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Influence of peroxisome proliferator-activated receptor alpha agonists on the intracellular turnover and secretion of apolipoprotein (Apo) B-100 and ApoB-48.

Journal article
Authors Daniel Lindén
Karin Lindberg
Jan Oscarsson
Lennart Asp
Lu Li
Maria Gustafsson
Jan Borén
Sven-Olof Olofsson
Published in The Journal of biological chemistry
Volume 277
Issue 25
Pages 23044-53
ISSN 0021-9258
Publication year 2002
Published at Wallenberg Laboratory
Institute of Medical Biochemistry
Institute of Physiology and Pharmacology, Dept of Physiology
Pages 23044-53
Language en
Links dx.doi.org/10.1074/jbc.M110416200
www.ncbi.nlm.nih.gov/entrez/query.f...
Keywords Acetylcysteine, analogs & derivatives, pharmacology, Animals, Apolipoprotein B-100, Apolipoprotein B-48, Apolipoproteins B, metabolism, Cell Line, Cells, Cultured, Clofibrate, pharmacology, Cytosol, metabolism, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Enzyme Activation, Enzyme Inhibitors, pharmacology, Female, Immunoblotting, Oleic Acid, pharmacology, Palmitic Acid, metabolism, Protein Binding, Protein Biosynthesis, Pyrimidines, pharmacology, RNA, Messenger, metabolism, Rats, Rats, Sprague-Dawley, Receptors, Cytoplasmic and Nuclear, agonists, metabolism, Time Factors, Transcription Factors, agonists, metabolism, Transcription, Genetic, Transfection, Triglycerides, metabolism, Tumor Cells, Cultured
Subject categories Medical cell biology

Abstract

The peroxisome proliferator-activated receptor (PPAR) alpha agonist WY 14,643 increased the secretion of apolipoprotein (apo) B-100, but not that of apoB-48, and decreased triglyceride biosynthesis and secretion from primary rat hepatocytes. These effects resulted in decreased secretion of apoB-100-very low density lipoprotein (VLDL) and an increased secretion of apoB-100 on low density lipoproteins/intermediate density lipoproteins. ApoB-48-VLDL was also replaced by more dense particles. The proteasomal inhibitor lactacystin did not influence the recovery of apoB-100 or apoB-48 in primary rat hepatocytes, indicating that co-translational (proteasomal) degradation is of less importance in these cells. Treatment with WY 14,643 made the recovery of apoB-100 sensitive to lactacystin, most likely reflecting the decreased biosynthesis of triglycerides. The PPAR alpha agonist induced a significant increase in the accumulation of pulse-labeled apoB-100 even after a short pulse (2-5 min). There was also an increase in apoB-100 nascent polypeptides, indicating that the co-translational degradation of apoB-100 was inhibited. However, a minor influence on an early posttranslation degradation cannot be excluded. This decreased co-translational degradation of apoB-100 explained the increased secretion of the protein. The levels of apoB-48 remained unchanged during these pulse-chase experiments, and albumin production was not affected, indicating a specific effect of PPAR alpha agonists on the co-translational degradation of apoB-100. These findings explain the difference in the rate of secretion of the two apoB proteins seen after PPAR alpha activation. PPAR alpha agonists increased the expression and biosynthesis of liver fatty acid-binding protein (LFABP). Increased expression of LFABP by transfection of McA-RH7777 cells increased the secretion of apoB-100, decreased triglyceride biosynthesis and secretion, and increased PPAR alpha mRNA levels. These findings suggest that PPAR alpha and LFABP could interact to amplify the effect of endogenous PPAR alpha agonists on the assembly of VLDL.

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