A proteome analysis of livers from obese (ob/ob) mice treated with the peroxisome proliferator WY14,643

Edvardsson, Ulrika; Alexandersson, Maria; Löwenhielm, Helena Brockenhuus von; Nyström, Ann-Christin; Ljung, Bengt; Nilsson, Fred; Dahllöf, Björn

doi:10.1002/(sici)1522-2683(19990101)20:4/5<935::aid-elps935>3.0.co;2-6

Cited by 64 publications

(33 citation statements)

References 26 publications

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“…31) Recent studies, however, have demonstrated that PPARg-specific antagonists including rosiglitazone and troglitazone up-regulated the expression of PPARa-responsive genes such as acyl-CoA oxidase and peroxisomal bifunctional enzyme. [25][26][27] Although it cannot be ruled out that rosiglitazone and troglitazone activated PPARa, these data suggest that some PPARa-responsive genes can be regulated by PPARg as well. In this study, we observed an increase in PPARg mRNA levels in db/db mice, consistent with a previous study.…”

Section: Fig 2 P450 Mrna Levels In the Liver Of C57 And Db/db Micesupporting

confidence: 53%

Changes in the Expression of Cytochromes P450 and Nuclear Receptors in the Liver of Genetically Diabetic db/db Mice

Yoshinari

Takagi

Sugatani

et al. 2006

Biological & Pharmaceutical Bulletin

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Physiological and pathophysiological conditions often affect the expression of drug metabolizing enzymes such as cytochromes P450 (P450s). Diabetes is one such factor and it is of great interest to understand its effects on drug metabolism, since diabetic patients generally have increased need for pharmacotherapy. We have recently reported the coordinated reduction of CYP2B1/2 and their transcriptional regulator constitutive androstane receptor (CAR), a member of the nuclear receptor superfamily, in the liver of genetically obese/diabetic Zucker fatty rats (Xiong, H., Yoshinari, K., et al., Drug Metab. Dispos., 30, 918-923, 2002). In this study, we investigated the expression of P450s and liver-enriched nuclear receptors in the liver of genetically diabetic db/db mice. Surprisingly, both CYP2B10 and CAR levels were increased in db/db mice. CYP4A expression was also increased at both mRNA and protein levels in db/db mice, while those of peroxisome proliferator-activated receptor a a, a key regulator for the transcriptional activation of CYP4As, were comparable to those in age-matched C57BL/6 mice. Our results demonstrate that db/db mice and Zucker fatty rats exhibit different expression profiles of P450s and nuclear receptors despite their similar characteristics for obesity and diabetes resulting from a defect in the leptin signaling pathway.

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Section: Fig 2 P450 Mrna Levels In the Liver Of C57 And Db/db Micesupporting

confidence: 53%

Changes in the Expression of Cytochromes P450 and Nuclear Receptors in the Liver of Genetically Diabetic db/db Mice

Yoshinari

Takagi

Sugatani

et al. 2006

Biological & Pharmaceutical Bulletin

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“…This is consistent with our observation that treatment with rosiglitazone resulted in a non-significant reduction in fasting plasma TG levels in the fructose-fed hamster, an animal model of mild hypertriglyceridemia associated with VLDL oversecretion. A marked reduction of plasma TG levels after treatment with thiazolidinediones has been more consistently shown in various mouse and rat models of insulin resistance and type 2 diabetes, animal models that display a much more pronounced fasting hypertriglyceridemia than the one usually found in insulin-resistant humans (23,34,35) and in our hamster model. In the present study, the reduction of VLDL secretion in the fructose-fed hamster accounted for the reduction of plasma TG levels associated with rosiglitazone treatment, since VLDL-TG clearance was not different with rosiglitazone treatment.…”

