The Insulin Receptor Translocates to the Nucleus to Regulate Cell Proliferation in Liver

Insulin's metabolic effects in the liver are widely appreciated, but insulin's ability to act as a hepatic mitogen is less well understood. Because the insulin receptor (IR) can traffic to the nucleus, and Ca2+ signals within the nucleus regulate cell proliferation, we investigated whether insulin's mitogenic effects result from activation of Ca2+-signaling pathways by IRs within the nucleus. Insulin-induced increases in Ca2+ and cell proliferation depended upon clathrin- and caveolin-dependent translocation of the IR to the nucleus, as well as upon formation of inositol 1,4,5,-trisphosphate (InsP(3)) in the nucleus, whereas insulin's metabolic effects did not depend on either of these events. Moreover, liver regeneration after partial hepatectomy also depended upon the formation of InsP(3) in the nucleus, but not the cytosol, whereas hepatic glucose metabolism was not affected by buffering InsP(3) in the nucleus. Conclusion: These findings provide evidence that insulin's mitogenic effects are mediated by a subpopulation of IRs that traffic to the nucleus to locally activate InsP(3)-dependent Ca2+-signaling pathways. The steps along this signaling pathway reveal a number of potential targets for therapeutic modulation of liver growth in health and disease. (Hepatology 2014;58:274-283)