TY - JOUR
T1 - Mitochondrial long chain fatty acid β-oxidation in man and mouse
AU - Chegary, Malika
AU - Brinke, Heleen te
AU - Ruiter, Jos P.N.
AU - Wijburg, Frits A.
AU - Stoll, Maria S.K.
AU - Minkler, Paul E.
AU - van Weeghel, Michel
AU - Schulz, Horst
AU - Hoppel, Charles L.
AU - Wanders, Ronald J.A.
AU - Houten, Sander M.
N1 - Funding Information:
The authors thank Sacha Ferdinandusse and Simone Denis for helpful discussions. This work was supported by the Netherlands Organisation for Scientific Research (VIDI-grant No. 016.086.336 to SMH) and the NIH (DK066107 to CLH).
PY - 2009/8
Y1 - 2009/8
N2 - Several mouse models for mitochondrial fatty acid β-oxidation (FAO) defects have been developed. So far, these models have contributed little to our current understanding of the pathophysiology. The objective of this study was to explore differences between murine and human FAO. Using a combination of analytical, biochemical and molecular methods, we compared fibroblasts of long chain acyl-CoA dehydrogenase knockout (LCAD-/-), very long chain acyl-CoA dehydrogenase knockout (VLCAD-/-) and wild type mice with fibroblasts of VLCAD-deficient patients and human controls. We show that in mice, LCAD and VLCAD have overlapping and distinct roles in FAO. The absence of VLCAD is apparently fully compensated, whereas LCAD deficiency is not. LCAD plays an essential role in the oxidation of unsaturated fatty acids such as oleic acid, but seems redundant in the oxidation of saturated fatty acids. In strong contrast, LCAD is neither detectable at the mRNA level nor at the protein level in men, making VLCAD indispensable in FAO. Our findings open new avenues to employ the existing mouse models to study the pathophysiology of human FAO defects.
AB - Several mouse models for mitochondrial fatty acid β-oxidation (FAO) defects have been developed. So far, these models have contributed little to our current understanding of the pathophysiology. The objective of this study was to explore differences between murine and human FAO. Using a combination of analytical, biochemical and molecular methods, we compared fibroblasts of long chain acyl-CoA dehydrogenase knockout (LCAD-/-), very long chain acyl-CoA dehydrogenase knockout (VLCAD-/-) and wild type mice with fibroblasts of VLCAD-deficient patients and human controls. We show that in mice, LCAD and VLCAD have overlapping and distinct roles in FAO. The absence of VLCAD is apparently fully compensated, whereas LCAD deficiency is not. LCAD plays an essential role in the oxidation of unsaturated fatty acids such as oleic acid, but seems redundant in the oxidation of saturated fatty acids. In strong contrast, LCAD is neither detectable at the mRNA level nor at the protein level in men, making VLCAD indispensable in FAO. Our findings open new avenues to employ the existing mouse models to study the pathophysiology of human FAO defects.
KW - Cellular metabolism
KW - Fatty acid oxidation
KW - Inborn errors of metabolism
KW - Long chain acyl-CoA dehydrogenase
KW - Mouse model
KW - Very long chain acyl-CoA dehydrogenase
UR - http://www.scopus.com/inward/record.url?scp=67650502781&partnerID=8YFLogxK
U2 - 10.1016/j.bbalip.2009.05.006
DO - 10.1016/j.bbalip.2009.05.006
M3 - Article
C2 - 19465148
AN - SCOPUS:67650502781
SN - 1388-1981
VL - 1791
SP - 806
EP - 815
JO - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
JF - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
IS - 8
ER -