Jittima Weerachayaphorn, PhD

Project Title: Altered nuclear calcium (Ca2+) in hepatocytes as a driver of chronic liver disease

Chronic liver disease affects a billion people worldwide and often results in cirrhosis. Although a variety of liver diseases can result in cirrhosis, a unifying feature is that the liver’s ability to repair itself and regenerate is impaired. Disruptions in nuclear calcium (Ca2+) signaling in hepatocytes have been identified as a critical factor influencing liver regeneration and fibrosis. Our group has demonstrated that loss of type II inositol 1,4,5-trisphosphate receptor (ITPR2), the predominant Ca2+ release channel in hepatocytes, impairs nuclear Ca2+ signaling, cell proliferation, and liver regeneration. Furthermore, ITPR2 is absent in hepatocytes from patients with chronic liver disease. This suggests that the loss of ITPR2 in hepatocytes is a common feature of chronic liver disease leading to cirrhosis, raising questions on how ITPR2 is important for nuclear Ca2+-mediated proliferation and liver regeneration. Existing evidence highlights the importance of intranuclear Ca2+ and b-catenin translocation into the nucleus, which is crucial for liver regeneration. Our preliminary data indicate that nuclear b-catenin levels decrease alongside reduced intranuclear ITPR2 and diminished nuclear Ca2+ signaling in hepatocytes from a metabolic dysfunction-associated steatohepatitis (MASH) mouse model. The hypothesis of this project is that ITPR2 in the nucleus is essential for generating intranuclear Ca2+ and facilitating b-catenin’s entry into the nucleus to drive liver regeneration. This project aims to investigate the role of nuclear ITPR2-mediated Ca2+ signaling in regulating β-catenin’s entry into the nucleus and to determine how ITPR2 localizes in the nucleus of hepatocytes to regulate nuclear Ca2+ signaling. This work will identify mechanisms that preserve liver regeneration despite chronic inflammation, providing new insights for the development of therapeutic strategies for chronic liver disease.