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PubMedDate not supplied

Therapeutic treatment of DMBA-induced mammary tumors with PPAR ligands.

The objective of this study was to evaluate the ability of troglitazone (a thiazolidinedione) and Wy-14,643 (a clofibrate) to inhibit progression of non-detectable and detectable mammary tumors in rats induced by 7,12 dimethylbenz(a)anthracene (DMBA) when compared to those receiving no treatment or tamoxifen. Although not as effective as tamoxifen in decreasing overall tumor incidence, Wy-14,643 reduced the percentage and number of malignant tumors that developed when compared to both troglitazone and control. Treatment of detectable tumors with either Wy-14,643 or troglitazone induced regression or stasis of total tumor volume in 40-50% of the animals, compared to only 10% in control and 65% in tamoxifen treated animals. Moreover, each PPAR ligand was as effective as tamoxifen in preventing additional tumor development. In summary, both PPAR ligands were more effective than no treatment in preventing tumor progression once detected. However, only the PPAR-alpha activator, Wy-14,643 was able to reduce the development of malignant tumors when administered prior to detection.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2001

PPAR-gamma ligands inhibit growth of human esophageal adenocarcinoma cells through induction of apoptosis, cell cycle arrest and reduction of ornithine decarboxylase activity.

Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, is involved in suppression of growth of several types of tumors such as liposarcoma, breast cancer, prostate cancer, and colon cancer, possibly through induction of cell cycle arrest and/or apoptosis. In this study, we demonstrated expression of PPAR-gamma mRNA and protein in human esophageal carcinoma cells. Expression of PPAR-gamma protein was higher in an adenocarcinoma cell line (TE-7 cells) than in a squamous cell carcinoma cell line (TE-1 cells). PPAR-gamma ligands such as 15-deoxy-Delta12,14-prostaglandin J2 and troglitazone significantly inhibited the growth of TE-7 cells but had less or no effect on growth of TE-1 cells. 15d-PGJ2 and troglitazone induced apoptosis in TE-7 cells but not in TE-1 cells. Troglitazone caused G1 cell cycle arrest and reduced ornithine decarboxylase activity (ODC) in TE-7 cells but not in TE-1 cells. Inhibition by PPAR-gamma ligands of growth of esophageal adenocarcinoma cells may thus be due to induction of apoptosis, G1 cell cycle arrest and reduction of ODC activity.

Adenocarcinoma↗

PubMed2000

Thiazolidinedione hepatotoxicity: a class effect?

Type 2 diabetes mellitus, which affects approximately 7% of the population, is a disease of relative insulin insufficiency manifested by insulin resistance in skeletal muscle, liver and adipose tissue. This results in increased hepatic glucose production with compensatory hyperinsulinaemia. The secondary hyperinsulinaemia is associated with an increased incidence of hepatocellular carcinoma and non-alcoholic steatohepatitis (NASH). It is estimated that insulin resistance is present in 50-70% of patients with NASH and that the incidence of NASH in type 2 diabetes is 60-80%. The prevalence of cirrhosis in established type 2 diabetes is as high as 10% and the prevalence of hepatitis C is 3-11%. It was in this setting that the insulin sensitisers were developed. The thiazolidinediones represent a significant and unique pharmacological breakthrough for the management of type 2 diabetes mellitus. The first of the drugs, troglitazone, proved to be hepatotoxic and has been withdrawn from the market. Two cases of hepatotoxicity of rosiglitazone have been reported. It remains unclear whether or not hepatotoxicity is a class effect or is related to the unique tocopherol side chain of troglitazone. However, it appears that the incidence of hepatotoxicity of rosiglitazone is much lower than that of troglitazone. It is not yet known if any hepatotoxicity occurs with pioglitazone.

Chemical and Drug Induced Liver Injury↗

PubMed2002

[Anti-inflammatory effect of peroxisome proliferator-activated receptor-gamma incultured human mesangial cells].