Section: Discussionmentioning

confidence: 91%

“…Catheters were inserted the day before these studies into the femoral vein and artery. A bolus (20 Ci) of [2-3 H]glycerol (PerkinElmer Life Sciences) was injected intravenously, and blood samples were collected at times 10, 15,20,25,30,35,40, and 50 min after the injection to measure VLDL-TG levels and to determine the rate of decline of VLDL-TG [3-3 H]glycerol SA. The fractional clearance rate of VLDL-TG (pool/min) was assessed by the slope of the natural logarithm of VLDL-TG [2-3 H] glycerol SA over time, determined by linear regression over the linear portion of the down-slope, as previously described (16).…”

Section: In Vivo Protocolsmentioning

confidence: 89%

Ameliorated Hepatic Insulin Resistance Is Associated with Normalization of Microsomal Triglyceride Transfer Protein Expression and Reduction in Very Low Density Lipoprotein Assembly and Secretion in the Fructose-fed Hamster

Carpentier¹,

Taghibiglou²,

Leung³

et al. 2002

Journal of Biological Chemistry

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To determine whether reduction of insulin resistance could ameliorate fructose-induced very low density lipoprotein (VLDL) oversecretion and to explore the mechanism of this effect, fructose-fed hamsters received placebo or rosiglitazone for 3 weeks. Rosiglitazone treatment led to normalization of the blunted insulinmediated suppression of the glucose production rate and to a ϳ2-fold increase in whole body insulin-mediated glucose disappearance rate (p < 0.001). Rosiglitazone ameliorated the defect in hepatocyte insulin-stimulated tyrosine phosphorylation of the insulin receptor, IRS-1, and IRS-2 and the reduced protein mass of IRS-1 and IRS-2 induced by fructose feeding. Protein-tyrosine phosphatase 1B levels were increased with fructose feeding and were markedly reduced by rosiglitazone. Rosiglitazone treatment led to a ϳ50% reduction of VLDL secretion rates (p < 0.05) in vivo and ex vivo. VLDL clearance assessed directly in vivo was not significantly different in the FR (fructose-fed ؉ rosiglitazone-treated) versus F (fructose-fed ؉ placebo-treated) hamsters, although there was a trend toward a lower clearance with rosiglitazone. Enhanced stability of nascent apolipoprotein B (apoB) in fructose-fed hepatocytes was evident, and rosiglitazone treatment resulted in a significant reduction in apoB stability. The increase in intracellular mass of microsomal triglyceride transfer protein seen with fructose feeding was reduced by treatment with rosiglitazone. In conclusion, improvement of hepatic insulin signaling with rosiglitazone, a peroxisome proliferator-activated receptor ␥ agonist, is associated with reduced hepatic VLDL assembly and secretion due to reduced intracellular apoB stability.The typical dyslipidemia of insulin-resistant states and Type 2 diabetes consists of hypertriglyceridemia due to VLDL 1 overproduction, low high density lipoprotein cholesterol, and small dense low density lipoprotein particles (1). Elevated plasma free fatty acid (FFA) flux from peripheral and intra-abdominal adipose tissue depots due to resistance to the insulin antilipolytic and esterification effect in adipose tissue is felt to play an important role in driving VLDL assembly and secretion in insulin resistant states (2-4). Nevertheless, previous studies in humans suggest that insulin also has an important direct effect on the liver in controlling VLDL secretion (5-7).Rat and mouse models of insulin resistance and type 2 diabetes have provided important insights into the molecular mechanisms of insulin resistance. These animal models may not, however, be ideal for the study of human lipoprotein disorders because, unlike humans, their livers secrete both apoB48 and apoB100-containing VLDL, and they do not necessarily develop VLDL oversecretion as the basis for their hypertriglyceridemia (8, 9). Unlike livers from rat or mouse, the liver of the golden Syrian hamster secretes only apoB100-containing VLDL, and its lipoprotein metabolism more closely resembles that of humans (10). We have shown that insulin resistance in the fru...

