| 1. |
- Améen, Caroline, 1975, et al.
(författare)
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Activation of peroxisome proliferator-activated receptor alpha increases the expression and activity of microsomal triglyceride transfer protein in the liver
- 2005
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Ingår i: J Biol Chem. ; 280:2, s. 1224-9
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Tidskriftsartikel (refereegranskat)abstract
- 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) alpha agonist, increases apoB-100 secretion despite decreased triglyceride synthesis. In this study, we sought to determine whether PPARalpha 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 PPARalpha activates transcription of the gene. Wy did not affect MTP expression in the intestine or in cultured hepatocytes from PPARalpha-null mice. A retinoid X receptor agonist (9-cis-retinoic acid), but not a PPARgamma agonist (rosiglitazone), increased MTP mRNA expression in cultured hepatocytes from both wild type and PPARalpha-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, PPARalpha 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.
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| 2. |
- Edvardsson, Ulrika, 1967, et al.
(författare)
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Insulin and oleic acid increase PPARgamma2 expression in cultured mouse hepatocytes.
- 2006
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Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 0006-291X. ; 340:1, s. 111-7
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Tidskriftsartikel (refereegranskat)abstract
- Hepatic PPARgamma expression is increased in several animal models of diabetes and obesity, and liver-specific overexpression of PPARgamma induces liver steatosis. The aim of this study was to investigate the regulation of PPARgamma expression in primary mouse hepatocytes. PPARgamma2, but not PPARgamma1, was up-regulated by insulin and to a lesser extent by oleic acid. Insulin increased transcription of the PPARgamma2 gene via phosphatidylinositol 3-kinase activation. The PPARgamma agonist, rosiglitazone, increased PPARgamma2 expression, but not PPARgamma1, only in the presence of insulin. Also aP2 mRNA expression was induced by rosiglitazone to a higher degree in the presence of insulin, while acyl-CoA oxidase was increased independently of insulin. In summary, PPARgamma2 is increased in hepatocytes by oleic acid and insulin. These results may help to understand the regulation of PPARgamma expression in liver, which possibly plays a role in the development of liver steatosis.
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| 3. |
- Edvardsson, Ulrika, 1967, et al.
(författare)
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PPARalpha activation increases triglyceride mass and adipose differentiation-related protein in hepatocytes.
- 2006
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Ingår i: Journal of lipid research. - 0022-2275. ; 47:2, s. 329-40
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Tidskriftsartikel (refereegranskat)abstract
- Adipose differentiation-related protein (ADRP) is a lipid droplet-associated protein that is expressed in various tissues. In mice treated with the peroxisome proliferator-activated receptor alpha (PPARalpha) agonist Wy14,643 (Wy), hepatic mRNA and protein levels of ADRP as well as hepatic triglyceride content increased. Also in primary mouse hepatocytes, Wy increased ADRP expression and intracellular triglyceride mass. The triglyceride mass increased in spite of unchanged triglyceride biosynthesis and increased palmitic acid oxidation. However, Wy incubation decreased the secretion of newly synthesized triglycerides, whereas apolipoprotein B secretion increased. Thus, decreased availability of triglycerides for VLDL assembly could help to explain the cellular accumulation of triglycerides after Wy treatment. We hypothesized that this effect could be mediated by increased ADRP expression. Similar to PPARalpha activation, adenovirus-mediated ADRP overexpression in mouse hepatocytes enhanced cellular triglyceride mass and decreased the secretion of newly synthesized triglycerides. In ADRP-overexpressing cells, Wy incubation resulted in a further decrease in triglyceride secretion. This effect of Wy was not attributable to decreased cellular triglycerides after increased fatty acid oxidation because the triglyceride mass in Wy-treated ADRP-overexpressing cells was unchanged. In summary, PPARalpha activation prevents the availability of triglycerides for VLDL assembly and increases hepatic triglyceride content in part by increasing the expression of ADRP.
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| 4. |
- Edvardsson, Ulrika, 1967
(författare)
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PPARs in the regulation of gene expression and lipid metabolism in the liver
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, regulating genes involved in carbohydrate, lipid and lipoprotein metabolism. Synthetic PPARalpha agonists used in clinic are the fibrates, and their hypotriglyceridemic effect is believed to be the result of decreased VLDL triglyceride secretion and increased turnover of triglyceride-rich lipoprotein particles in the circulation. Synthetic PPARgamma agonists, used in clinic to treat type 2 diabetes, are the thiazolidinediones (TZDs), and PPARgamma in adipose tissue is believed to be the primary target for the TZDs.TZD treatment of obese mice resulted in increased expression of proteins taking part in the peroxisomal fatty acid beta-oxidation in the liver, whereas this effect was abolished in lean mice. This difference in effect might be explained by the finding that obese mice expressed higher levels of PPARgamma2 in the liver as compared to the lean mice. In primary mouse hepatocyte cultures, insulin and oleic acid were shown to increase the level of PPARgamma2, whereas PPARgamma1 expression was unaffected. The stimulatory effect of insulin on PPARgamma2 transcription was mediated via the phosphatidylinositol 3-kinase pathway. Both in vitro, in cultured hepatocytes, and in vivo, treatment with the PPARalpha agonist Wy14,643 (Wy) resulted in increased expression and activity of microsomal triglyceride transfer protein (MTP), which is rate limiting in the VLDL assembly and secretion. Increased MTP expression was paralleled by increased apoB100 secretion, suggesting that the stimulatory effect of Wy on apoB100 secretion could be mediated via increased MTP expression. Wy was also shown to increase the hepatic expression of adipose differentiation-related protein (ADRP) in vivo in mice and in vitro in cultured mouse hepatocytes. Wy increased the hepatic triglyceride content despite increased fatty acid oxidation and unchanged triglyceride synthesis. However, Wy was shown to inhibit the triglyceride secretion, which might contribute to the cellular triglyceride accumulation. Similar to Wy incubation, ADRP overexpression in mouse hepatocytes resulted in decreased triglyceride secretion and increased cellular triglyceride mass. In ADRP overexpressing cells, Wy further inhibited the triglyceride secretion although the ADRP protein expression was unaltered. Since the triglyceride content was unaffected by Wy in ADRP overexpressing cells, incubation with Wy did not result in lack of cellular triglycerides for VLDL secretion. Rather, PPAR Ñ activation prevents the availability of triglycerides for VLDL assembly, in part by increasing the expression of ADRP.In summary, this study shows that the diabetes-associated increase in hepatic PPARgamma2 could be due to increased insulin signaling, and important for the effects of PPARgamma agonists in liver. Moreover, PPARalpha activation influences hepatic expression of MTP and ADRP that contributes to the increased secretion of triglyceride-poor apoB-containing lipoproteins following PPARalpha activation.
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