OBJECTIVE: To investigate whether peroxisome proliferator-activator receptor-gamma (PPARgamma) could retard the inflammatory challenge from human mesangial cells. METHODS: Based on the inflammatory mesangial cell model followed by IL-1beta, the levels of IL-6 and TNF-gamma in the supernatants were measured by enzyme-linked immunosorbant assay (ELISA). PPARgamma protein expression of human mesangial cell lines (HMCL) lysate was detected with Western blot. PPARgamma, IL-6 and TNF-gamma mRNA expression in HMCL lysate were measured by semi-quantitative RT-PCR assay. RESULTS: The levels of IL-6 and TNF-gamma in HMCL supernatants were dramatically increased when cultured HMCL were stimulated by IL-1beta (10 ng/ml). Protein and mRNA expressions of PPARgamma in IL-1beta challenge cells were significantly increased than observed in untreated cells. However, PPARgamma agonist troglitazone down-regulated mRNA and protein expression of PPARgamma from IL-1beta challenge HMCLs. PPARgamma agonists troglitazone, rosiglitazone, and 15-deoxy-Delta(12, 14)-prosglandin J(2) significantly decreased the upexpression of TNF-alpha and IL-6 in HMCL supernatants stimulated by IL-1beta. Furthermore, troglitazone down-regulated TNF-alpha and IL-6 mRNA expression levels of HMCLs. CONCLUSION: These data suggest that PPARgamma play an important role in response to inflammatory stress in mesangial cells. PPARgamma may prove to be a pharmacological target in glomerulonephritis.

Cells, Cultured↗

PubMed2003

Growth inhibition of pancreatic cancer cells through activation of peroxisome proliferator-activated receptor gamma/retinoid X receptor alpha pathway.

Peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand activated transcription factor, forms a heterodimer with retinoid X receptor alpha (RXRalpha), and its transcriptional activity is thought to be maximal in the presence of both PPARgamma and RXRalpha ligands. Though previous studies suggested that thiazolidinediones (TZDs), known as PPARgamma ligands, inhibit the growth of certain types of cancer cells, little is known about the growth inhibitory effects mediated though activation of PPARgamma/RXRalpha. We examined the effects of troglitazone (one type of TZDs) and 9-cis retinoic acid, a RXRalpha ligand, on activation of PPARgamma/RXRalpha and growth inhibition of human pancreatic cancer cell lines (AsPC1, BxPC3, PSN1, PCI6, Panc1, KMP-4, and KMP-7). Combined treatment of troglitazone and 9-cis retinoic acid showed enhanced transcriptional activity and enhanced antiproliferative effects. In PSN1 cells, G1 cell cycle arrest and apoptosis were induced by troglitazone and these effects were enhanced with additional 9-cis RA. Our findings suggest that activation of PPARgamma/RXRalpha pathway might play an important role in growth inhibition of pancreatic cancer cells via G1 cell cycle arrest and apoptosis. This nuclear receptor might be a suitable molecular target for treatment of pancreatic cancers.

Alitretinoin↗

PubMed2003

HER2 regulation of peroxisome proliferator-activated receptor gamma (PPARgamma) expression and sensitivity of breast cancer cells to PPARgamma ligand therapy.

Induction of terminal differentiation of cancer cells is an evolving novel therapeutic approach, and accordingly, peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand-stimulated transcription factor with differentiation-promoting activity and overexpressed in a variety of cancers, has emerged as one of the promising therapeutic targets. Because c-erbB family growth factor receptor 2 (HER2) overexpression is one of the most recognizable molecular dysfunctions in breast tumors, in the studies presented here, we explored the effect of HER2 overexpression on the status of PPARgamma expression and on the sensitivity of breast cancer cells to PPARgamma-ligand troglitazone-induced growth inhibition. We show that HER2 overexpression in MCF7 breast cancer cells enhanced the expression of PPARgamma-mRNA and -protein. Furthermore, PPARgamma expression was dramatically increased in 11 of 16 breast tumors as compared with the adjacent normal tissue. In addition, HER2 up-regulation resulted in a partial inhibition of transcriptional activity of the endogenous PPARgamma, stimulation to differentiation, and resistance to troglitazone-mediated inhibition of anchorage-independent growth of breast cancer cells. Conversely, down-regulation of HER2 by anti-HER2 monoclonal antibody Herceptin led to a decreased level of PPARgamma protein and sensitization of breast cancer cells to the inhibitory effects of troglitazone. In summary, these findings show for the first time that HER2 up-regulates PPARgamma expression and modulates the sensitivity of breast cancer cells to PPARgamma ligand therapy.

