Melanie Gillingham, PhD
3181 SW Sam Jackson Park Road
Mail Code: L103
Portland, OR 97239
Office: 503 494-1682
Fax: 503 494-6886
During periods of moderate exercise, fasting, or illness, the oxidation of fatty acids provides essential energy for the heart and muscle and ketone bodies for the central nervous system. Inherited disorders in the ability to oxidize fatty acids can present with severe hypoglycemia (low blood glucose) and cardiomyopathy in infancy or exercise intolerance and rhabdomyolysis in adolescents and adults. Over 22 different disorders of the fatty acid oxidation pathway have been identified. Our laboratory investigates the metabolic consequences of genetic disorders in the fatty acid oxidation pathway including inherited deficiency of very-long chain acyl CoA dehydrogenase(VLCAD), long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD), carnitine palmitoyltransferase 2 (CPT2), and carnitine palmitoyltransferase 1A (CPT1A).The overall goal of our research is to twofold: 1) to learn more about the role of fatty acid oxidation in general biology and 2) to develop novel treatments for these rare disorders of fatty acid metabolism.
Novel insights into general biology:
There is a relationship between fatty acid oxidation, glucose oxidation, and insulin sensitivity but controversy exists as to whether insulin resistance results from intrinsic defects in mitochondrial energy utilization or from the accumulation of cellular fatty acid metabolic intermediates that impair insulin signaling. Patients with long-chain fatty acid oxidation disorders have not been reported to develop insulin resistance and remain glucose sensitive, despite increased total body fat and elevated free fatty acids. In addition, VLCAD knockout mice remain insulin sensitive after a high fat diet but wild-type mice develop insulin resistance. We are currently working on studies in both human subjects and mouse models that examine the role of decreased long-chain fatty acid oxidation on the protection from diet-induced insulin resistance.
Our current trial compares insulin sensitivity during a hyperinsulinemic, euglycemic clamp between subjects with a long-chain fatty acid oxidation disorder such as VLCAD or LCHAD deficiency and normal matched control subjects. More information about our clinical trial can be found here:
Treatment of Fatty Acid Oxidation Disorders:
The treatment for long-chain fatty acid oxidation disorders has been primarily with a modified diet including avoiding fasting, and frequent high carbohydrate meals. We have been investigating alternative nutritional approaches including using medium-chain triglyceride (MCT) supplements prior to exercise to improve exercise tolerance, and high protein, low-fat diets to increase lean body mass and improve metabolic control.
We recently completed a study investigating the effects of triheptanoin or C7, an odd carbon medium-chain fatty acid supplement, on myopathy and muscle pain in long-chain fatty acid oxidation disorders. More information about our clinical trial can be found here: http://clinicaltrials.gov/ct2/show/NCT01379625
Fatty Acid Oxidation and Retina:
One of the complications of LCHAD deficiency is vision loss because of a degeneration of the retina, a part of the eye that is essential for us to see. This degeneration of the retina is called retinopathy and the cause of retinopathy in children with LCHAD is not known. We are currently conducting in vitro studies to investigate the cause of LCHAD retinopathy and develop novel treatments.
Our previous study found a correlation between blood levels of an LCHAD metabolite, long chain 3-hydroxyacylcarnitines and progression of retinopathy. Our hypothesis is that these metabolites are toxic to the retina. We have not been able to test this hypothesis because an LCHADD animal or LCHADD retinal cell culture model does not exist. Recent advances in science have made it possible to directly reprogram cultured skin cells or fibroblasts into stem cells; cells that have the potential to become any type of cell in the body. Fibroblasts are frozen from skin biopsies of patients obtained to diagnosis LCHADD. If patient fibroblasts were reprogrammed, the stem cells would have LCHAD deficiency like the original fibroblast from which they were derived. The LCHADD stem cells can then be programmed to become retina cells.
In this project we are generating stem cells from the cultured skin cells of patients with LCHADD. We will then program the LCHAD deficient stem cells to become retinal cells to create an LCHAD deficient retinal cell. We hypothesize that the LCHADD retinal cells will accumulate long-chain 3-hydroxyacylcarnitines. The accumulation of these metabolites will result in cell death.
