Another interesting finding was that addition of cholesterol to the
HF diet attenuated glucose intolerance. Although hepatic steatosis is
generally associated with insulin resistance, the direct causes of
impaired insulin action are lipid intermediates such as ceramide and
diacylglycerol [51,52]. It has been suggested that sequestration of
these lipid intermediates within lipid droplets can reduce their
interference with the insulin signaling in the cytosol without reducing
hepatic steatosis [53,54]. Clearly, addition of cholesterol into the HF
diet enlarged lipid droplets in the liver. Whether this may sequester
lipid intermediates to reduce their inhibition of insulin action
remained to be investigated. Another possibility for the attenuated
glucose intolerance by cholesterol might be due to increased SCD1
(Supplementary Figure) as previously observed [55]. As unsaturated
fatty acids are relatively benign to insulin action [56], increased SCD1
may attenuate insulin resistance by converting detrimental saturated
fatty acids [57] to unsaturated fatty acids.