Antibodies, Monoclonal↗

PubMed2003

The effect of peroxisome proliferator-activated receptor-gamma ligand on urological cancer cells.

Peroxisome proliferator activator-receptor (PPAR)-gamma ligand induces growth arrest of cancer cells through apoptosis. In this study, we examined the effects of PPAR-gamma inhibitors on cell proliferation in renal cell carcinoma (RCC), bladder tumor (BT), and prostatic carcinoma (PC) cell lines. We investigated the inhibitory effect of PPAR-gamma ligands, troglitazone and 15-deoxy-Delta12,14-prostaglandin J2 (15dPGJ2) on RCC, BT and PC-derived cell lines using MTT assay and Hoechst staining. PPAR-gamma ligands (troglitazone and 15dPGJ2) induced the reduction of cell viability with the half-maximal concentration of growth inhibition of RCC, BT, and PC cell lines. Furthermore, counting cells at days 1, 2 and 3, clearly showed marked inhibition of cell proliferation using troglitazone and 15dPGJ2. All PPAR-gamma inhibitors stopped the growth of all RCC, BT and PC cells. Cells treated with PPAR-gamma inhibitors showed chromatin condensation, cellular shrinkage, small membrane-bound bodies (apoptotic bodies), and cytoplasmic condensation. These cellular changes were typically redundant characteristics of apoptosis. PPAR-gamma ligands may mediate potent antiproliferative effects against RCC, BT and PC cells through differentiation. Thus, PPAR-gamma may become a new target in treatment of urological tumors.

Antineoplastic Agents↗

PubMed2006

[Effects of peroxisome proliferators-activated receptor gamma agonists on transforming growth factor-beta1 and Smads signal pathway: experiment with rat renal fibroblasts].

OBJECTIVE: To study the effects of peroxisome proliferators-activated receptor gamma (PPARgamma) agonists on transforming growth factor (TGF)-beta1-induced fibrotic responses in renal fibroblasts, so as to investigate its effects in prevention of tubulointerstitial fibrosis. METHODS: Rat renal fibroblasts of the line NRK/49F were cultured and divided into groups. In group 1 TGFbeta1 of the concentrations of 0, 1, 2, 5, and 10 ng/ml was added and co-cultured for 24 h. In group 2 TGFbeta1 of the concentration of 5 ng/ml was added and co-cultured for 0, 6, 12, and 24 h respectively. Groups 3, 4, and 5 were pretreated with 10 micromol/L15d-PGJ2, PPARgamma ligand, 10 micromol/L troglitazone, agonist of, and 10 micromol/L ciglitazone, both PPARgamma agonists, respectively for 2 h, then treated with 5 ng/ml TGFbeta1. A blank control group was set up. The cultured cells were collected. RT-PCR was used to detect the mRNA expression of TGF-beta1-indued fibronectin (FN). Western blotting was used to detect the expression of TGF-beta1-induced FN, Smad, and phosphorylated Smad (p-Smad) proteins. RESULTS: TGF-beta1 enhanced the FN mRNA expression in a dose- and time-dependent manner. The FN mRNA expression of the 5 ng/ml TGF-beta1 group was 3.7 times that of the control group (P < 0.05). The FN mRNA expression of the 15d-PGJ2, troglitazone-, and ciglitazone-pretreated groups were lower than that of the 5 ng/ml TGF-beta1 group by 37.3%, 41.5%, and 22.7% respectively (all P < 0.05). The p-Smad2/3 protein expression levels of the TGF-beta1 group began to increase 15 minutes after stimulation, increased in a time-dependent manner, peaked 1 hour after, and began to decrease 2 hours later. However, the levels of protein expression of total Smad2 and Smad3 did not change significantly in all groups. Both 2 ng/ml TGFbeta1 and 5 ng/ml TGFbeta1 significantly induced the increase of protein expression of p-Smad2/3 (all P < 0.05). The levels of protein expression of p-Smad2 and p-Smad3 of the 5 ng/ml TGFbeta1 group were 3.42 and 0.97 times those of the 2 ng/ml TGFbeta1 (both P < 0.05). The levels of protein expression of p-Smad2/3 of the 15d-PGJ2, troglitazone-, and ciglitazone-pretreated groups were all significantly lower than that of the 5 ng/ml TGFbeta1 group by 61.2%, 53.0%, and 59.5% (all P < 0.05), However, there was no significant difference among different drug-treated groups (all P > 0.05). CONCLUSION: Possibly through abrogating TGF-beta1/Smads signaling pathway, PPARgamma agonists inhibit TGF-beta1-induced renal fibroblast extracellular matrix synthesis and may play a potential role in preventing tubulointerstitial fibrosis as a novel approach to prevent the progress of end stage renal dysfunction.

