| Research theme | Physiology of mitochondrial fatty acid β-oxidation |
|---|---|
| Principal Investigator | Sander M. Houten, PhD |
| Group members | Ot (A.J.) Bakermans, PhD student Maxim Boek, Research technician Vincent de Boer, PhD Heleen te Brinke, Research technician Simone Denis, Research technician Eugène Diekman, PhD student Olga Pougovkina, PhD student Michel van Weeghel, PhD student |
Mitochondrial fatty acid β-oxidation (FAO) plays a crucial role in energy homeostasis of organs such as liver, heart and skeletal muscle. During fasting when glucose supply becomes limited, FAO is a vital energy source. For most FAO enzymes, a recessively inherited defect is known, leading to an overall high cumulative incidence (~1 in 10,000). Typical clinical features of these FAO defects are fasting-induced hypoketotic hypoglycemia, and cardiac and skeletal myopathy. Many countries, including the Netherlands have included FAO defects in expanded neonatal screening programs, because hypoglycemia can lead to coma or sudden death, but is prevented by avoidance of fasting. The treatment opportunities for (cardio)myopathy are suboptimal and new developments are hampered by a lack of fundamental insight into the consequences of a FAO defect. The goal of this research line is to define the pathogenetic mechanisms that underlie the various symptoms of FAO defects and to design rational therapeutic strategies for patients affected with FAO defects.
FAO also plays a role in the pathophysiology of other metabolic derangements such as insulin resistance. The second objective of this research line is to define the impact of FAO on the regulation of cellular metabolism with a focus on protein acetylation and deacetylation.
Key publications
Houten SM, Wanders RJ (2010) A general introduction to the biochemistry of mitochondrial fatty acid beta-oxidation. J. Inherit. Metab. Dis. 33:469-477.
Wanders RJ, Ruiter JP, IJLst L, Waterham HR, Houten SM (2010) The enzymology of mitochondrial fatty acid beta-oxidation and its application to follow-up analysis of positive neonatal screening results. J. Inherit. Metab. Dis. 33:479-494.
Houten SM, Chegary M, Te Brinke H, Wijnen WJ, Glatz JF, Luiken JJ, Wijburg FA, Wanders RJ (2009) Pyruvate dehydrogenase kinase 4 expression is synergistically induced by AMP-activated protein kinase and fatty acids. Cell. Mol. Life Sci. 66:1283-1294.
Chegary M, Brinke HT, Ruiter JP, Wijburg FA, Stoll MS, Minkler PE, van Weeghel M, Schulz H, Hoppel CL, Wanders RJ, Houten SM (2009) Mitochondrial long chain fatty acid beta-oxidation in man and mouse. Biochim. Biophys. Acta. 1791:806-815.
Chegary M, Te Brinke H, Doolaard M, IJlst L, Wijburg FA, Wanders RJ, Houten SM (2008) Characterization of l-aminocarnitine, an inhibitor of fatty acid oxidation. Mol. Genet. Metab. 93:403-410.