Role of fatty acyl-CoA synthetases in the development of lipid induced insulin resistance in skeletal muscle cells
Biochemistry
Cell Biology
Final Report Abstract
The two different experimental approaches performed during the period of the Project funded by the DFG revealed new surprising correlations between ACS Enzymes and lipid induced insulin resistance in skeletal muscle. This is the first study revealing a clear functional correlation between ACSL enzyme activity and the onset of T2D in human skeletal muscle. While expecting a reduced acyl-CoA synthetase activity being beneficial regarding insulin resistance our results revealed the opposite. The Analyses of human muscle biopsies showed a lower ACS activity in muscle of insulin resistant individuals compared to normal weight controls. Experiments in our cellculture system provide further evidence for this correlation. Cells having reduced ACS activity showed a higher extend of impaired insulin signalling than the control cells. With these results we had to rethink our initial hypothesis. Instead of reducing the acyl-CoA synthetase activity to generate less harmful lipid metabolites, a higher ACSL activity enable the muscle to deal more efficiently with the high burden of unesterified fatty acids. And moreover, having more of the mitochondrial localized ACSl1 enzyme expressed may help the muscle to increase ß-oxidation and so, combined with appropriate consumption (e.g. exercises), evaporating the surplus lipid metabolites by oxidative phosphorylation. Fewer lipid metabolites interfering with the insulin signalling would restore the muscle’s insulin sensitivity. In this way, a higher level of active ACSL1 enzyme could be beneficial in regard to prevent the development of fatty acid induced muscle insulin resistance by having an insulin sensitizing effect. Studies with ACSL1-silenced mouse adipocytes showed a reduced insulinstimulated glucose uptake in these knockdown cells, underscoring our assumption of an insulin sensitizing effect of ACLS1 activity in human muscle. These novel findings clearly linking ACSL1 to muscle insulin resistance and suggest that the increased acyl-CoA levels are likely due to decreased consumption but not overproduction. Moreover, these data provide a valid basis for further investigations in cell culture models allowing to define the role of ACSL1 in the development of insulin resistance and T2D in more detail. One key question would be if alone a boost of the ACSL1 expression and hence the total muscle ACS activity, will be enough to have a slowing down or even protective effect on the development of fatty acid induced insulin resistance in skeletal muscle. Taking together, to us, the observed results revealed ACSL1 as a promising target to impede the fatty acid induced insulin resistance in skeletal muscle by helping the muscle to increase the consumption of fatty acyl-CoAs through ß-oxidation and so reducing the load of interfering metabolites. The exciting Data obtained during this project help to set more light on the yet still understudied interaction between ACS enzymes and fatty acid induced insulin resistance in human muscle.