Animals↗

PubMed2006

[PPARgamma1 overexpression on caveolin-1 expression of Raw264.7 cells].

OBJECTIVE: To investigate the effect of PPARgamma1 gene overexpression on caveolin-1 mRNA and protein expressions in a murine macrophage cell line Raw264.7. METHODS: Replication-deficient recombinant adenovirus expression vector of PPARgamma1 was constructed using the AdEasy system. Raw264.7 cells were randomly treated as follows: P group (PPARgamma1 gene overexpression), T group (Troglitazone 40 micromol/L in DMSO), PT group (PPARgamma1 gene overexpression and Troglitazone) and control group. Changes of PPARgamma1 and caveolin-1 at mRNA and protein levels were investigated. RESULTS: Caveolin-1 expression can be detected by RT-PCR in Raw264.7, by immunocytochemistry method in cell and nuclear membrane but not by immunoblotting at protein level. Caveolin-1 expression at mRNA and protein levels in Raw264.7 were significantly higher in P, T and PT groups compared to control group and the expression was also significantly higher in PT group than that in P group and T group (P < 0.05). PPARgamma expression was significantly increased in PT group and P group where remained unchanged in T group compared to control group. CONCLUSION: PPARgamma1 overexpression can upregulate caveolin-1 expression in macrophages. Troglitazone upregulated caveolin-1 expression in the absence of increased PPARgamma1 expressions at mRNA and protein levels.

Adenoviridae↗

PubMed2004

Effects of insulin sensitizers on plaque vulnerability associated with elevated lipid content in atheroma in ApoE-knockout mice.

Acute coronary syndromes are generally precipitated by rupture of lipid-laden, relatively acellular, vulnerable atherosclerotic plaques with thin fibrous caps. We investigated whether a high-fat diet alters insulin sensitivity and whether insulin sensitizers (troglitazone and rosiglitazone) alter the composition of otherwise lipidladen atherosclerotic plaques in mice deficient in apolipoprotein E (ApoE). ApoE-knockout mice were fed a high-fat (n=30) or standard chow (n=10) diet for two weeks. Thereafter, those fed the high-fat diet were treated with troglitazone (n=10), rosiglitazone (n=10) or no drug (n=10) for 16 weeks beginning at 8 weeks of age. Carbohydrate metabolism was assessed with intraperitoneal glucose tolerance tests and insulin tolerance tests. Plaque composition was characterised with confocal laser scanning microscopy. The high-fat diet induced insulin resistance in the absence of weight gain. Compared with control animals on the high-fat diet, animals given troglitazone (400 mg/kg/day) or rosiglitazone (4 mg/kg/day) had significantly less area under the curve (AUC) for insulin ( p<0.05) and glucose disposal ( p<0.05). Despite significant increases in insulin sensitivity with drug treatment, no change in HDL-cholesterol and triglyceride levels, nor reduction in atheroma size or lipid content was noted. Thus, improvement in insulin resistance induced by a high-fat diet in this animal model of vasculopathy did not alter plaque composition.

Animals↗

PubMed2007

Adipokines regulate systemic insulin sensitivity in accordance to existing energy reserves.

