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- Améen, Caroline, 1975, et al.
(författare)
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Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver.
- 2004
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 287:6
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Tidskriftsartikel (refereegranskat)abstract
- We investigated whether the sexually dimorphic secretory pattern of growth hormone (GH) in the rat regulates hepatic gene expression of sterol regulatory element-binding protein-1c (SREBP-1c) and its target genes. SREBP-1c, fatty acid synthase (FAS), and glycerol-3-phosphate acyltransferase (GPAT) mRNA were more abundant in female than in male livers, whereas acetyl-CoA carboxylase-1 (ACC1) and stearoyl-CoA desaturase-1 (SCD-1) were similarly expressed in both sexes. Hypophysectomized female rats were given GH as a continuous infusion or as two daily injections for 7 days to mimic the female- and male-specific GH secretory patterns, respectively. The female pattern of GH administration increased the expression of SREBP-1c, ACC1, FAS, SCD-1, and GPAT mRNA, whereas the male pattern of GH administration increased only SCD-1 mRNA. FAS and SCD-1 protein levels were regulated in a similar manner by GH. Incubation of primary rat hepatocytes with GH increased SCD-1 mRNA levels and decreased FAS and GPAT mRNA levels but had no effect on SREBP-1c mRNA. GH decreased hepatic liver X receptor-alpha (LXRalpha) mRNA levels both in vivo and in vitro. Feminization of the GH plasma pattern in male rats by administration of GH as a continuous infusion decreased insulin sensitivity and increased expression of FAS and GPAT mRNA but had no effect on SREBP-1c, ACC1, SCD-1, or LXRalpha mRNA. In conclusion, FAS and GPAT are specifically upregulated by the female secretory pattern of GH. This regulation is not a direct effect of GH on hepatocytes and does not involve changed expression of SREBP-1c or LXRalpha mRNA but is associated with decreased insulin sensitivity.
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| 2. |
- Lindén, Daniel, 1971
(författare)
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Growth hormone and PPARa in the regulation of lipoprotein metabolism
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In humans, apolipoprotein B (apoB)-100 is produced in the liver and apoB-48 is formed in the intestine. In the rat, however, the two forms of apoB are produced in the liver, leading to the formation of VLDL consisting of either apoB-48 or apoB-100. The mRNA for apoB-48 is produced by insertion of a stop codon in the mRNA for apoB-100, an enzyme-dependent event called apoB mRNA editing. From previous results, it is clear that growth hormone (GH) treatment in vivo stimulates the VLDL secretion in both rats and humans. However, during GH treatment, the liver is exposed to increased levels of insulin and fatty acids, which have been shown to increase VLDL secretion. Using primary rat hepatic cell cultures, GH incubation increased the apoB mRNA editing and triglyceride synthesis and decreased the apoB-100 secretion. Moreover, GH increased the secretion of apoB-48-VLDL and combined incubation with oleic acid had an additive effect. The importance of increased insulin secretion for the effect of GH in vivo was investigated in hypophysectomised (Hx) rats. Increased insulin levels did not mediate the observed effects of GH on serum lipoprotein levels. However, GH treatment increased the hepatic triglyceride secretion rate, an effect that was blunted by insulin treatment. Both GH and insulin increased the expression of lipogenic enzymes in Hx rats, indicating that these effects of GH could be mediated via increased insulin secretion. GH was found to decrease the expression of peroxisome proliferator-activated receptor a (PPARa) both in hepatocyte cultures and in Hx rats. In spite of decreased PPARa levels, GH increased the expression of liver fatty acid binding protein. The importance of PPARa for VLDL production was investigated in PPARa null mice. PPARa-deficient hepatocytes had an increased capacity for apoB and VLDL secretion. Female, in contrast to male PPARa null mice had increased hepatic triglyceride secretion rate and serum apoB levels. Moreover, when fed a high-fat diet, male PPARa null mice displayed increased serum apoB and LDL cholesterol levels.In summary, GH was found to have direct effects on apoB and VLDL production and secretion and increased insulin levels could not explain most of the effects of GH in vivo. GH decreased PPARa expression both in vitro and in vivo. PPARa null mice have higher secretion and serum levels of apoB-containing lipoproteins.
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| 3. |
- Lindén, Daniel, 1971, et al.
(författare)
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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.
- 2002
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Ingår i: The Journal of biological chemistry. - 0021-9258. ; 277:25, s. 23044-53
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Tidskriftsartikel (refereegranskat)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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