title: Acyl coenzyme A thioesterase 7 regulates neuronal fatty acid metabolism to prevent neurotoxicity.
abstract: Numerous neurological diseases are associated with dysregulated lipid metabolism; however, the basic metabolic control of fatty acid metabolism in neurons remains enigmatic. Here we have shown that neurons have abundant expression and activity of the long-chain cytoplasmic acyl coenzyme A (acyl-CoA) thioesterase 7 (ACOT7) to regulate lipid retention and metabolism. Unbiased and targeted metabolomic analysis of fasted mice with a conditional knockout of ACOT7 in the nervous system, Acot7(N-/-), revealed increased fatty acid flux into multiple long-chain acyl-CoA-dependent pathways. The alterations in brain fatty acid metabolism were concomitant with a loss of lean mass, hypermetabolism, hepatic steatosis, dyslipidemia, and behavioral hyperexcitability in Acot7(N-/-) mice. These failures in adaptive energy metabolism are common in neurodegenerative diseases. In agreement, Acot7(N-/-) mice exhibit neurological dysfunction and neurodegeneration. These data show that ACOT7 counterregulates fatty acid metabolism in neurons and protects against neurotoxicity.
authors: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Center for Metabolism and Obesity Research, Baltimore, Maryland, USA.
authors: Jessica M
authors: JM
authors: Ellis
authors: G William
authors: GW
authors: Wong
authors: Michael J
authors: MJ
authors: Wolfgang
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D050171:Dyslipidemias / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004734:Energy Metabolism; D005215:Fasting / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism* / Q000633:toxicity; D005260:Female; D015870:Gene Expression; D055786:Gene Knockout Techniques; D008297:Male; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010170:Palmitoyl-CoA Hydrolase / Q000235:genetics* / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; C521939:Acot7 protein, mouse; D010170:Palmitoyl-CoA Hydrolase