Retinoid X receptor agonist elevation of serum triglycerides in rats by potentiation of retinoic acid receptor agonist induction or by action as single agents 2 2Abbreviations: RARs, retinoic acid receptors; and RXRs, retinoid X receptors.

Standeven, Andrew M.; Thacher, Scott M.; Yuan, Yang-Dar; Escobar, Maria; Vidyasagar, V.; Beard, Richard L.; Chandraratna, Roshantha A.S.

doi:10.1016/s0006-2952(01)00803-6

Cited by 32 publications

(23 citation statements)

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“…Each retinoid was applied at receptor-saturating concentrations (K d values in Table 1). TTNPB is an RAR-selective retinoid and AGN194204 is an RXRselective retinoid (Strickland et al, 1983;Standeven et al, 2001). As shown in Figure 1b, AGN193198 more efficiently suppresses cell number than TTNPB or AGN194204.…”

Section: Agn193198 Inhibits Pancreatic Cancer Cell Proliferation Morementioning

confidence: 98%

A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis

2005

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acid), on pancreatic cancer cell proliferation and survival. AGN193198 treatment reduces BxPC-3 cell proliferation more efficiently than high-affinity retinoid acid receptor (RAR)-or retinoid X receptor (RXR)-selective retinoids. Moreover, AGN193198 does not activate transcription from RAR or RXR response elements and its effects on cell survival are not reversed by treatment with RAR-or RXR receptorselective antagonists. These results suggest that the AGN193198-dependent inhibition of BxPC-3 cell function is not mediated via activation of the classical retinoid receptors. Cell cycle analysis of AGN193198-treated BxPC-3 cells indicates that AGN193198 causes accumulation of cells in G2/M. This change is associated with a marked reduction in regulators of S (cyclin A, cyclindependent kinase (cdk)2), G2/M (cyclin B1, cdk1, cdc25c) and G1 (cyclin D1, cyclin E, cdk2, cdk4) phase, and an increase in p21 and p27 level. Kinases assays reveal that cdk1, cdk2 and cdk4 activity are suppressed in AGN193198-treated cells. In addition, reduced cell proliferation is associated with enhanced procaspase (3, 8 and 9) and PARP cleavage. Z-VAD-FMK, a pancaspase inhibitor, inhibits AGN193198-dependent caspase activation and attenuates cell death. Z-VAD-FMK inhibits PARP cleavage, but does not alter the AGN193198-dependent reduction in cell cycle regulatory protein expression and activity, suggesting that caspase activation and suppression of cell cycle regulatory protein levels are independent processes. AGN193198 produces similar responses in other pancreatic cancer cell lines including AsPC-1 and MIA PaCa-2. These studies suggest that AGN193198 may be useful for the treatment of pancreatic cancer.

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Section: Agn193198 Inhibits Pancreatic Cancer Cell Proliferation Morementioning

confidence: 98%

A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis

2005

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“…Lauric acid was obtained from Fluka (Buchs, Switzerland). Radiolabeled [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]-lauric acid (1.85 GBq/ mmol) was from Amersham Biotech (Amersham, UK). Culture media and glutamine were purchased from Gibco BRL (Cergy-Pontoise, France), sera from Perbio (France), insulin from Sigma and hydrocortisone hemisuccinate from Upjohn Pharmacia (Guyancourt, France).…”

Section: Chemicalsmentioning

confidence: 99%

CYP4A11 is repressed by retinoic acid in human liver cells

et al. 2006

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CYP4A11, the major fatty acid x-hydroxylase in human liver is involved in the balance of lipids, but its role and regulation are both poorly understood. We studied the effects of retinoids on the regulation of CYP4A11 in the human hepatoma cell line HepaRG. Treatment of HepaRG cells with all-trans-retinoic acid resulted in a strong decrease in CYP4A11 gene expression and apoprotein content and, furthermore, was associated with a 50% decrease in the microsomal lauric acid hydroxylation activity. Such a strong suppression of CYP4A11 expression by retinoids could have a major impact on fatty acid metabolism in the liver.

