ACOT7

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, Acot7N−/−, 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 Acot7N−/− mice. These failures in adaptive energy metabolism are common in neurodegenerative diseases. In agreement, Acot7N−/− mice exhibit neurological dysfunction and neurodegeneration. These data show that ACOT7 counterregulates fatty acid metabolism in neurons and protects against neurotoxicity.

Abstract: Acyl-CoA thioesterases (ACOTs) are a group of enzymes that catalyze the hydrolysis of fatty acyl-CoAs to free fatty acids and CoA, with the potential to regulate the intracellular levels of these molecules. In this study, we show that a cytosolic isoform, ACOT7, is expressed at a significant level in the mesenteric lymph nodes (MLNs) of mice. While crude preparations of the mesenteric visceral fat contained significant levels of palmitoyl-CoA thioesterase activity, enzyme activity was concentrated 6.9-fold in MLNs compared with the residual adipose portion after excision of MLNs. When MLN homogenates were centrifuged, 82% of the enzyme activity was recovered in the cytosolic fraction, concomitant with almost exclusive recovery of ACOT7. Immunoprecipitation using anti-ACOT7 antibody estimated that 87% of enzyme activity in the homogenates was accounted for by ACOT7. On MLN sections, the germinal centers of secondary lymphoid follicles were immunostained with the antibody. In MLNs of mice fasted for 16 h, ACOT7 levels were induced 1.8-fold, which reflected a 1.5-fold increase in enzyme activity. These findings suggest that ACOT7 may be involved in dietary intake-associated responses in fatty acid metabolism in MLNs.

Abstract: Purpose Gastric cancer (GC) has a very poor prognosis when diagnosed at a late stage. Acyl-CoA thioesterase 7 (ACOT7) is a major isoform of the acyl coenzyme family that catalyzes the hydrolysis of fatty acyl-CoAs into unesterified free fatty acid and coenzyme A. The purpose of this study was to investigate the expression levels of ACOT7 in GC and mechanisms related therewith. Materials and methods Screening of systematic biology studies revealed ACOT7 as a key gene in GC, as well as involvement of the long non-coding RNA NMRAL2P in ACOT7 expression. In this study, GC tissues and adjacent tissue samples were obtained from 10 GC patients at the Department of Gastrointestinal Surgery. GES1 and SGC-7901 cells were collected and treated to silence ACOT7 and overexpress NMRAL2P. The expressions of ACOT7 and NMRAL2P were detected by real-time quantitative PCR and Western blot. Additionally, cell proliferation, apoptosis, migration, and invasion were examined. Results ACOT7 was upregulated in gastric tumor tissues and GC cell lines. ACOT7 gene silencing induced a less malignant phenotype and was closely correlated to reduced cell proliferation and migration, altered cell cycle, and increased apoptosis. Furthermore, NMRAL2P was downregulated in tumor tissues and GC cell lines. NMRAL2P overexpression induced a more malignant phenotype and significantly inhibited the expression of ACOT7. Importantly, NMRAL2P indirectly methylated ACOT7 by binding to DNMT3b, thereby suppressing ACOT7 expression. Conclusion NMRAL2P activation suppresses ACOT7 expression in GC. Thus, ACOT7 could be a promising target for the treatment of GC.

Abstract: Increased lipid metabolism in muscle is associated with insulin resistance and therefore, many strategies have been employed to alter fatty acid metabolism and study the impact on insulin action. Metabolism of fatty acid requires activation to fatty acyl CoA by Acyl CoA synthases (ACSL) and fatty acyl CoA can be hydrolysed by Acyl CoA thioesterases (Acot). Thioesterase activity is low in muscle, so we overexpressed Acot7 in muscle of chow and high-fat diet (HFD) rats and investigated effects on insulin action. Acot7 overexpression modified specific phosphatidylcholine and phosphatidylethanolamine species in tibialis muscle of chow rats to levels similar to those observed in control HFD muscle. The changes in phospholipid species did not alter glucose uptake in tibialis muscle under hyperinsulinaemic/euglycaemic clamped conditions. Acot7 overexpression in white extensor digitorum longus (EDL) muscle increased complete fatty acid oxidation ex-vivo but was not associated with any changes in glucose uptake in-vivo, however overexpression of Acot7 in red EDL reduced insulin-stimulated glucose uptake in-vivo which correlated with increased incomplete fatty acid oxidation ex-vivo. In summary, although overexpression of Acot7 in muscle altered some aspects of lipid profile and metabolism in muscle, this had no major effect on insulin-stimulated glucose uptake.