| 1. |
- Egecioglu, Emil, 1977, et al.
(författare)
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Growth hormone receptor deficiency results in blunted ghrelin feeding response, obesity, and hypolipidemia in mice.
- 2006
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 290:2
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Tidskriftsartikel (refereegranskat)abstract
- We have previously shown that growth hormone (GH) overexpression in the brain increased food intake, accompanied with increased hypothalamic agouti-related protein (AgRP) expression. Ghrelin, which stimulates both appetite and GH secretion, was injected intracerebroventricularly to GHR-/- and littermate control (+/+) mice to determine whether ghrelin's acute effects on appetite are dependent on GHR signaling. GHR-/- mice were also analyzed with respect to serum levels of lipoproteins, apolipoprotein (apo)B, leptin, glucose, and insulin as well as body composition. Central injection of ghrelin into the third dorsal ventricle increased food consumption in +/+ mice, whereas no change was observed in GHR-/- mice. After ghrelin injection, AgRP mRNA expression in the hypothalamus was higher in +/+ littermates than in GHR-/- mice, indicating a possible importance of AgRP in the GHR-mediated effect of ghrelin. Compared with controls, GHR-/- mice had increased food intake, leptin levels, and total and intra-abdominal fat mass per body weight and deceased lean mass. Moreover, serum levels of triglycerides, LDL and HDL cholesterol, and apoB, as well as glucose and insulin levels were lower in the GHR-/- mice. In summary, ghrelin's acute central action to increase food intake requires functionally intact GHR signaling. Long-term GHR deficiency in mice is associated with high plasma leptin levels, obesity, and increased food intake but a marked decrease in all lipoprotein fractions.
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| 2. |
- 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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| 3. |
- Andersson, Irene, 1978, et al.
(författare)
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Increased atherosclerotic lesion area in apoE deficient mice overexpressing bovine growth hormone
- 2006
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150. ; 188:2, s. 331-40
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Tidskriftsartikel (refereegranskat)abstract
- Human growth hormone (GH) excess is linked to increased cardiovascular morbidity and mortality. However, little is known about the effect of GH excess on atherosclerosis. We developed a new mouse model to assess the hypothesis that GH overexpression accelerates atherosclerotic lesion formation. apoE(-/-) mice were crossed with bovine GH (bGH) transgenic mice to yield apoE(-/-) mice overexpressing bGH (apoE(-/-)/bGH). The mice were fed either standard or Western diet. At 22 weeks, atherosclerotic lesion area of thoracic aorta was larger in apoE(-/-)/bGH mice compared with littermate apoE(-/-) mice fed either diet (standard: +161+/-50%, Western: +430+/-134%). Aortic sinus lesions were more severe in apoE(-/-)/bGH mice fed standard diet compared with littermate apoE(-/-) mice. apoE(-/-)/bGH mice had lower (VLDL+LDL)/HDL ratios compared with littermate apoE(-/-) mice, while systolic blood pressure was higher in apoE(-/-)/bGH mice, irrespective of diet. The levels of serum amyloid A and hepatic CRP mRNA were higher in apoE(-/-)/bGH mice than in littermate apoE(-/-) mice. In conclusion, this study shows that excess GH augments the development of atherosclerosis in apoE(-/-) mice. The mechanisms could be direct effects of GH on cellular processes in the vessel wall or the result of concomitant processes such as hypertension or a general inflammatory state.
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| 4. |
- 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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| 5. |
- 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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| 6. |
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| 7. |
- Li, Lu, 1964, et al.
