The role Acyl-CoA thioesterases play in mediating intracellular lipid metabolism

Upregulation of Fatty Acyl-CoA Thioesterases in the Heart and Skeletal Muscle of Rats Fed a High-Fat Diet

“…20,21) Although the roles of ACOT in lipid metabolism have not been fully established, a model concerning the roles of ACOT1 and ACOT2 is emerging. 7,8,[20][21][22][23] In this model, fatty acids entering a cell across the plasma membrane are rapidly activated to acyl-CoA and partitioned into the oxidative and nonoxidative metabolic pathways. 20,21) In the heart and soleus muscle, where the expression level of cytosolic ACOT1 is very low, mitochondrial fatty acid oxidation may be the default primary pathway for acyl-CoA metabolism.…”

“…8,20,21) Moreover, some of the fatty acids released by acyl-CoA hydrolysis via ACOT1 may reach and activate a nuclear receptor, peroxisome proliferator-activated receptor alpha (PPAR alpha), which in turn stimulates the expression of genes related to lipid catabolism, including ACOT itself [24][25][26] and uncoupling protein 3 (UCP3) 27) to form a positive feedback loop. 8) On the other hand, in the mitochondrial matrix, acyl-CoA transported via CPT is subjected to beta-oxidation. However, some of the acyl-CoA is hydrolyzed by ACOT2 and regenerates CoA-SH, which is required for pyruvate dehydrogenase, 2-ketoglutarate dehydrogenase and 3-ketoacyl-CoA thiolase reactions.…”

“…Thus, an additional futile cycle mediated by ACOT2 would be promoted. 7,8,[21][22][23] In the futile cycle, AMP produced by acyl-CoA synthetase provides an adenine nucleotide substrate for proton gradientdriven ATP synthesis, which may serve to maintain the expected ETC activity.…”

“…For example, ACOT1 (formerly known as CTE-I or ACH2) and ACOT7a (CTE-II, BACH or ACT) are localized in the cytosol while ACOT2 (MTE-I or ARTISt) and ACOT7b (MTE-II or LACH1) are present in mitochondria. [8][9][10] These catalytic properties of ACOT mean that it is capable of lowering the increased levels of acyl-CoA imported by carnitine palmitoyltransferase (CPT) across the mitochondrial membranes from the cytosol. Accordingly, ACOT could counteract the enhanced beta-oxidation and reduce the mitochondrial stress caused by the imbalance between beta-oxidation and TCA cycle/ETC activity during fatty acid overload.…”

Alternative exon usage selectively determines both tissue distribution and subcellular localization of the acyl-CoA thioesterase 7 gene products

“…Several evolutionary unrelated enzymes and protein families of Acots have now been identified (for review see (3,4)). The peroxisome proliferatorinduced activity in mitochondria and cytosol is due to induction of two protein families (5-7), which were named Type-I and Type-II acyl-CoA thioesterases (8).…”