Adipocyte-derived hormones, including adiponectin and leptin, regulate systemic insulin sensitivity in accordance to existing triglyceride reserves. Leptin levels reflect existing fat mass and the adipokine negatively regulates insulin action in adipose tissue. Adiponectin, on the other hand, preserves insulin sensitivity via transient increments of AMPK activity and its circulating levels seem to reflect the adipogenic capacity of adipose tissue. Because adiponectin and insulin synergize in their postprandial actions, it seems evident that inadequate adiponectin production causes systemic insulin resistance. As a consequence, compounds that either increase adiponectin production or mimic its actions can be considered as an efficient strategy for improving insulin sensitivity in type 2 diabetics. We have previously shown that troglitazone and metformin exert opposing actions on adiponectin production, indicating that combined use of troglitazone and metformin is a more efficient strategy as compared to metformin treatment. Here, we will provide additional arguments which stress the need for a fixed dose of troglitazone and metformin in order to preserve endogenous adiponectin production. Finally, after delineating critical nodes of insulin and adipokine crosstalk, putative pathways are proposed by which adiponectin and leptin cooperatively regulate systemic insulin sensitivity in accordance to existing fat mass. By amplifying insulin action downstream of PI3K, leptin exerts negative feedback on insulin signaling via mTOR-dependent pathways that target IRS-1 for serine phosphorylation and protein degradation. Adiponectin-mediated increments of AMPK activity, on the other hand, may attenuate mTOR signaling, leading to the preservation of insulin sensitivity in periods of increased nutrient availability. Considering that leptin and adiponectin are inversely associated with BMI, the proposed model provides a plausible explanation for the observation that leptin exerts strong negative feedback on systemic insulin sensitivity, while increasing PIP3 availability.

Adiponectin↗

PubMed2005

Agonists of peroxisome proliferator-activated receptor-gamma attenuate the Abeta-mediated impairment of LTP in the hippocampus in vitro.

The data we present here suggest that agonists of peroxisome proliferator-activated receptor-gamma (PPARgamma) can attenuate the effects of beta-amyloid peptide (Abeta). Alzheimer's disease is associated with elevated levels of Abeta, and enhanced expression of PPARgamma. In this study, we determined that application of Abeta([1-40]) could impair hippocampal post-tetanic potentiation (PTP) and long-term potentiation (LTP) in vitro. We investigated the effects of PPARgamma agonists; troglitazone, ciglitazone and 15-deoxy-delta(12,14) prostaglandin J2 (PGJ2) on synaptic transmission and plasticity in area CA1. Both ciglitazone and PGJ2 increased baseline synaptic transmission significantly, without altering paired-pulse facilitation. PGJ2 produced a significant reduction in LTP, whereas ciglitazone and troglitazone had no significant effect. In addition, prior application of each ligand attenuated the previously observed Abeta([1-40])-mediated impairment of LTP. The effect of troglitazone on the Abeta([1-40])-mediated impairment of LTP was not reversed by the PPARgamma antagonist, GW-9662. These findings demonstrate that PPARgamma agonists attenuate the effects of Abeta on LTP, and support the potential use of these agents to alleviate the symptoms of Alzheimer's disease. We also suggest that PPARgamma agonists may regulate expression of hippocampal LTP in vitro.

Amyloid beta-Peptides↗

PubMed1999

Activation of PPARgamma inhibits cell growth and induces apoptosis in human gastric cancer cells.

We investigated the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and the role of PPARgamma in cell growth in human gastric cancer cells. Reverse transcription-polymerase chain reaction, Northern blot and Western blot analyses showed that a human gastric cancer cell line, MKN45, expressed PPARgamma mRNA and protein. Luciferase assay in MKN45 cells showed that troglitazone, a selective ligand for PPARgamma, transactivated the transcription of a peroxisome proliferator response element-driven promoter. Troglitazone or pioglitazone, selective ligands for PPARgamma, inhibited the growth of MKN45 cells in a dose-dependent manner. Co-incubation of MKN45 cells with troglitazone induced DNA ladder formation. These results suggest that human gastric cancer cells express PPARgamma and that activation of PPARgamma inhibits cell growth and induces apoptosis in gastric cancer cells.

Acyl-CoA Oxidase↗

PubMed1997

Thiazolidinediones.

