Bezafibrate lowers very long‐chain fatty acids in X‐linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation
Open Access
- 24 March 2012
- journal article
- research article
- Published by Wiley in Journal of Inherited Metabolic Disease
- Vol. 35 (6), 1137-1145
- https://doi.org/10.1007/s10545-012-9471-4
Abstract
X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding ALDP, an ATP-binding-cassette (ABC) transporter located in the peroxisomal membrane. ALDP deficiency results in impaired peroxisomal β-oxidation and the subsequent accumulation of very long-chain fatty acids (VLCFA; > C22:0) in plasma and tissues. VLCFA are primarily derived from endogenous synthesis by ELOVL1. Therefore inhibiting this enzyme might constitute a feasible therapeutic approach. In this paper we demonstrate that bezafibrate, a PPAR pan agonist used for the treatment of patients with hyperlipidaemia reduces VLCFA levels in X-ALD fibroblasts. Surprisingly, the VLCFA-lowering effect was independent of PPAR activation and not caused by the increase in either mitochondrial or peroxisomal fatty acid β-oxidation capacity. In fact, our results show that bezafibrate reduces VLCFA synthesis by decreasing the synthesis of C26:0 through a direct inhibition of fatty acid elongation activity. Taken together, our data indicate bezafibrate as a potential pharmacotherapeutic treatment for X-ALD. A clinical trial is currently ongoing to evaluate the effect in patients with X-ALD.Keywords
This publication has 42 references indexed in Scilit:
- Mammalian peroxisomal ABC transporters: from endogenous substrates to pathology and clinical significanceBritish Journal of Pharmacology, 2011
- The role of ELOVL1 in very long‐chain fatty acid homeostasis and X‐linked adrenoleukodystrophyEMBO Molecular Medicine, 2010
- Lovastatin in X-Linked AdrenoleukodystrophyNew England Journal of Medicine, 2010
- PPARα: Energy Combustion, Hypolipidemia, Inflammation and CancerNuclear Receptor Signaling, 2010
- Rat Liver Peroxisomes after Fibrate TreatmentJournal of Biological Chemistry, 2007
- Inhibition of peroxisome-proliferator-activated receptor (PPAR)α by MK886Biochemical Journal, 2001
- Clinical Pharmacokinetics of Fibric Acid Derivatives (Fibrates)Clinical Pharmacokinetics, 1998
- ALDP expression in fibroblasts of patients with X‐linked adrenoleukodystrophyJournal of Inherited Metabolic Disease, 1995
- A Two-Year Trial of Oleic and Erucic Acids (“Lorenzo's Oil”) as Treatment for AdrenomyeloneuropathyNew England Journal of Medicine, 1993
- Adrenoleukodystrophy: Evidence that abnormal very long chain fatty acids of brain cholesterol esters are of exogenous originBiochemical and Biophysical Research Communications, 1980