Figure 5

Saturated FFA mediated impairment in skeletal muscle and its reversal by nSMase inhibition. Sphingomyelin can be converted into ceramide by nSMases. Palmitate mediated up-regulation of nSMases can expedite this process of ceramide generation. Increased ceramide can lead to an inhibition on insulin signaling pathway thereby reducing glucose oxidation. In this condition PGC1α levels are reduced with a concomitant decrease in muscle oxidative capacity. Because of impaired oxidative function and palmitate overload, fat storage in form of TG is increased. Palmitate overload mediated increased ceramide levels elevate cellular oxidative stress, ER stress and inflammation which can severely affect cell survival. Elevated stress and inflammation can directly inhibit insulin signaling and can impair oxidative capacity (represented as dashed arrows). Palmitate mediated impact on cellular responses is represented by a thick up or down arrow placed just after particular cellular response. Inhibition of nSMase under this background reverses palmitate mediated impact on cellular response.