Our next step is to develop a gene therapy vector that can restore normal LCHAD activity into the cells and determine if the gene therapy vector makes the cells healthy and similar to control or wild-type cells.
The Myers Family Foundation generously donated initial funding for this project. The Marcello Miracle Foundation donated additional funds. This project recently received a generous grant from the Irene M Scully/Peterson Foundation. We are currently searching for a post-doctoral fellow with experience in iPSCs and/or gene therapy vector development to join our research team. Interested candidates should apply online by visiting www.ohsujobs.com, refer to recruitment IRC51219.
Support Fatty Acid Oxidation and Retina Research Today
Donations can also be made by check; please make check(s) payable to: OHSU Foundation Account 23711 Genetics Research
Mail to: OHSU Foundation Mail Stop 45 PO Box 4000 Portland, OR 97208-9852
Contact the OHSU Foundation for questions about giving: www.ohsufoundation.org
Gillingham MB, Weleber RG, Neuringer M, Connor WE, Mills M, van Calcar S, et al. Effect of optimal dietary therapy upon visual function in children with long-chain 3-hydroxyacyl CoA dehydrogenase and trifunctional protein deficiency. Mol Genet Metab. 2005;86(1-2):124-33. Epub 2005/07/26. doi:10.1016/j.ymgme.2005.06.001. PubMed PMID: 16040264;PubMed Central PMCID:PMC2694051.
Fletcher AL, Pennesi ME, Harding CO, Weleber RG, Gillingham MB.Observations regarding retinopathy in mitochondrial trifunctional protein deficiencies. Mol Genet Metab. 2012;106(1):18-24. Epub 2012/03/31. doi:10.1016/j.ymgme.2012.02.015. PubMed PMID: 22459206;PubMed Central PMCID:PMC3506186.
Behrend AM, Harding CO, Shoemaker JD, Matern D, Sahn DJ, Elliot DL, et al.Substrate oxidation and cardiac performance during exercise in disorders of long chain fatty acid oxidation. Mol Genet Metab. 2012;105(1):110-5. Epub2011/10/28. doi: 10.1016/j.ymgme.2011.09.030. PubMed PMID: 22030098;PubMedCentral PMCID: PMC3253922.
Gillingham MB, Scott B, Elliott D, Harding CO. Metabolic control during exercise with and without medium-chain triglycerides (MCT) in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein(TFP) deficiency. Mol Genet Metab. 2006;89(1-2):58-63. Epub 2006/08/01. doi:10.1016/j.ymgme.2006.06.004. PubMed PMID: 16876451;PubMed Central PMCID:PMC2706834.
Martin JM, Gillingham MB, Harding CO. Use of propofol for short duration procedures in children with long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)or trifunctional protein (TFP) deficiencies. Mol Genet Metab.2014;112(2):139-42. Epub 2014/05/02. doi: 10.1016/j.ymgme.2014.03.012. PubMedPMID: 24780638;PubMed Central PMCID: PMC4121654.
Gillingham MB, Harding CO, Schoeller DA, Matern D, Purnell JQ. Altered body composition and energy expenditure but normal glucose tolerance among humans with a long-chain fatty acid oxidation disorder. Am J Physiol EndocrinolMetab. 2013;305(10):E1299-308. Epub 2013/09/26. doi:10.1152/ajpendo.00225.2013. PubMed PMID: 24064340;PubMed Central PMCID:PMC3840216.
Gillingham MB, Hirschfeld M, Lowe S, Matern D, Shoemaker J, Lambert WE, etal. Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant. Mol Genet Metab.2011;104(3):261-4. Epub 2011/07/19. doi: 10.1016/j.ymgme.2011.06.017. PubMedPMID: 21763168;PubMed Central PMCID: PMC3197793.
Gessner BD, Gillingham MB, Birch S, Wood T, Koeller DM. Evidence for an association between infant mortality and a carnitine palmitoyltransferase 1Agenetic variant. Pediatrics. 2010;126(5):945-51. Epub 2010/10/13. doi:10.1542/peds.2010-0687. PubMed PMID: 20937660.