- Loss of long-chain acyl-CoA synthetase isoform-1 (ACSL1) in mouse skeletal muscle (Acsl1M−/−) severely reduces acyl-CoA synthetase activity and fatty acid oxidation. However, the effects of decreased fatty acid oxidation on skeletal muscle function, histology, use of alternative fuels, and mitochondrial function and morphology are unclear. We observed that Acsl1M−/− mice have impaired voluntary running capacity and muscle grip strength and that their gastrocnemius muscle contains myocytes with central nuclei, indicating muscle regeneration.
- Hepatic insulin resistance in the setting of steatosis is attributable at least in part to the accumulation of bioactive lipids that suppress insulin signaling. The mitochondria-associated glycerol-3-phosphate acyltransferase 1 (GPAT1) catalyzes the first committed step in glycerolipid synthesis, and its activity diverts fatty acids from mitochondrial β-oxidation. GPAT1 overexpression in mouse liver leads to hepatic steatosis even in the absence of overnutrition. The mice develop insulin resistance owing to the generation of saturated diacylglycerol and phosphatidic acid molecular species that reduce insulin signaling by activating PKCϵ and by suppressing mTORC2, respectively.
- Fatty acid channeling into oxidation or storage modes depends on physiological conditions and hormonal signaling. However, the directionality of this channeling may also depend on the association of each of the five acyl-CoA synthetase isoforms with specific protein partners. Long-chain acyl-CoA synthetases (ACSLs) catalyze the conversion of long-chain fatty acids to fatty acyl-CoAs, which are then either oxidized or used in esterification reactions. In highly oxidative tissues, ACSL1 is located on the outer mitochondrial membrane (OMM) and directs fatty acids into mitochondria for β-oxidation.
- Background: GPAT4 is a major glycerol-3-phosphate acyltransferase (GPAT) isoform in brown adipose tissue (BAT).Results: Compared with control cells, brown adipocytes lacking GPAT4 oxidize 40% more exogenous fatty acids.Conclusion: GPAT4 in BAT is required to limit oxidation of exogenous fatty acid.Significance: The function of each GPAT isoform is tissue-specific and evolved to perform a unique function within a physiological context.