Role of peroxisome proliferator-activated receptor-gamma (PPARgamma) during liver regeneration in rats

Background and Aim:  Peroxisome proliferator-activated receptor-gamma (PPARγ), a member of the nuclear receptor superfamily, is widely expressed in adipocytes and other tissues, including the liver. Several reports have shown that PPARγ activation induced cell-cycle arrest and apoptosis in tumor cells. We investigated the role of the PPARγ/ligand system and the effect of the PPARγ agonist during liver regeneration.
Methods:  Expression of PPARγ and serum levels of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) by enzyme immunoassay were evaluated in rats following partial hepatectomy (PH group). Further, the effect of the PPARγ agonist, pioglitazone, on liver regeneration (PH + PGZ group) was evaluated by proliferating cell nuclear antigen labeling index, relative liver weight, and expression of cell-cycle regulators.
Results:  The number of PPARγ-stained hepatocytes decreased at 24 h (PH, 15.8 ± 2.2%; sham, 35.5 ± 2.4%; P  < 0.001) and increased in the late phase of liver regeneration compared to the sham-operated group ( P  < 0.001 at 48–120 h). The peaks of serum 15d-PGJ2 (627.0 ± 91.1 pg/ml) and PPARγ expression (90.6 ± 3.1%) coincided in the late phase of liver regeneration. Also, oral administration of pioglitazone inhibited hepatocyte proliferation, in terms of the proliferating cell nuclear antigen (PCNA) labeling index and p27 expression during the late phase of liver regeneration, and caused a transient reduction in liver mass when compared to the PH group.
Conclusions:  These results indicate that the PPARγ/ligand system may be one of the key negative regulators of hepatocyte proliferation and may be responsible for the inhibition of liver growth in the late phase of liver regeneration.     

Stimulation of adipogenesis, peroxisome proliferator-activated receptor-gamma (PPARgamma), and thyrotropin receptor by PPARgamma agonist in human orbital preadipocyte fibroblasts

The symptoms and signs of Graves' ophthalmopathy (GO) result from both an accumulation of hydrated hyaluronan in the orbital muscles and connective tissues and an expansion of the orbital adipose tissues. Recent studies have suggested a link between the stimulation of adipogenesis within the orbit in GO and the expression in these tissues of TSH receptor (TSHR), the putative orbital autoantigen. To further investigate this association, we treated orbital fibroblasts from patients with GO with rosiglitazone, a thiazolidinedione agonist of the PPARgamma receptor that stimulates adipocyte differentiation. We found this compound to be a potent stimulator of functional TSHR expression as well as TSHR and PPARgamma mRNA levels in differentiated cultures. In addition, rosiglitazone treatment stimulated recruitment and differentiation of a subset of cells within these cultures into mature lipid-laden adipocytes. These results suggest that TSHR expression in GO orbital preadipocyte fibroblasts is linked to adipogenesis, and that ligation of the PPARgamma receptor results in differentiation of these cells. It is possible that endogenous PPARgamma ligands play a role in stimulating orbital adipogenesis in GO, and that future treatments may be aimed at antagonism of various components of the PPARgamma signaling system.     

The cardiovascular effects of peroxisome proliferator-activated receptor agonists

Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation.     

Treatment of thyroid cancer with histone deacetylase inhibitors and peroxisome proliferator-activated receptor-gamma agonists.

Among the most promising new antineoplastic therapies for poorly differentiated or undifferentiated thyroid cancer are the histone deacetylase inhibitors and the peroxisome proliferator-activated receptor (PPAR)-gamma agonists. These two classes of drugs have been shown to inhibit growth and induce apoptosis and redifferentiation in a variety of hematologic and solid cancer cell lines and animal models. In this article we review the molecular mechanisms, in vitro and in vivo studies, and clinical applications of the histone deacetylase inhibitors and PPAR-gamma agonists in the treatment of thyroid cancer.     

Interferon-gamma-inducible alpha-chemokine CXCL10 involvement in Graves' ophthalmopathy: modulation by peroxisome proliferator-activated receptor-gamma agonists