(författare)
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Epigallocatechin gallate increases the formation of cytosolic lipid droplets and decreases the secretion of apoB-100 VLDL
- 2006
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Ingår i: J Lipid Res. - 0022-2275. ; 47:1, s. 67-77
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Tidskriftsartikel (refereegranskat)abstract
- Epigallocatechin gallate (EGCG) increases the formation of cytosolic lipid droplets by a mechanism that is independent of the rate of triglyceride biosynthesis and involves an enhanced fusion between lipid droplets, a process that is crucial for their growth in size. EGCG treatment reduced the secretion of both triglycerides and apolipoprotein B-100 (apoB-100) VLDLs but not of transferrin, albumin, or total proteins, indicating that EGCG diverts triglycerides from VLDL assembly to storage in the cytosol. This is further supported by the observed increase in both intracellular degradation of apoB-100 and ubiquitination of the protein (indicative of increased proteasomal degradation) in EGCG-treated cells. EGCG did not interfere with the microsomal triglyceride transfer protein, and the effect of EGCG on the secretion of VLDLs was found to be independent of the LDL receptor. Thus, our results indicate that EGCG promotes the accumulation of triglycerides in cytosolic lipid droplets, thereby diverting lipids from the assembly of VLDL to storage in the cytosol. Our results also indicate that the accumulation of lipids in the cytosol is not always associated with increased secretion of VLDL.
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| 8. |
- Ljungberg, Anna, 1977, et al.
(författare)
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Importance of PPAR alpha for the effects of growth hormone on hepatic lipid and lipoprotein metabolism
- 2007
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Ingår i: Growth Horm IGF Res. - : Elsevier BV. - 1096-6374. ; 17:2, s. 154-64
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Growth hormone (GH) enhances lipolysis in adipose tissue, thereby increasing the flux of fatty acids to other tissues. Moreover, GH increases hepatic triglyceride synthesis and secretion in rats and decreases the action of peroxisome proliferator-activated receptor (PPAR)alpha. PPARalpha is activated by fatty acids and regulates hepatic lipid metabolism in rodents. The aim of this study was to investigate the importance of PPARalpha for the effects of GH on hepatic gene expression and lipoprotein metabolism. DESIGN: Bovine GH was given as a continuous infusion (5mg/kg/day) for 7 days to PPARalpha-null and wild-type (wt) mice. Plasma and liver lipids and hepatic gene expression were measured. In separate experiments, hepatic triglyceride secretion was measured. RESULTS: GH treatment decreased hepatic triglyceride content and increased hepatic triglyceride secretion rate and serum cholesterol levels. Furthermore, GH increased hepatic acylCoA:diacylglycerol acyltransferase (DGAT)2 mRNA levels, but decreased the hepatic mRNA expression of acyl-CoA oxidase, medium-chain acyl-CoA dehydrogenase and PPARgamma1. All these GH effects were independent of PPARalpha. However, the effect of GH on Cyp4a10, PPARgamma2, and DGAT1 was different between the genotypes. GH treatment decreased Cyp4a10 mRNA expression in wt mice, but increased the expression in PPARalpha-null mice. In contrast, GH decreased the expression of DGAT1 and PPARgamma2 in PPARalpha-null mice, but not in wt mice. CONCLUSIONS: Most of the effects of GH on lipid and lipoprotein metabolism were independent of PPARalpha. However, GH had unique effects on Cyp4a10, DGAT1, and PPARgamma2 gene expression in PPARalpha-null mice showing cross-talk between GH and PPARalpha signalling in vivo.
