Transcriptional Regulation of Cidea, Mitochondrial Cell Death-inducing DNA Fragmentation Factor α-Like Effector A, in Mouse Liver by Peroxisome Proliferator-activated Receptor α and γ

Abstract

Cidea (cell death-inducing DNA fragmentation factor ␣-like effector A), a member of a novel family of proapoptotic proteins, is expressed abundantly in the brown adipose tissue of the mouse. Although Cidea mRNA is not detectable in the mouse liver, we now show that peroxisome proliferator-activated receptor (PPAR) ␣ ligands Wy-14,643 and ciprofibrate increase the Cidea mRNA level in a PPAR␣-dependent manner, whereas Cidea induction in liver by PPAR␥ overexpression is PPAR␣ independent. Increase in Cidea mRNA content in liver did not alter the expression of uncoupling protein 1 (Ucp1) gene, which regulates thermogenesis, lipolysis, and conservation of energy. Although Cidea is considered to be a proapoptotic factor, Cidea induction in liver did not result in increased apoptosis. To elucidate the mechanism by which PPAR␣ and PPAR␥ regulate Cidea gene expression in the liver, we analyzed the promoter region of the Cidea gene. Three putative peroxisome proliferator response elements (PPREs) are found in the Cidea gene promoter. Transactivation, gel-shift, and chromatin immunoprecipitation assays indicated that the proximal PPRE in Cidea gene (Cidea-PPRE1 at ؊680/؊668) is functional for both PPAR␣ and -␥. We conclude that Cidea is a novel target gene for both PPAR␣ and -␥ in the liver where these two transcription factors utilize the same PPRE region for dual regulation. The induction of Cidea in liver with these PPAR␣ and -␥ agonists suggests a possible role for Cidea in energy metabolism and a less likely role in hepatocyte apoptosis.

Hepatitis C virus infection and apoptosis

“…NS2 is a transmembrane protein localized in the endoplasmatic reticulum (ER) that directly binds and inhibits CIDE-B-induced apoptosis (cell death-inducing DFF45 (DNA-fragmentation-factor)-like effector [93] ). CIDE-B-induced apoptosis is assumed to occur via the mitochondrial pathway [94,95] .…”

Characterization of the human CIDEA promoter in fat cells

“…The murine CIDEA promoter was recently described in liver cells 7 and we therefore compared the 5 0 flanking region of the human CIDEA with the murine promoter. Interestingly, the murine sequence contains a long (approx 745-bp) 5 0 UTR from the TSS to the ATG, whereas the corresponding human sequence is only 14-bp.…”

“…7 Moreover, PPARg is essential for adipocyte differentiation and regulates CIDEA expression in murine liver. 7 We therefore analyzed the putative human promoter CIDEA sequence for possible PPRE elements and tested the effect of the PPARg agonist BRL49653 on murine adipocytes transfected with the CIDEA promoter. By bioinformatic analysis, we could not detect any PPREs in the human sequence.…”

“…To date only the transcriptional regulation of the murine CIDEA promoter in liver has been characterized. 7 In this study, we characterized the human CIDEA promoter in human fat cells and 3T3-L1 cells and studied the effect of TNF-a on promoter activity. Furthermore, several SNPs in the 5 0 flanking region of human CIDEA have recently been described 6 and we assessed the effect of the three most common haplotypes in this region on the transcriptional regulation of CIDEA.…”

Adipogenic potential of stem cells derived from rabbit subcutaneous and visceral adipose tissue in vitro

“…Perilipin and Cidea are down-regulated at the transcriptional level by PPARγ, demonstrating the importance of this mechanism during the formation and growth of lipid droplets into adipocytes (Arimura et al 2004;Viswakarma et al 2007). Based on the achieved results, we suspect lack of activation of PPARγ for visceral and their relevant supernatant groups, which in turn lower their adipogenic potential.…”