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“…In these studies, addition of TZD to the P␥ hepatocytes was capable of attenuating ␤-catenin levels even in the presence of cycloheximide as shown in Fig. 4B (compare ϩCHX/ϩTZD samples in lanes 6 -8 with ϩCHX/ ϪTZD samples in lanes [3][4][5], indicating that attenuation of ␤-catenin levels involve a post-translational mechanism. To further establish that PPAR␥2 effects ␤-catenin protein stability, pulse-chase analysis was performed with 35 S-labeled ␤-catenin.…”

Section: Ppar␥2 Inhibited Expression Of Endogenous and Ectopic ␤-Catementioning

confidence: 99%

“…The PPAR␥ subfamily consists of two isoforms, PPAR␥1 and PPAR␥2, of which PPAR␥1 is expressed in many tissues, whereas PPAR␥2 is preferentially expressed in adipose tissue (2). Expression of functional PPAR␥ in the liver is elevated during obesity (3)(4)(5) as well in hepatocellular carcinoma (6,7). The PPAR isotypes can regulate transcription of target genes in response to a corresponding ligand (8,9).…”

mentioning

confidence: 99%

Peroxisome Proliferator-activated Receptor γ Activation Can Regulate β-Catenin Levels via a Proteasome-mediated and Adenomatous Polyposis Coli-independent Pathway

Sharma

Pradeep

Wong

et al. 2004

Journal of Biological Chemistry

124

111

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The transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥) belongs to the family of nuclear hormone receptors and consists of two isotypes, PPAR␥1 and PPAR␥2. Our earlier studies have shown that troglitazone (TZD)-mediated activation of PPAR␥2 in hepatocytes inhibits growth and attenuates cyclin D1 transcription via modulating CREB levels. Because this process of growth inhibition was also associated with an inhibition of ␤-catenin expression at a post-translational level, our aim was to elucidate the mechanism involved. ␤-Catenin is a multifunctional protein, which can regulate cell-cell adhesion by interacting with Ecadherin and other cellular processes via regulating target gene transcription in association with TCF/LEF transcription factors. Two adenomatous polyposis coli (APC)-dependent proteasomal degradation pathways, one involving glycogen synthase kinase 3␤ (GSK3␤) and the other involving p53-Siah-1, degrade excess ␤-catenin in normal cells. Our immunofluorescence and Western blot studies indicated a TZD-dependent decrease in cytoplasmic and membrane-bound ␤-catenin, indicating no increase in its membrane translocation. This was associated with a reduction in E-cadherin expression. PPAR␥2 activation inhibited GSK3␤ kinase activity, and pharmacological inhibition of GSK3␤ activity was unable to restore ␤-catenin expression following PPAR␥2 activation. Additionally, this ␤-catenin degradation pathway was operative in cells, with inactivating mutations of both APC and p53. Inhibition of the proteasomal pathway inhibited PPAR␥2-mediated degradation of ␤-catenin, and incubation with TZD increased ubiquitination of ␤-catenin. We conclude that PPAR␥2-mediated suppression of ␤-catenin levels involves a novel APC/ GSK3␤/p53-independent ubiquitination-mediated proteasomal degradation pathway.

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A proteome analysis of livers from obese (ob/ob) mice treated with the peroxisome proliferator WY14,643

Cited by 64 publications

References 26 publications

Changes in the Expression of Cytochromes P450 and Nuclear Receptors in the Liver of Genetically Diabetic db/db Mice

Changes in the Expression of Cytochromes P450 and Nuclear Receptors in the Liver of Genetically Diabetic db/db Mice

Ameliorated Hepatic Insulin Resistance Is Associated with Normalization of Microsomal Triglyceride Transfer Protein Expression and Reduction in Very Low Density Lipoprotein Assembly and Secretion in the Fructose-fed Hamster

Peroxisome Proliferator-activated Receptor γ Activation Can Regulate β-Catenin Levels via a Proteasome-mediated and Adenomatous Polyposis Coli-independent Pathway

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