The thiazolidinediones are a unique class of compounds that exert direct effects on the mechanisms of insulin resistance and result in improved insulin action and reduced hyperinsulinemia. Troglitazone is the first of these compounds to be approved for use in humans and has the potential not only to reduce glycemia and insulin requirements in type II diabetes but to improve other components of the insulin resistance syndrome including dyslipidemia, hypertension, and accelerated cardiovascular disease. Such compounds also hold promise for the prevention of type II diabetes and for the treatment of other insulin-resistant states including polycystic ovary disease. In addition to the novel mechanism of action through binding and activation of PPARs, troglitazone has other unique advantages, including once-a-day administration, a low incidence of minor side effects, no known drug interactions, hepatic metabolism and secretion, and potent antioxidant properties. Thiazolidinedione compounds such as troglitazone provide an important additional resource for the health care provider in the management of type II diabetes and other components of the insulin resistance syndrome.

Diabetes Mellitus, Type 2↗

PubMed2005

Cytokines and peroxisome proliferator-activated receptor gamma ligand regulate phagocytosis by pancreatic stellate cells.

BACKGROUND & AIMS: Pancreatic stellate cells have been characterized as the major source of extracellular matrix and cytokine production in the pancreas. This study showed that pancreatic stellate cells have a phagocytic function. METHODS: The morphological features of periacinar phagocytic cells were investigated by immunohistochemically staining serial sections of the pancreas from male WBN/Kob rats and an animal model of acute pancreatitis for glial fibrillary acidic protein and alpha-smooth muscle actin. Pancreatic stellate cells were assayed for phagocytic activity by incubating them with senescent polymorphonuclear neutrophils or fluorescence-labeled latex beads in the presence or absence of cytokines, growth factors, and peroxisome proliferator-activated receptor gamma ligand. The role of CD36 and peroxisome proliferator-activated receptor gamma in phagocytosis was investigated by blocking endogenous CD36 and peroxisome proliferator-activated receptor gamma activity with anti-CD36 antibody and peroxisome proliferator-activated receptor gamma small interfering RNAs, respectively. RESULTS: Phagocytic cells were observed in areas of inflammation, and they were identical to the glial fibrillary acidic protein-positive and alpha-smooth muscle actin-positive cells, thus suggesting that they were pancreatic stellate cells. Aged polymorphonuclear neutrophils were ingested into the cytoplasm of the pancreatic stellate cells. Transforming growth factor beta, tumor necrosis factor alpha, and interleukin 1beta decreased the phagocytic activity of pancreatic stellate cells, whereas troglitazone induced a dose-dependent increase in both phagocytic activity and expression of CD36. Blockade of CD36 reduced troglitazone-induced phagocytosis. Silencing of the peroxisome proliferator-activated receptor gamma gene decreased phagocytosis and expression of CD36. CONCLUSIONS: Pancreatic stellate cells act as resident phagocytic cells, and CD36 promotes troglitazone-induced phagocytic activity via peroxisome proliferator-activated receptor gamma transactivation. Because phagocytosis is essential to limit the extent of inflammation, enhancement of phagocytic activity may provide an important approach to the treatment of pancreatic diseases.

Animals↗

PubMed1996

New therapeutic agents for the treatment of NIDDM.

Non-insulin dependent diabetes mellitus (NIDDM) is a heterogeneous disease with a world wide growing prevalence. Insulin resistance, particularly an impaired action of insulin on the glucose metabolism in skeletal muscles, has been assumed to be the primary factor in the pathophysiology of this disease and it is observed years before the precipitation of overt NIDDM. Almost half of the patient population already suffer from macroangiopathy at the time of diagnosis and the overall mortality rate primarily due to coronary heart disease is approximately 2.5 times higher as compared with healthy individuals. It can be assumed that these complications are closely linked to insulin resistance and a result of the "metabolic syndrome". Insulin resistance is obviously a strong predictive factor for NIDDM, but it is not sufficient for the development of overt diabetes. For the precipitation of overt NIDDM an impaired function of the pancreatic B-cells is also required which seems to be a consequence of the excessive demand for insulin in insulin resistant individuals. Increasing knowledge about the pathophysiology of type II diabetes led to completely new approaches for the treatment of this disease. In this context compounds exhibiting an effect on the peripheral insulin resistance are of special interest and the promising results of clinical trials with troglitazone, a thiazolidinedione derivative, can be regarded as a proof of this newly discovered therapeutic concept. Since the primary effect of this compound is to improve the response of peripheral target tissues to insulin, this should result in a better glycemic control and a concomitant decrease of the circulating insulin levels. Although troglitazone can be regarded as a first approach to a new therapeutic regimen, we are only at the beginning of a new and very exciting area. Future research efforts should be focussed on the discovery of therapeutic agents with higher potency and the fact that not all patients can be treated with troglitazone (non-responder) leads to the assumption that different patient populations may require different therapeutic agents. The effect of insulin sensitizers on insulin resistance and hyperinsulinemia may be of important consequence since insulin resistance has been linked to an increased risk of coronary artery disease as a major cause of mortality in NIDDMs.

