Knocking Out Peroxisome Proliferator-Activated Receptor (PPAR) α Inhibits Radiation-Induced Apoptosis in the Mouse Kidney through Activation of NF-κB and Increased Expression of IAPs

Objective. High-fat-diet- (HFD-) induced hepatic cell apoptosis is common in mice with nonalcoholic fatty liver disease (NAFLD). We aim to investigate the effect of Ginsenoside Rb1 (GRb1) on hepatocyte apoptosis. Methods. C57BL/6J mice with HFD were used to induce a liver-injured model with cell apoptosis. In addition, GRb1 was used to treat HFD-induced apoptosis in a liver with or without inhibitor of peroxisome proliferator-activated receptor γ (PPAR-γ). Results. Compared with C57BL/6J mice with common chow, there are downregulated PPAR-γ but upregulated cell apoptosis in the liver of mice with HFD. Furthermore, GRb1 elevated the hepatic PPAR-γ level and suppressed hepatocytic apoptosis. However, GW9662 abolished the effects of GRb1 on apoptosis in the liver. Conclusions. GRb1 alleviated HFD-induced apoptosis of hepatocytes of mice via PPAR-γ.

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Cotreatment with Pioglitazone, a Synthetic Ligand for Peroxisome Proliferator-Activated Receptor γ (PPARγ), Enhances Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis of Human Leukemia Cells.

Blood ◽

10.1182/blood.v104.11.4377.4377 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4377-4377

Author(s):

Joo-In Park ◽

Hoon Han ◽

Ji-Seon Han ◽

Hyuk-Chan Kwon ◽

Jin-Yeong Han ◽

...

Keyword(s):

Cell Growth ◽

Cell Line ◽

Myeloid Cell ◽

Leukemia Cells ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Myeloid Cell Line ◽

Synthetic Ligand ◽

Induced Apoptosis ◽

Acute Myeloid

Abstract Imatinib (STI571, Glivec) is the choice treatment for Bcr/Abl-positive malignancies. Emergence of resistance to Imatinib warrants the exploration of novel well-tolerated anticancer agents. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor family, which mainly associates with the adipocyte differentiation, but also appears to facilitate cell differentiation or apoptosis in certain malignant cells. Previous studies imply that the PPARγ activation pathway may be a possible intervention mode for treatment of leukemia, which is resistant to imatinib (STI571). In this study, we investigated the effects of pioglitazone, a synthetic ligand for PPARg, on the cell growth and TRAIL-induced apoptosis in a novel imatinib (STI571) resistant acute myeloid cell line (SR-1), which we have established from an STI571 resistant blast crisis patient, as well as HL-60 cells. HL-60 and SR-1 cells are relatively resistant to TRAIL-induced apoptosis. Pioglitazone alone inhibited the cell growth of SR-1 and HL-60 cells, but did not induce the apoptosis of these cell lines. However, simultaneous exposure of cells to 100 ng/ml TRAIL with either 25 μM pioglitazone or 50 μM piogliazone resulted in a striking increase in apoptosis. To clarify the mechanism of pioglitazone to sensitize the leukemia cells to TRAIL-induced apoptosis, we investigated the change of the proteins related to cell cycle and apoptosis by western blot. As results, we observed the significant decrease of X-linked inhibitor of apoptosis (XIAP) and the increased expression of p21 by cotreatment of pioglitazone with TRAIL. Taken together, these findings indicate that pioglitazone may have promising activity in augmenting TRAIL-induced apoptosis of human acute leukemia cells including the imatinib (STI571) resistant acute myeloid cell line.

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Increased expression of the lipocalin 24p3 as an apoptotic mechanism for MK886

Biochemical Journal ◽

10.1042/bj20021696 ◽

2003 ◽

Vol 372 (1) ◽

pp. 203-210 ◽

Cited By ~ 33

Author(s):

Zhimin TONG ◽

Xuli WU ◽

James P. KEHRER

Keyword(s):

Protein Expression ◽

Protein S ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Mrna And Protein Expression ◽

Induced Apoptosis ◽

Inhibitor Of Protein Synthesis ◽

New Protein ◽

Apoptotic Mechanism

MK886, a strong proapoptotic agent, is an inhibitor of 5-lipoxygenase (LOX) through binding to the 5-LOX-activating protein (FLAP). Although MK886-induced apoptosis is through a FLAP-independent pathway, the precise mechanisms are not understood. In the present study, a possible role of 24p3, a lipocalin, in MK886-induced apoptosis was investigated. Exposure of murine prolymphoid progenitor cells (FL5.12) to 20 μM MK886 for 16 h dramatically increased 24p3 mRNA and protein expression. Induction could also be achieved with another FLAP inhibitor, MK591. The induction of 24p3 by MK886 was dose- and time-dependent. The up-regulated 24p3 mRNA expression by MK886 was enhanced a further 3.1-fold by WY14643, an activator of peroxisome-proliferator-activated receptor α, whereas ciglitazone, an activator of peroxisome-proliferator-activated receptor γ attenuated the MK886-induced 24p3 expression by more than 50%. Neither WY14643 nor ciglitazone alone had any effect on the expression of 24p3. The induction of 24p3 by MK886 was dependent on the synthesis of new protein(s), since cycloheximide, an inhibitor of protein synthesis, prevented this effect. In all cases, including the inhibition of MK886-induced 24p3 protein expression by stable transfection with antisense cDNA of 24p3, the extent of apoptosis closely paralleled 24p3 levels. Apoptosis induced by MK886, or enhanced by WY14643, was accompanied by the cleavage and activation of caspase-3. The overexpression of bcl-2 or bcl-xL in FL5.12 cells inhibited apoptosis induced by MK886 as well as the enhancement of apoptosis by WY14643. Thus 24p3 is an MK886-inducible gene and may play an important role in MK886-induced apoptosis.

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