Ellis Laboratory

Omega-3 fatty acids are essential nutrients that are highly enriched in the brain and are neuroprotective, specifically the omega-3 docosahexaenoic acid (DHA) which is consumed via fish and/or algae intake. DHA has been shown to be neuroprotective in numerous neurological diseases, including dementia and Parkinson’s disease, and protection damage caused by traumatic brain injury. Strikingly, however, little is known about the fundamental regulatory mechanisms that control the incorporation of DHA into the brain. The Ellis lab recently filled this gap in knowledge by discovering that an enzyme called long-chain Acyl-CoA Synthetase 6 (Acsl6) is a major regulator of DHA content in neurons. This discovery was made by creating a novel conditional Acsl6-deficient mouse model (Acsl6^-/-) to show a massive ~50% loss of membrane DHA in n neurons. Accompanying this loss of brain omega-3 fatty acids, we have gone on to show increased neuroinflammation with age, impaired motor function, and have recently begun to assess the role of Acsl6 in Parkinson’s disease and recovery from traumatic brain injury. The work in the Ellis lab stands to shape therapeutic strategies and dietary recommendations to improve brain health and protect and treat numerous neurological diseases and conditions.

Key Relevant Papers

1. Fernandez RF, Pereyra AS, Diaz V, Wilson ES, Jackson SN, Litwa KA, Brenna JT, Hermann BP, Eells JB, Ellis JM*. Acyl-CoA synthetase 6 is required for brain docosahexaenoic acid retention and neuroprotection during aging. JCI Insights. 2021 Jun 8;6(11):144351. PMID: 34100386
2. Fernandez RF, Kim SQ, Zhao Y, Foguth RM, Weera MM, Counihan JL, Nomura DM, Chester JM, Cannon JR, Ellis JM*. Acyl-CoA Synthetase 6 enriches the neuroprotective omega-3 fatty acid DHA in the brain. Proc Natl Acad Sci, 2018;115:12525-12530. PMID: 30401738
3. Fernandez RF, Weglarczyk P, Zokaei S, Huguenin S, Scafidi J, Scafidi SS, Ellis JM. Aging effects on lipid metabolism in response to traumatic brain injury. J Neurochem. 2025 Sep;169(9):e70227. PMID: 40939097

Fat has been classical seen as the bad hat metabolic research for nearly 50 years. However, the use of fat as a critical bioenergetic fuel is often overlooked and underestimated. We believe fat as a fuel source plays numerous critical roles and preserves health across many cell types throughout the body. To demonstrate this, the Ellis lab has been investigating the requirement for the bioenergetic process of fatty acid oxidation (FAO) in skeletal muscle. We have made several surprising discoveries that highlight the high requirement of FAO for the health and contractile function in highly oxidative muscle types. Whereas, in highly glycolytic muscles FAO is generally not required for health and function, at least until a stressor such exercise or high fat diet occurs. Our ongoing investigations are focused on how the length of the fatty acid influences its bioenergetic availability in both muscle and liver to better understand the dietary optimization, i.e. to avoid the bad and enhance the good fats, that influence exercise performance, metabolic disease, insulin resistance/diabetes and fatty liver disease.

Key Relevant Papers

1. Pereyra AS, Fernandez RF, Amorese A, Castro JN, Lin CT, Spangenburg EE, Ellis JM*. Loss of mitochondrial long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis. Mol Metab 2024 Nov;89:122015.
2. Pereyra AS, McLaughlin K, Buddo KA, Ellis JE*. Medium-chain fatty acid oxidation is independent of L-carnitine in liver and kidney but not in heart and skeletal muscle. Am. J. Physiol. Gastrointest. Liver Physiol. 2023. Oct 1;325(4):G287-G294. PMID 37461880.
3. Pereyra AS, Lin CT, Sanchez DM, Laskin J, Spangenburg EE, Neufer PD, Fisher-Wellman K, Ellis JM*. Skeletal muscle undergoes fiber type metabolic switch without myosin heavy chain switch in response to defective fatty acid oxidation. Mol Metab 2022 Feb 9;101456. PMID: 35150906
4. Pereyra AP, Harris KL, Soepriatna AH, Waterbury QA, Barathi SS, Zhang Y, Fisher-Wellman KH, Goergen CJ, Goetzman ES, Ellis JM*. Octanoate is differentially metabolized in liver and muscle and fails to rescue cardiomyopathy in CPT2 deficiency. J Lipid Res. 2021 Mar 20;62:100069. PMID: 33757734
5. Pereyra AP, Rajan A, Ferreira CR, Ellis JM*. Loss of muscle carnitine palmitoyltransferase 2 prevents diet-induced obesity and insulin resistance despite long-chain acylcarnitine accumulation. Cell Rep. 2020 Nov 10;33(6):108374. PMID: 33176143