Animals↗

PubMed2002

Octanoate attenuates adipogenesis in 3T3-L1 preadipocytes.

Preadipocytes exposed to octanoate accumulate less lipid than cells exposed to long-chain fatty acids. This effect of octanoate involves significant attenuation of expression of key adipogenic transcription factors, including peroxisome proliferator-activated receptor (PPAR)gamma, steroid regulatory binding element protein (SREBP)-1c and CCAAT element binding protein (C/EBPalpha) at both the mRNA and protein levels. Expression of differentiation markers, including adipocyte fatty acid binding protein (ALBP), glycerol-3-phosphate dehydrogenase (GPDH) and leptin, was also significantly diminished by octanoate. However, octanoate did not prevent the decrease in preadipocyte factor-1 (Pref-1) expression that occurs during adipogenesis, nor did it inhibit the early induction of C/EBPbeta,delta. Treatment with synthetic PPARgamma ligands partially offset the inhibitory effect of octanoate on differentiation. Ectopic expression of PPARgamma2 in 3T3-L1 cells partially restored lipid accretion and GPDH activity in octanoate-treated cells. Adding octanoate together with troglitazone attenuated the effects of troglitazone on adipocyte differentiation in both normal 3T3-L1 cells and engineered 3T3-L1 cells that expressed ectopic PPARgamma2, implying that octanoate might compete against troglitazone for its binding to PPARgamma. These results suggest that octanoate may block adipogenesis at least in part by its influence on the expression/activation of PPARgamma.

3T3 Cells↗

PubMed2002

Linkage between retinoid and fatty acid receptors: implications for breast cancer prevention.

Certain dietary retinoids and polyunsaturated fatty acids (PUFAs) consistently inhibit progression of mammary carcinogenesis both in animal studies and cell culture, but clinically, their effect is inconsistent. New evidence of synergistic interaction between the nuclear receptors for the two groups of nutritional agents suggests that appropriate selective ligands from each group might be combined in breast cancer chemoprevention studies. Peroxisome proliferator-activated receptor (PPAR) gamma is a nuclear receptor that is activated by PUFAs, eicosanoids and antidiabetic agents such as troglitazone. Such activation can cause growth inhibition in human mammary cancer cells in culture and the effect is enhanced by ligands of retinoic acid receptor (RAR) and retinoid X receptor (RXR). In mouse mammary tissue in organ culture, an RXR-selective ligand has been shown to enhance the effect of troglitazone in suppressing carcinogen-induced pre-neoplastic changes. A PPAR/RXR heterodimer is involved in tumour growth inhibition and has been shown to bind directly to nuclear oestrogen response elements (ERE) independently of oestrogen receptor (ER) activity. A combination of an RXR-selective retinoid with either troglitazone or else a long-chain n-3 PUFA, is proposed for a short-term study in postmenopausal women after primary surgery for intraductal breast cancer. The resulting activation of PPAR/RXR expression may increase response to retinoid administration, especially in the presence of obesity and insulin resistance, because of the ability of PPAR gamma ligands to reduce insulin-like growth factor I (IGF-I) concentrations. Serial core biopsies of breast tissue over a short term are proposed to identify changes in phenotype, which may influence progression to invasiveness. In addition to cytomorphological criteria, expression of ER alpha and beta, RAR alpha and beta, and IGF-I receptor in the nucleus should be examined.

Animals↗