LRH-1-dependent programming of mitochondrial glutamine processing drives liver cancer

Abstract

Various 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 α-ketoglutarate in turn inhibit mTORC1 signaling to eventually block cell growth and proliferation. Collectively, these studies highlight the importance of LRH-1 in coordinating glutamineinduced metabolism and signaling to promote hepatocellular carcinogenesis.Supplemental material is available for this article.Received January 7, 2016; revised version accepted May 12, 2016.During tumorigenesis, cancer cells usually switch from oxidative metabolism to a highly glycolytic metabolic status (Vander Heiden et al. 2009). While glucose is predominantly metabolized into lactate rather than entering the tricarboxylic acid (TCA) cycle, cancer cells particularly rely on glutamine to replenish TCA cycle intermediates. This process, termed anaplerosis, is accomplished through the conversion of glutamine to α-ketoglutarate (α-KG) via a two-step deamination reaction catalyzed by glutaminases and then by glutamate dehydrogenase 1 (GLUD1) or transaminases Wise et al. 2008;Csibi et al. 2013;Son et al. 2013). Cancer cells therefore critically depend on glutamine as a fuel for proliferation, and abrogation of glutamine metabolism blocks tumorigenesis, indicating an accessible therapeutic window for cancer treatment (Hensley et al. 2013).Liver receptor homolog 1 (LRH-1; also called NR5A2) is a nuclear receptor that is enriched in enterohepatic tissues, where it has diverse molecular and physiological functions (Stein and Schoonjans 2015). LRH-1 has been linked to cell proliferation and cancer development in the intestine (Botrugno et al. 2004;Schoonjans et al. 2005) and pancreas (Petersen et al. 2010;Benod et al. 2011). In the liver, LRH-1 regulates various metabolic processes, including bile acid synthesis (Mataki et al. 2007;Lee et al. 2008;Out et al. 2011), glucose sensing and processing (Oosterveer et al. 2012), and reverse cholesterol transport (Stein et al. 2014). Although the function of LRH-1 in the liver has been extensively studied, its commanding role in intermediary metabolism has never been connected to tumorigenesis.In this study, we report that LRH-1 promotes diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) by coordinating glutamine-induced anabolic metabo...

Enhancement of hepatic autophagy increases ureagenesis and protects against hyperammonemia

“…Supplementations in vivo with an α-KG analog that rescued mTORC1 activity and prevented ammonia-induced autophagy provide robust evidence for an α-KG-dependent modulation of hepatic mTORC1 activity during hyperammonemia. Hence, our data are consistent with previous studies showing a direct correlation between α-KG levels and mTORC1 activity (20,24,(47)(48)(49). The activity of the oxygen sensors EGLN/prolyl hydroxylases that require oxygen and α-KG for hydroxylation of target proteins has been proposed to explain α-KG-dependent activation of mTORC1 (48).…”

TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma

“…Furthermore, another target can be the liver receptor homolog (LRH-1), implicated in coordinating glutamine-induced metabolism and hepatocarcinogenesis. Xu et al demonstrated that LRH-1 deletion inhibited HCC cell proliferation through different mechanism, such as reduction of glutamine deamination and glutaminolysis and inhibition of mTOR signaling [171].…”

Structure and Dynamics of the Liver Receptor Homolog 1–PGC1α Complex

“…Glucose transport, metabolism, and capture are regulated by LRH-1 via control of proteins such as the GLUT4 transporter in skeletal muscle and glucokinase in the liver (Oosterveer et al, 2012;Bolado-Carrancio et al, 2014). On the other hand, aberrant activation of LRH-1 drives tumorigenesis and tumor-cell proliferation in several cancer types (Chand et al, 2010;Thiruchelvam et al, 2011;Bianco et al, 2014;Lin et al, 2014;Bayrer et al, 2015;Nadolny and Dong, 2015;Xu et al, 2016). Because of this vital transcriptional program, LRH-1 is garnering attention as a new therapeutic target for treatment of diseases such as nonalcoholic fatty liver disease, diabetes, and cancer.…”