title: Bezafibrate induces FALDH in human fibroblasts; implications for Sjögren-Larsson syndrome.
abstract: Sjögren-Larsson syndrome (SLS) is caused by a deficiency of fatty aldehyde dehydrogenase (FALDH), encoded by the ALDH3A2 gene. In animal studies, the expression of the murine ortholog of FALDH, has been shown to be under the control of peroxisome proliferator-activated receptor alpha (PPARalpha). In the present study, we investigated whether the hypolipidemic drug bezafibrate, which is a pan-agonist of all PPAR-isoforms, might induce FALDH activity in human fibroblasts of control subjects and SLS patients that still have some residual FALDH activity. Our results show that FALDH activity was induced 1.4-fold after a 3-day treatment with 800 microM bezafibrate in fibroblasts of control subjects. Interestingly, in fibroblasts of two SLS patients homozygous for the p.R228C substitution, FALDH activity could be induced to 37% of control values by bezafibrate treatment. mRNA analysis in fibroblasts of these patients also revealed a mean 1.8-fold induction of FALDH mRNA after bezafibrate treatment. No induction was observed in fibroblasts of patients with mutations that cause instability of FALDH mRNA or that result in a protein without any residual activity. These data suggest that bezafibrate treatment could be effective in patients with expression of FALDH protein and some residual enzyme activity. Further research is needed to resolve whether patients could benefit from treatment with bezafibrate.
authors.affiliation: Laboratory Genetic Metabolic Diseases, Departments of Clinical Chemistry and Pediatrics, Emma's Children's Hospital, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Gloerich
authors.forename: L
authors.initials: L
authors.lastname: Ijlst
authors.forename: R J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: S
authors.initials: S
authors.lastname: Ferdinandusse
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D001629:Bezafibrate / Q000627:therapeutic use*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D016111:Sjogren-Larsson Syndrome / Q000188:drug therapy* / Q000201:enzymology; D015854:Up-Regulation
chemical_list: D000960:Hypolipidemic Agents; D047492:Peroxisome Proliferator-Activated Receptors; D000445:Aldehyde Oxidoreductases; C038828:long-chain-aldehyde dehydrogenase; D001629:Bezafibrate