PMID- 28392417
OWN - NLM
STAT- MEDLINE
DCOM- 20181127
LR  - 20181127
IS  - 0925-4439 (Print)
IS  - 0925-4439 (Linking)
VI  - 1863
IP  - 6
DP  - 2017 Jun
TI  - Pharmacological inhibition of carnitine palmitoyltransferase 1 restores 
      mitochondrial oxidative phosphorylation in human trifunctional protein deficient 
      fibroblasts.
PG  - 1292-1299
LID - S0925-4439(17)30117-5 [pii]
LID - 10.1016/j.bbadis.2017.04.005 [doi]
AB  - BACKGROUND: Mitochondrial Trifunctional Protein deficiency (TFPD) is a severe 
      genetic disease characterized by altered energy metabolism and accumulation of 
      long-chain (LC) acylcarnitines in blood and tissues. This accumulation could 
      impair the mitochondrial oxidative phosphorylation (OxPhos), contributing to the 
      non-optimal outcome despite conventional diet therapy with medium-chain 
      triglycerides (MCT). METHOD: Acylcarnitine and OxPhos parameters were measured in 
      TFPD-fibroblasts obtained from 8 children and cultured in medium mimicking 
      fasting (LCFA) or conventional treatment (MCT), with or without Etomoxir (ETX) an 
      inhibitor of carnitine palmitoyltransferase 1 (CPT1) activity, and were compared 
      to results obtained with fibroblasts from 5 healthy-control children. The effects 
      of various acylcarnitines were also tested on control fibroblasts. RESULTS: In 
      the LCFA-condition, TFPD-fibroblasts demonstrated a large accumulation of 
      LC-acylcarnitines associated with decreased O(2)-consumption (63+/-3% of control, 
      P<0.001) and ATP production (67+/-5%, P<0.001) without modification of coupling 
      efficiency. A dose-dependent decrease in O(2)-consumption was reproduced in 
      control fibroblasts by addition of increasing dose of LC-acylcarnitines, while it 
      was almost preserved with MC-acylcarnitines. The MCT-condition reduced 
      LC-acylcarnitine accumulation and partially improved O(2)-consumption (80+/-3%, 
      P<0.01) in TFPD-fibroblasts. The addition of ETX in both LCFA- and MCT-conditions 
      normalized acylcarnitine profiles and restored O(2)-consumption and ATP 
      production at the same levels than control. CONCLUSION: Accumulation of 
      LC-acylcarnitines plays a major role in the pathophysiology of TFPD, reducing 
      OxPhos capacities. These deleterious effects could be partially prevented by 
      MCT-therapy and totally corrected by ETX. Inhibition of CPT1 may be view as a new 
      therapeutic target for patients with a severe form of TFPD.
CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
FAU - Lefort, Bruno
AU  - Lefort B
AD  - CHU de Tours, Medecine Pediatrique, Tours, France, and INSERM U1069, Universite 
      Francois Rabelais, Tours, France. Electronic address: bruno.lefort@univ-tours.fr.
FAU - Gouache, Elodie
AU  - Gouache E
AD  - CHU de Tours, Medecine Pediatrique, Tours, France, and INSERM U1069, Universite 
      Francois Rabelais, Tours, France.
FAU - Acquaviva, Cecile
AU  - Acquaviva C
AD  - CHU de Lyon, Maladies Hereditaires du Metabolisme, Lyon, France.
FAU - Tardieu, Marine
AU  - Tardieu M
AD  - CHU de Tours, Medecine Pediatrique, Tours, France, and INSERM U1069, Universite 
      Francois Rabelais, Tours, France.
FAU - Benoist, Jean Francois
AU  - Benoist JF
AD  - CHU Robert Debre, Biochimie, Paris, France.
FAU - Dumas, Jean-Francois
AU  - Dumas JF
AD  - INSERM U1069, Universite Francois Rabelais, Tours, France.
FAU - Servais, Stephane
AU  - Servais S
AD  - INSERM U1069, Universite Francois Rabelais, Tours, France.
FAU - Chevalier, Stephan
AU  - Chevalier S
AD  - INSERM U1069, Universite Francois Rabelais, Tours, France.
FAU - Vianey-Saban, Christine
AU  - Vianey-Saban C
AD  - CHU de Lyon, Maladies Hereditaires du Metabolisme, Lyon, France.
FAU - Labarthe, Francois
AU  - Labarthe F
AD  - CHU de Tours, Medecine Pediatrique, Tours, France, and Inserm U1069, Universite 
      Francois Rabelais de Tours, PRES Centre-Val de Loire Universites, Tours, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170406
PL  - Netherlands
TA  - Biochim Biophys Acta Mol Basis Dis
JT  - Biochimica et biophysica acta. Molecular basis of disease
JID - 101731730
RN  - 0 (Epoxy Compounds)
RN  - EC 2.3.1.16 (Mitochondrial Trifunctional Protein)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - MSB3DD2XP6 (etomoxir)
RN  - Trifunctional Protein Deficiency With Myopathy And Neuropathy
SB  - IM
MH  - Cardiomyopathies/*metabolism/pathology
MH  - Carnitine O-Palmitoyltransferase/*antagonists & inhibitors/metabolism
MH  - Epoxy Compounds/*pharmacology
MH  - Female
MH  - Fibroblasts/*metabolism/pathology
MH  - Humans
MH  - Infant
MH  - Infant, Newborn
MH  - Lipid Metabolism, Inborn Errors/*metabolism/pathology
MH  - Male
MH  - Mitochondria/*metabolism/pathology
MH  - Mitochondrial Myopathies/*metabolism/pathology
MH  - Mitochondrial Trifunctional Protein/*deficiency/drug effects/metabolism
MH  - Nervous System Diseases/*metabolism/pathology
MH  - Oxidative Phosphorylation/*drug effects
MH  - Rhabdomyolysis/*metabolism/pathology
OTO - NOTNLM
OT  - Acylcarnitines
OT  - Etomoxir
OT  - Long-chain 3-hydroxyacyl-CoA dehydrogenase
OT  - Mitochondria
OT  - Mitochondrial trifunctional protein deficiency
OT  - Oxidative phosphorylation
EDAT- 2017/04/11 06:00
MHDA- 2018/11/28 06:00
CRDT- 2017/04/11 06:00
PHST- 2016/12/19 00:00 [received]
PHST- 2017/03/20 00:00 [revised]
PHST- 2017/04/05 00:00 [accepted]
PHST- 2017/04/11 06:00 [pubmed]
PHST- 2018/11/28 06:00 [medline]
PHST- 2017/04/11 06:00 [entrez]
AID - S0925-4439(17)30117-5 [pii]
AID - 10.1016/j.bbadis.2017.04.005 [doi]
PST - ppublish
SO  - Biochim Biophys Acta Mol Basis Dis. 2017 Jun;1863(6):1292-1299. doi: 
      10.1016/j.bbadis.2017.04.005. Epub 2017 Apr 6.