Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome proliferator

Abstract

X-linked adrenoleukodystrophy (X-ALD) is a demyelinating disease due to mutations in the ABCD1 (ALD) gene, encoding a peroxisomal ATP-binding cassette transporter (ALDP). Overexpression of adrenoleukodystrophy-related protein, an ALDP homologue encoded by the ABCD2 (adrenoleukodystrophy-related) gene, can compensate for ALDP deficiency. 4-Phenylbutyrate (PBA) has been shown to induce both ABCD2 expression and peroxisome proliferation in human fibroblasts. We show that peroxisome proliferation with unusual shapes and clusters occurred in liver of PBA-treated rodents in a PPARα-independent way. PBA activated Abcd2 in cultured glial cells, making PBA a candidate drug for therapy of X-ALD. The Abcd2 induction observed was partially PPARα independent in hepatocytes and totally independent in fibroblasts. We demonstrate that a GC box and a CCAAT box of the Abcd2 promoter are the key elements of the PBA-dependent Abcd2 induction, histone deacetylase (HDAC)1 being recruited by the GC box. Thus, PBA is a nonclassical peroxisome proliferator inducing pleiotropic effects, including effects at the peroxisomal level mainly through HDAC inhibition.

Docosahexaenoic acid mediates peroxisomal elongation, a prerequisite for peroxisome division

“…Overexpression of Pex11pb gives rise to high levels of peroxisome proliferation (Kobayashi et al, 2007;Li and Gould, 2002;Schrader et al, 1998), similar to treatment with peroxisome proliferators such as clofibrate (Crane and Masters, 1986) and 4-phenylbutyrate (Gondcaille et al, 2005;Kemp et al, 1998;Wei et al, 2000). Ectopic expression of a dominant-negative form of DLP1 results in the accumulation of elongated peroxisomes (Koch et al, 2003;Li and Gould, 2003;Tanaka et al, 2006), similar to that observed in a dlp1 mutant CHO cell line (Tanaka et al, 2006) and in fibroblasts from patients with impaired DLP1 function .…”

Functional rescue of mutant ABCA1 proteins by sodium 4-phenylbutyrate

“…The ABCA1 expression vectors used here are driven by a heterologous CMV promoter and histone deacetylase inhibitors are known to exert a transcriptional effect on the CMV promoter ( 24 ). Functional improvements for other mutant proteins by 4-PBA have been attributed to increased expression ( 8,10,25 ), which suggests a global effect on transcription. Interestingly, we observed an opposite transcriptional effect of 4-PBA in fi broblasts harboring mutant ABCA1 proteins.…”

Proliferation and fission of peroxisomes — An update

“…BM 15766, an inhibitor of cholesterol biosynthesis at the 7-dehydrocholesterol-Δ7-reductase step, was shown to induce peroxisome proliferation without significantly increasing fatty acid β-oxidation enzyme levels, thus implying a PPARα-independent signal transduction. Phenylbutyrate was also shown to induce peroxisome proliferation in the absence of the nuclear receptor PPARα, although a potential role for PPARγ has not been ruled out [5,52,154]. In a high content screen probing more than 15,000 drugs, 10 new compounds were reported to induce peroxisome proliferation in HepG2 cells, which are supposed to be refractory to PPARα-mediated peroxisome proliferation [148].…”