NDLI: Overview of lipid peroxidation products and hepatic protein modification in alcoholic liver disease.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Smathers, Rebecca L. Galligan, James J. Stewart, Benjamin J. Petersen, Dennis R.
Description	Country affiliation: United States Author Affiliation: Smathers RL ( Molecular Toxicology Program, Department of Pharmaceutical Sciences, University of Colorado Denver, USA.)
Abstract	OBJECTIVES: Oxidative stress is one component of alcoholic liver disease (ALD) that is manifested in the peroxidation of cellular lipids producing the electrophile, 4-hydroxynonenal (4-HNE). This electrophile is proposed to modify essential cellular proteins resulting in loss of protein function and cellular homeostasis. Studies were initiated to identify hepatic proteins that are targets of 4-HNE modification and determine their relationship with progression of the early stages of ALD. METHODS: Rat and mouse models were developed using the Lieber-DeCarli diet to simulate early stages of ALD consisting of fatty liver (steatosis) and hepatocellular injury indicated by a 1.5-2-fold elevation of plasma ALT activity. Liver samples obtained from control and ethanol treated animals were subjected to two-dimensional electrophoresis and immunoblotting using polyclonal antibodies generated against 4-HNE epitopes for detection of proteins modified by 4-HNE. Following identification of 4-HNE adducted proteins, the respective recombinant proteins modified with physiologic concentrations of 4-HNE were evaluated to determine the functional consequences of 4-HNE modification. RESULTS: One group of proteins identified included Hsp70, Hsp90 and protein disulfide isomerase (PDI), all of which are involved in protein folding or processing are targets of adduction. In vitro assays indicated significant impairment of the protein activities following modification with physiologically relevant concentrations of 4-HNE. Liver fatty acid binding protein, L-FABP, was also identified as a target and additional studies revealed that the levels of this protein were significantly decreased because of chronic ethanol ingestion. Erk1/2 was identified as a target for modification and subsequently determined to have impaired activity. CONCLUSIONS: Inhibition of Hsp70, Hsp90 and PDI function could be involved in initiation of the early phases of ER stress contributing to stimulation and accumulation of hepatic lipids. Likewise, impairment of L-FABP activity could also disrupt lipid transport also contributing to steatosis. The modification and inhibition of Erk1/2 by 4-HNE may also contribute to the decreased hepatocellular proliferation associated with ALD. Collectively, these results provide new information concerning the mechanisms whereby the modification of hepatic proteins by 4-HNE contributes to ALD.
File Format	HTM / HTML
ISSN	00092797
e-ISSN	18727786
DOI	10.1016/j.cbi.2011.02.021
Journal	Chemico-Biological Interactions
Issue Number	1-2
Volume Number	192
Language	English
Publisher	Elsevier
Publisher Date	2011-06-30
Publisher Place	Ireland
Access Restriction	Open
Subject Keyword	Discipline Biochemistry Discipline Pharmacology Lipid Peroxidation Liver Diseases, Alcoholic Metabolism Liver Proteins Amino Acid Sequence Animals Mice Mice, Inbred C57bl Molecular Sequence Data Rats, Sprague-dawley Research Support, N.i.h., Extramural
Content Type	Text
Resource Type	Article
Subject	Medicine Toxicology

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OVERVIEW OF LIPID PEROXIDATION PRODUCTS AND HEPATIC PROTEIN MODIFICATION IN ALCOHOLIC LIVER DISEASE

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