Steve Shoelson’s laboratory identifies physiological and pathological mechanisms in metabolism with the potential for development of new therapeutics. Through a series of basic and clinical studies (TINSAL-T2D) we showed that salicylate, the world’s oldest anti-inflammatory drug, lowers blood sugar and lipids in patients with diabetes. We have taken these discoveries back to the laboratory to understand molecular mechanisms and to expand the approach.
Several new lines of investigation have spun off from TINSAL-T2D and studies of salicylate’s mechanism of action:
- Based on the discovery that salicylate binds and activates AMPK, we subsequently found that AMPK activation is also required for salicylate’s anti-inflammatory effects through NF-kB inhibition. This occurs through canonical inhibition of mTORC1 via TSC1/2 and Rheb, with KLF2 activation downstream of mTORC1 inhibiting NF-kB.
- We have identified another route to activating AMPK using approved drugs for treating gout. By inhibiting of xanthine oxidase (XO), the final step in purine metabolism, XO inhibitors including allopurinol raise levels of upstream purines, including AMP, which activates AMPK. Basic and clinical studies underway are expanding on this important discovery.
- We initially studied HSF1 because it had been shown that salicylate activates it in vitro and in C. elegans. We found this was not relevant to the in vivo actions of salicylate in mammals. However, we went on to discover that feeding activates the HSF1 transcriptional program in liver to maintain protein folding homeostasis in the face of mTOR driven increases in protein synthesis and growth. This is the first demonstration of a normal physiological function for HSF1, as opposed to a stress response, in mammals.
- Studies on inflammation in the pathogenesis of T2D led us to hypothesize potential roles of leukotrienes in the recruitment of specific leukocytes to adipose tissue or liver, potentially including neutrophils and NK cells. 5) We have found that externalized phosphatidylinositides (PIPs) represent a new “eat me” expressed on apoptotic cells that is recognized by phagocyte CD14.