Michael Karin, Ph.D.
University of California, San Diego
An NIEHS-funded study suggested that prolonged activation of a protein nuclear factor called erythroid 2-related factor 2 (NRF2) may contribute to liver enlargement and fatty liver diseases. Normally, NRF2 plays an important role in regulating antioxidant defenses. In this study, researchers found that NRF2 also activated a protein called AKT, which is involved in glucose metabolism and other cell processes, and led to persistent production of growth factors associated with liver enlargement.
When cells are healthy and unstressed by oxidants, NRF2 is generally kept low by a protein called kelch-like ECH-associated protein 1 (KEAP1). However, oxidative stress leads to inactivation of KEAP1, so NRF2 levels build up within a cell. Using a new mouse model with liver cells that express a KEAP1-resistant form of NRF2, the researchers studied what happens when NRF2 was persistently activated. Without KEAP1 to regulate NRF2, the researchers found rapid liver enlargement, known as hepatomegaly.
NRF2-induced hepatomegaly is similar to hepatomegaly induced by too much insulin, in a process that relies on activation of AKT. So the research team investigated the involvement of insulin and AKT in NRF2-induced hepatomegaly. Although they found no evidence for excessive insulin production, AKT was activated in mouse livers and played a key role in the hepatomegaly process.
The scientists also discovered that inhibiting AKT completely reversed hepatomegaly and restored normal liver size and physiology in mice. According to the authors, the finding suggested that AKT inhibitors, which have already been evaluated in humans for their anti-cancer activity, may potentially be used for treating and reversing hepatomegaly.
Citation: He F, Antonucci L, Yamachika S, Zhang Z, Taniguchi K, Umemura A, Hatzivassiliou G, Roose-Girma M, Reina-Campos M, Duran A, Diaz-Meco MT, Moscat J, Sun B, Karin M. 2020. NRF2 activates growth factor genes and downstream AKT signaling to induce mouse and human hepatomegaly. J Hepat 72(6):1182-1195.