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“…However, the elevations in the serum were not as pronounced by 7 days of treatment. The differences in mice and rats may be due to adaptation of the periphery in mice, with an increase in the ability to clear triglycerides produced in the liver, perhaps by modulation of lipoprotein lipase activity (28).…”

Section: Discussionmentioning

confidence: 99%

Distinct Mechanisms of Glucose Lowering by Specific Agonists for Peroxisomal Proliferator Activated Receptor γ and Retinoic Acid X Receptors

Hansen

et al. 2005

Journal of Biological Chemistry

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Agonists for the nuclear receptor peroxisomal proliferator-activated receptor-␥ (PPAR␥) and its heterodimeric partner, retinoid X receptor (RXR), are effective agents for the treatment of type 2 diabetes. To gain insight into the antidiabetic action of these compounds, we treated female Zucker diabetic rats (ZFF) with AGN194204, which we show to be a homodimer-specific RXR agonist, or the PPAR␥ agonist, troglitazone. Hyperinsulinemic-euglycemic clamps in ZFF showed that troglitazone and AGN194204 reduced basal endogenous glucose production (EGP) ϳ30% and doubled the insulin suppression of EGP. AGN194204 had no effect on peripheral glucose utilization, whereas troglitazone increased insulin-stimulated glucose utilization by 50%, glucose uptake into skeletal muscle by 85%, and de novo skeletal muscle glycogen synthesis by 300%. Troglitazone increased skeletal muscle Irs-1 and phospho-Akt levels following in vivo insulin treatment, whereas AGN194204 increased hepatic Irs-2 and insulin stimulated phospho-Akt in liver. Gene profiles of AGN194204-treated mouse liver analyzed by Ingenuity Pathway Analysis identified increases in fatty acid synthetic genes, including Srebp-1 and fatty acid synthase, a pathway previously shown to be induced by RXR agonists. A network of down-regulated genes containing Foxa2, Foxa3, and G-protein subunits was identified, and decreases in these mRNA levels were confirmed by quantitative reverse transcription-PCR. Treatment of HepG2 cells with AGN194204 resulted in inhibition of glucagon-stimulated cAMP accumulation suggesting the G-protein down-regulation may provide an additional mechanism for hepatic insulin sensitization by RXR. These studies demonstrate distinct molecular events lead to insulin sensitization by high affinity RXR and PPAR␥ agonists. Thiazolidinediones (TZDs)2 and other compounds that bind and enhance the transcriptional activity of peroxisomal proliferator-activated receptor ␥ (PPAR␥) have proven to be effective treatments for insulin-resistant diabetes (1, 2). The increase in insulin sensitivity that occurs after treatment with TZDs likely involves actions in adipose tissue, muscle, and liver (3-6), although the complete set of genes that are modulated to result in improved insulin action by TZDs remains unknown. The heterodimeric partner of PPAR␥ receptor is the retinoid X receptor (RXR) (7). In overexpression studies, binding of ligand to the RXR receptor has been reported to result in the recruitment of coactivators to the RXR/PPAR␥ heterodimer (8) and increased transcription from idealized peroxisomal proliferator response elements (PPREs). Some RXR activators can increase transcription of genes in vitro that are also increased by PPAR␥ ligands (8, 9). Like TZDs, RXR agonists can differentiate 3T3-L1 adipocytes (10), and administration of specific, high affinity RXR agonists to hyperglycemic ob/ob (11) and db/db (12) mice is effective in lowering glucose levels. These results have led to the hypothesis that the antihyperglycemic effect of RXR agonists is due to tra...

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Retinoid X receptor agonist elevation of serum triglycerides in rats by potentiation of retinoic acid receptor agonist induction or by action as single agents 2 2Abbreviations: RARs, retinoic acid receptors; and RXRs, retinoid X receptors.

Cited by 32 publications

References 32 publications

A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis

A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis

CYP4A11 is repressed by retinoic acid in human liver cells

Distinct Mechanisms of Glucose Lowering by Specific Agonists for Peroxisomal Proliferator Activated Receptor γ and Retinoic Acid X Receptors

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