CONTEXT: CXC alpha-chemokine CXCL10/inducing protein-10 play an important role in the initial phases of autoimmune thyroid disorders. Human thyrocytes in primary culture produce large amounts of CXCL10 when stimulated by interferon-gamma (IFNgamma) and TNFalpha. OBJECTIVE: Serum CXCL10 levels (sCXCL10) were measured in patients with active or inactive Graves' ophthalmopathy (GO). The effects of IFNgamma and TNFalpha stimulation and peroxisome proliferator-activated receptor-gamma (PPARgamma) activation on CXCL10 secretion in primary cultures of thyrocytes, orbital fibroblasts, and preadipocytes were tested. PATIENTS: Sixty consecutive patients with Graves' disease, 60 age- and sex-matched patients with GO, and 60 controls were studied. RESULTS: sCXCL10 was higher (P < 0.0001) in Graves' disease (120 +/- 83 pg/ml; n = 60) and GO (122 +/- 71; n = 60) patients than in age- and sex-matched euthyroid controls (72 +/- 32; n = 60). Among GO patients, sCXCL10 levels were significantly higher in those (n = 14) with active disease (171 +/- 197) than in those with inactive disease (114 +/- 45 pg/ml; P < 0.003). In primary cultures of thyrocytes, retrobulbar fibroblasts and retrobulbar preadipocytes from GO patients, CXCL10 production was absent under basal conditions; dose-dependent secretion of CXCL10 was not induced by TNFalpha alone, whereas stimulation with IFNgamma or TNFalpha plus IFNgamma induced CXCL10 release. Treatment of all cell types with the PPARgamma agonist, rosiglitazone, dose-dependently (0.1-10 microm) suppressed IFNgamma- plus TNFalpha-induced CXCL10 release. CONCLUSIONS: We conclude that in GO, thyrocytes and retrobulbar cell types participate in the self-perpetuation of inflammation by releasing chemokines under the influence of cytokines. PPARgamma activation plays an inhibitory role in this process.     

The peroxisome proliferator-activated receptor alpha (PPARalpha): role in hepatocarcinogenesis

The peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor superfamily and mediates most of the known biological effects of peroxisome proliferators. The latter represents a large group of chemicals that include the fibrate hyperlipidemic drugs, the pthalate plasticizers, various solvents and degreasing agents, and endogenous hormones and fatty acids. Peroxisome proliferators are classical members of the nongenotoxic group of chemical carcinogens that do not require metabolic activation to electrophiles in order to exert their harmful effects. These chemicals are of particular concern to regulatory agencies since they can only be detected by long-term carcinogen bioassays using rodents. The mechanism of the carcinogenic action of peroxisome proliferators is beginning to emerge. PPARalpha-null mice are resistant to hepatocarcinogenesis indicating that this receptor is necessary for cancer. However, recent studies indicate that Kupffer cells, in a PPARalpha independent manor, are required for the major effects of peroxisome proliferators on cell proliferation. An interaction between PPARalpha and estrogen carcinogenesis has also been elucidated.     

Pro12Ala mutation in the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) and severe obesity: a case-control study

OBJECTIVE: To explore the association of the Pro12Ala mutation in the peroxisome proliferator-activated receptor gamma2 with severe obesity and the features of the metabolic syndrome in a population-based sample of Caucasians. PARTICIPANTS AND METHODS: The study is based on a case-control design: 95 non-diabetic severely obese (body mass index, BMI > 35 kg/m2) cases and 280 normal weight (BMI < 25 kg/m2), age- and sex-matched controls selected from the same population were studied. Height, weight, waist circumference, as well as blood pressure were measured according to a standard protocol. BMI at age 25 y was calculated on the basis of current height and reported weight at age 25 y Biochemical measurements included fasting glucose, triglycerides, high-density lipoprotein cholesterol and insulin. DNA analysis was conducted by PCR and gel electrophoresis. RESULTS: Age and gender distribution were similar in obese and normal weight participants. The percentage of people with the Pro12Ala mutation was not significantly different in obese or normal weight participants (20% and 15%, respectively; P = 0.32). Conversely, in obese participants with obesity starting in early adulthood (ie with BMI at age 25 above 26.9kg/m2 which represents the median of the whole obese group), the Pro12Ala mutation was observed significantly more frequently than in the normal weight controls (29% vs 15%; chi square = 4.5, P < 0.05; odds ratio 2.4; 95% CI 1.03-5.36). No association of the Pro12Ala variant with any of the component of the metabolic syndrome measured in the study was observed in either obese, juvenile obese or normal weight participants. CONCLUSIONS: Results of this study indicate that the Pro12Ala mutation does not play a major role as a determinant of severe obesity and/or features of the metabolic syndrome in the general population. However, this mutation may be of greater importance as a contributor to early onset obesity.     

糖尿病合并Graves眼病者需慎用过氧化物酶体增殖物激活受体γ激动剂

过氧化物酶体增殖物激活受体（PPAR）γ激动剂噻唑烷二酮类药物的应用是近年2型糖尿病治疗的主要进展之一。但自2003年以来,陆续有报道在合并Graves眼病（GO）的糖尿病患者中应用噻唑烷二酮类药物后,GO有恶化倾向^[1-4],因而有关PPARγ与GO发病的关系越来越引起人们的重视。     

Pivotal role of peroxisome proliferator-activated receptor gamma (PPARgamma) in regulation of erythroid progenitor cell proliferation and differentiation

OBJECTIVE: The aim of this study was to reveal the role of peroxisome proliferator-activated receptor gamma (PPARgamma) in erythropoiesis. METHODS: The effects of PPARgamma ligands on cellular proliferation and differentiation were investigated in erythroid colony-forming cells (ECFCs) purified from human peripheral blood. RESULTS: RT-PCR analysis revealed that PPARgamma mRNA is expressed in ECFCs. Synthetic PPARgamma ligands, troglitazone or pioglitazone, suppressed cellular proliferation without inducing apoptosis and delayed maturation of ECFCs, as determined by flow cytometry. The delay in erythroid maturation by troglitazone was confirmed by the down-regulation of gamma-globin, beta-globin and GATA-1 mRNA, and the maintenance of GATA-2 mRNA. CONCLUSIONS: Our results suggest that PPARgamma modulates the differentiation process of erythroid progenitor cells, and plays a crucial role in regulating the balance of hematopoiesis.     