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| 9. |
- Ljungberg, Anna, 1977
(författare)
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The role of PPARalpha and growth hormone in hepatic lipid metaboism and atherosclerosis
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dyslipidemia mainly results from oversecretion of apoB-containing lipoproteins from theliver and is one of the most important risk factors for the development of atherosclerosis.Growth hormone (GH) plays a key role in the regulation of lipoprotein metabolism and thus,disturbances in GH secretion are associated with dyslipidemia and cardiovascular disease.GH influences the activity of the nuclear hormone receptor peroxisome proliferator-activatedreceptor (PPAR)alpha, which regulates genes involved in lipid metabolism through interactionwith coactivators. PPARgamma coactivator-1 (PGC-1) has been shown to coactivate severaltranscription factors, including PPARalpha.GH transgenic mice on apoE-deficient background had larger atherosclerotic lesion area inthe thoracic aorta and more advanced lesions in aortic sinus compared to littermate controls.Changes in serum lipoproteins were most likely not involved in the accelerated lesionformation in GH transgenic mice since their lipoprotein profile was not worsened. Instead,higher blood pressure and an increased inflammatory response could contribute to thiseffect. Treatment of mice with a high dose of GH increased triglyceride secretion, serumapoB and cholesterol levels, whereas liver triglycerides were reduced. Most of the studiedeffects of GH were similar in PPARalpha-deficient and wild-type mice and thus independent ofPPARalpha. However, hepatic PPARgamma2 and Cyp4a10 mRNA expression were PPARalpha dependent,indicating that PPARalpha is important for the effect of GH on hepatic PPARgamma signaling and omega-oxidation. Treatment of mice and incubation of mouse hepatocytes with the PPARalpha agonistWy14,643 (Wy) resulted in hepatic triglyceride accumulation in parallel with increasedexpression of adipose differentiation-related protein (ADRP). Studies in mouse hepatocytesshowed that the increased triglyceride content was associated with inhibited triglyceridesecretion. ADRP overexpression also resulted in accumulation of triglycerides and decreasedtriglyceride secretion. The decreased secretion was not due to lack of triglycerides. Rather,PPARalpha activation prevents the availability of cytosolic triglycerides for VLDL assembly, inpart by increasing the expression of ADRP. Hepatic overexpression of PGC-1beta in miceinduced a hyperlipidemic response with a marked increase in apoB-containing lipoproteins.The hyperlipidemia was associated with increased diacylglycerol acyltransferase (DGAT)-1expression and plasma free fatty acids. The potentially beneficial effects of Wy on genescontrolling lipid metabolism were blunted by PGC-1beta overexpression.In summary, high GH levels are associated with increased atherosclerosis and hepatic VLDLsecretion. A few hepatic GH effects are dependent on PPARalpha. PPARalpha activation decreaseshepatic VLDL secretion by compartmentalization of intracellular triglycerides and hepaticPGC-1beta overexpression results in combined hyperlipidemia and decreased PPARalphasignaling.
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| 10. |
- Olsson, Bob, 1969, et al.
(författare)
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Bovine growth hormone transgenic mice are resistant to diet-induced obesity but develop hyperphagia, dyslipidemia, and diabetes on a high-fat diet
- 2005
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 146:2, s. 920-30
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Tidskriftsartikel (refereegranskat)abstract
- It is known that bovine GH (bGH) transgenic mice have increased body mass, insulin resistance, and altered lipoprotein metabolism when fed a normal diet (ND). In this study, the effects of 8 wk of high-fat diet (HFD) were investigated in 6-month-old male bGH mice. Although littermate controls had unchanged energy intake, energy intake was higher in the bGH mice on a HFD than on a low-fat diet. Nevertheless, the bGH mice were resistant to diet-induced weight gain, and only in the bGH mice did the HFD result in increased energy expenditure. Glucose oxidation was higher in the bGH mice compared with littermate controls on both a HFD and ND. In addition, the bGH mice had 0.5 C higher body temperature throughout the day and increased hepatic uncoupling protein 2 expression; changes that were unaffected by the HFD. On a HFD, the effect of bGH overexpression on serum triglycerides and apolipoprotein B was opposite to that on a ND, resulting in higher serum concentrations of triglycerides and apolipoprotein B compared with littermate controls. Increased serum triglycerides were explained by decreased triglyceride clearance. The HFD led to diabetes only in the bGH mice. In conclusion, bGH transgenic mice were resistant to diet-induced obesity despite hyperphagia, possibly due to increased energy expenditure. On a HFD, bGH mice became dyslipidemic and diabetic and thereby more accurately reflect the metabolic situation in acromegalic patients.
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