Emerging roles of GSK-3α in pathophysiology: Emphasis on cardiometabolic disorders

Glycogen synthase kinase-3 (GSK-3) is a widely expressed serine/threonine kinase regulates a variety of cellular processes including proliferation, differentiation and death. Mammals harbor two structurally similar isoforms GSK-3 alpha and beta that have overlapping as well as unique functions. Of the two, GSK-3 beta has been studied (and reviewed) in far greater detail with analysis of GSK-3 alpha often as an afterthought. It is now evident that systemic, chronic inhibition of either GSK-3 beta or both GSK-3 alpha/beta is not clinically feasible and if achieved would likely lead to adverse clinical conditions. Emerging evidence suggests important and specific roles for GSK-3 alpha in fatty acid accumulation, insulin resistance, amyloid-beta-protein precursor metabolism, atherosclerosis, cardiomyopathy, fibrosis, aging, fertility, and in a variety of cancers. Selective targeting of GSK-3 alpha may present a novel therapeutic opportunity to alleviate a number of pathological conditions. In this review, we assess the evidence for roles of GSK-3 alpha in a variety of pathophysiological settings.