Xu, PanOosterveer, Maaike H.Stein, SokratesDemagny, HadrienRyu, DongryeolMoullan, NormanWang, XuCan, EmineZamboni, NicolaComment, ArnaudAuwerx, JohanSchoonjans, Kristina2016-07-192016-07-192016-07-192016-06-0110.1101/gad.277483.116https://infoscience.epfl.ch/handle/20.500.14299/127624WOS:000378084000002Various tumors develop addiction to glutamine to support uncontrolled cell proliferation. Here we identify the nuclear receptor liver receptor homolog 1 (LRH-1) as a key regulator in the process of hepatic tumorigenesis through the coordination of a noncanonical glutamine pathway that is reliant on the mitochondrial and cytosolic transaminases glutamate pyruvate transaminase 2 (GPT2) and glutamate oxaloacetate transaminase 1 (GOT1), which fuel anabolic metabolism. In particular, we show that gain and loss of function of hepatic LRH-1 modulate the expression and activity of mitochondrial glutaminase 2 (GLS2), the first and rate-limiting step of this pathway. Acute and chronic deletion of hepatic LRH-1 blunts the deamination of glutamine and reduces glutamine-dependent anaplerosis. The robust reduction in glutaminolysis and the limiting availability of a-ketoglutarate in turn inhibit mTORC1 signaling to eventually block cell growth and proliferation. Collectively, these studies highlight the importance of LRH-1 in coordinating glutamine-induced metabolism and signaling to promote hepatocellular carcinogenesis.Hepatocellular carcinomacancer metabolismnuclear receptor NR5A2mitochondriaanaplerosismTORNADPHtext::journal::journal article::research article