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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.
Highlights
The peroxisome proliferator-activated receptor (PPAR)1 ␣ has a central role in the regulation of lipid metabolism, and unsaturated long-chain fatty acids (LCFAs) are among the natural ligands for this receptor [1]
Because LCFA has a key role in the biological activities of the two proteins, it is possible that PPAR␣ and liver fatty acidbinding protein (LFABP) have important roles in the regulation of the assembly and secretion of apoB-containing lipoproteins, processes that are highly dependent on LCFAs
PPAR␣ Agonists Increase ApoB Secretion, Decrease the Biosynthesis of Triglycerides, and Redistribute the Secreted ApoB from very low density lipoprotein (VLDL) to More Dense Lipoproteins—Treatment of primary hepatocytes with the PPAR␣ agonist WY 14,643 stimulated the secretion of apoB-100 (Fig. 3A), whereas there was no effect on the secretion of apoB-48 (Fig. 3B)
Summary
The peroxisome proliferator-activated receptor (PPAR)1 ␣ has a central role in the regulation of lipid metabolism, and unsaturated long-chain fatty acids (LCFAs) are among the natural ligands for this receptor [1]. Because LCFA has a key role in the biological activities of the two proteins, it is possible that PPAR␣ and LFABP have important roles in the regulation of the assembly and secretion of apoB-containing lipoproteins, processes that are highly dependent on LCFAs. The process involved in the assembly of these lipoproteins has recently been reviewed [23, 24]. The. Influence of PPAR␣ Agonists on ApoB-100 and ApoB-48 process is highly dependent on lipid biosynthesis and the availability of fatty acids It has recently been demonstrated that apoB undergoes degradation at three levels: (i) co-translationally, most likely from the translocon, a process that involves proteasomes [28, 29]; (ii) posttranslationally, by a hitherto unknown pathway [28]; and (iii) via the LDL receptor [28, 30]
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