The liver processes a broad range of molecules including nutrients, toxins, and drugs. Routine detoxification of these compounds in the liver is primarily orchestrated by the nuclear receptor Constitutive Androstance Receptor (CAR). Interestingly, CAR activation by its ligand TCPOBOP (TC), along with increasing the metabolic potential of the liver, induces hepatic DNA replication and subsequent liver growth. The mechanisms that facilitate this CAR-dependent liver growth are not fully understood. Unexpectedly, we discovered that CAR activation can increase de novo dNTP synthesis by inducing the expression of several enzymes involved in this process including Ribonucleotide Reductase M2 (RRM2). RRM2 is the catalytic subunit of Ribonucleotide Reductase, the rate-limiting enzyme responsible for dNTP biosynthesis. Importantly, we found that induction of RRM2 and subsequent increases in the dNTP concentrations were completely absent in Car-/- mice. These findings indicate that by increasing dNTP synthesis, CAR activation may afford a cellular milieu that is amenable for DNA synthesis and proliferation. In this proposal, we will determine (1) if CAR-mediated dNTP synthesis is necessary and sufficient to promote liver growth, and (2) if CAR-RRM2 axis promotes polyploidy and regeneration in the liver. Overall, this project will not only uncover the fundamental role for CAR in regulating cellular dNTP levels but also identify novel mechanism(s) by which CAR achieves its mitogenic effects.
The liver is constantly subjected to damage while metabolizing and detoxifying foreign compounds. However, it is protected by its inherent regenerative capacity which is overwhelmed during liver dysfunction. This project is designed to understand the mechanism by which CAR, a xenobiotic sensor, coordinates hepatocyte proliferation with metabolic function, which may allow us to develop novel therapeutic targets to protect against liver diseases affecting millions of individuals.
| Bangru, Sushant; Arif, Waqar; Seimetz, Joseph et al. (2018) Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration. Nat Struct Mol Biol 25:928-939 |
