific. We further examined whether the observed increase in PKC activation induced by MAA adducts in HSCs, in turn, causes a functional effect. We observed that BSA-MAA induces the increased secretion of urokinase-type plasminogen activator, a key component of the plasmin-generating system, and that PKC activation is necessary for this enhanced urokinase-type plasminogen activator secretion. These results indicate that MAA adducts via a PKC-mediated pathway may regulate plasmin-mediated matrix degradation in the liver, thereby contributing to the progression of hepatic fibrosis.

KW - Alcoholic liver disease

KW - Hepatic stellate cells

KW - MAA aducts

KW - PKC

KW - Urokinase-type plasminogen activator

UR - http://www.scopus.com/inward/record.url?scp=0036471578&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036471578&partnerID=8YFLogxK

U2 - 10.1016/S0006-2952(01)00883-8

DO - 10.1016/S0006-2952(01)00883-8

M3 - Article

C2 - 11853706

AN - SCOPUS:0036471578

VL - 63

SP - 553

EP - 562

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 3

ER -