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J. Biol. Chem., Vol. 280, Issue 2, 1224-1229, January 14, 2005
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Activation of Peroxisome Proliferator-activated Receptor 
Increases the Expression and Activity of Microsomal Triglyceride Transfer Protein in the Liver*
¶¶¶||
From the
Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, S-41345 Göteborg, Sweden, the Department of Physiology, Sahlgrenska University Hospital, S-40530 Göteborg, Sweden and ¶AstraZeneca Research and Development, S-43183 Mölndal, Sweden
Microsomal triglyceride transfer protein (MTP) is rate-limiting in the assembly and secretion of lipoproteins containing apolipoprotein (apo) B. Previously we demonstrated that Wy 14,643 (Wy), a peroxisome proliferator-activated receptor (PPAR) 
agonist, increases apoB-100 secretion despite decreased triglyceride synthesis. In this study, we sought to determine whether PPAR activation increases MTP expression and activity. Treatment with Wy increased hepatic MTP expression and activity in rats and mice and increased MTP expression in primary cultures of rat and mouse hepatocytes. Addition of actinomycin D blocked this increase and the MTP promoter (–136 to +67) containing a conserved DR1 element was activated by Wy, showing that PPAR activates transcription of the gene. Wy did not affect MTP expression in the intestine or in cultured hepatocytes from PPAR-null mice. A retinoid X receptor agonist (9-cis-retinoic acid), but not a PPAR
agonist (rosiglitazone), increased MTP mRNA expression in cultured hepatocytes from both wild type and PPAR-null mice. In rat hepatocytes incubated with Wy, MTP mRNA levels increased between 6 and 24 h, and MTP protein expression and apoB-100 secretion increased between 24 and 72 h. In conclusion, PPAR activation stimulates hepatic MTP expression via increased transcription of the Mtp gene. This effect is paralleled by a change in apoB-100 secretion, indicating that the effect of Wy on apoB-100 secretion is mediated by increased expression of MTP.
Received for publication, October 26, 2004
* This work was supported by Grant 14291 from the Swedish Medical Research Council, the King Gustav V and Queen Victoria's Foundation, AstraZeneca, and the Swedish Heart and Lung Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|| To whom correspondence should be addressed: Dept. of Integrative Pharmacology, HE 119, AstraZeneca R&D, S-43183 Mölndal, Sweden. Tel.: 46-31-706-57-85; Fax: 46-31-776-37-04; E-mail: jan.oscarsson{at}astrazeneca.com.
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