Treating the metabolic syndrome: telmisartan as a peroxisome proliferator-activated receptor-gamma activator

Hypertension commonly occurs as part of a genetically complex disorder of carbohydrate and lipid metabolism known as the metabolic syndrome. Most current antihypertensive drugs appear ineffective against the metabolic syndrome, which is a strong predictor of cardiovascular disease and death in affected patients. Angiotensin II can influence the activity of certain genes and cellular and biochemical pathways that may contribute to the pathogenesis of the metabolic syndrome. However, as a class, angiotensin II receptor blockers (ARBs) have proven only minimally to modestly effective in ameliorating the disturbances in carbohydrate and lipid metabolism that characterise the metabolic syndrome. Recent preclinical studies indicate that the ARB telmisartan acts as a selective peroxisome proliferators-activated receptor-gamma (PPARgamma) modulator when tested at concentrations that might be achievable with oral doses recommended for treatment of hypertension; this property does not appear to be shared by other ARBs. PPARgamma is a nuclear receptor that influences the expression of multiple genes involved in carbohydrate and lipid metabolism and is an attractive therapeutic target for the prevention and control of insulin resistance, type 2 diabetes and atherosclerosis. In cellular transactivation assays, telmisartan functioned as a partial agonist of PPARgamma and achieved 25-30% of maximal receptor activation attained with conventional PPARgamma ligands. Preclinical and clinical studies indicate that administration of telmisartan can improve carbohydrate and lipid metabolism without causing the side effects that accompany full PPARgamma activators. If the preliminary data are supported by the results of ongoing large-scale clinical studies, telmisartan could have a central role in the prevention and treatment of metabolic syndrome, diabetes and atherosclerosis.     

Thioredoxin-binding protein-2-like inducible membrane protein is a novel vitamin D3 and peroxisome proliferator-activated receptor (PPAR)gamma ligand target protein that regulates PPARgamma signaling

Thioredoxin binding protein-2 (TBP-2), which is identical with vitamin D3 (VD3) up-regulated protein 1 (VDUP1), plays a crucial role in the integration of glucose and lipid metabolism. There are three highly homologous genes of TBP-2/vitamin D3 up-regulated protein 1 in humans, but their functions remain unclear. Here we characterized a TBP-2 homolog, TBP-2-like inducible membrane protein (TLIMP). In contrast to TBP-2, TLIMP displayed no significant binding affinity for thioredoxin. TLIMP exhibited an inner membrane-associated pattern of distribution and also colocalized with transferrin and low-density lipoprotein, indicating endosome- and lysosome-associated functions. VD3 and ligands of peroxisome proliferator-activated receptor (PPAR)-gamma, an important regulator of energy metabolism and cell growth inhibition, induced the expression of TLIMP as well as TBP-2. Overexpression of TLIMP suppressed both anchorage-dependent and -independent cell growth and PPARgamma ligand-inducible gene activation. These results suggest that TLIMP, a novel VD3- or PPARgamma ligand-inducible membrane-associated protein, plays a regulatory role in cell proliferation and PPARgamma activation.     

Albumin regulates induction of peroxisome proliferator-activated receptor-gamma (PPARgamma) by 15-deoxy-delta(12-14)-prostaglandin J(2) in vitro and may be an important regulator of PPARgamma function in vivo

We observed that serum contains a factor(s) that inhibits the induction of peroxisome proliferator-activated receptor-gamma (PPARgamma) by 15-deoxy-Delta(12,14)-PGJ(2) (15dJ(2)). Ten percent FBS reduces 15dJ(2) induction of PPARgamma from over 150-fold to less than 15-fold in EP-JEG cells, a stably transfected choriocarcinoma cell line that expresses endogenous PPARgamma. By contrast, rosiglitazone, an unrelated pharmacological agonist of PPARgamma, is not inhibited by serum in this cell line. We have identified the inhibitory principal in serum as albumin. Serum albumin binds 15dJ(2) with a dissociation constant of 870 +/- 70 nM, effectively reducing the concentration of 15dJ(2) available to PPARgamma. Heat treatment of serum abolishes the inhibition, providing a way to test eicosanoid compounds independently of albumin's inhibitory effect. It is reasonable to assume that 15dJ(2) or structurally similar compounds or metabolites are the endogenous activators of PPARgamma. Therefore, albumin may be an important regulator of PPARgamma function in vivo.