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J. Biol. Chem., Vol. 277, Issue 25, 23044-23053, June 21, 2002

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Influence of Peroxisome Proliferator-activated Receptor  Agonists on the Intracellular Turnover and Secretion of Apolipoprotein (Apo) B-100 and ApoB-48^*

Daniel Lindén^§, Karin Lindberg^§¶, Jan Oscarsson, Catharina Claesson^¶, Lennart Asp^¶, Lu Li^¶, Maria Gustafsson, Jan Borén, and Sven-Olof Olofsson^¶**

From the Departments of ^¶ Medical Biochemistry and  Physiology and  Wallenberg Laboratory for Cardiovascular Research, Göteborg University, SE 405 30 Göteborg, Sweden

The peroxisome proliferator-activated receptor (PPAR)  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 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 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 activation. PPAR 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 mRNA levels. These findings suggest that PPAR and LFABP could interact to amplify the effect of endogenous PPAR agonists on the assembly of VLDL.

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