Formimidoyltransferase cyclodeaminase prevents the starvation-induced liver hepatomegaly and dysfunction through downregulating mTORC1

The liver is a crucial center in the regulation of energy homeostasis under starvation. Although downregulation of mammalian target of rapamycin complex 1 (mTORC1) has been reported to play pivotal roles in the starvation responses, the underpinning mechanisms in particular upstream factors that downregulate mTORC1 remain largely unknown. To identify genetic variants that cause liver energy disorders during starvation, we conduct a zebrafish forward genetic screen. We identify a liver hulk (lvh) mutant with normal liver under feeding, but exhibiting liver hypertrophy under fasting. The hepatomegaly in lvh is caused by enlarged hepatocyte size and leads to liver dysfunction as well as limited tolerance to starvation. Positional cloning reveals that lvh phenotypes are caused by mutation in the ftcd gene, which encodes the formimidoyltransferase cyclodeaminase (FTCD). Further studies show that in response to starvation, the phosphorylated ribosomal S6 protein (p-RS6), a downstream effector of mTORC1, becomes downregulated in the wild-type liver, but remains at high level in lvh. Inhibition of mTORC1 by rapamycin rescues the hepatomegaly and liver dysfunction of lvh. Thus, we characterize the roles of FTCD in starvation response, which acts as an important upstream factor to downregulate mTORC1, thus preventing liver hypertrophy and dysfunction.
Author summary Under starvation, the liver initiates a series of metabolic adaptations to maintain energy homeostasis that is critical for survival. During this process, mTORC1 pathway is downregulated to reduce anabolism and promote catabolism, ensuring adequate usage of limited resources. However, mechanisms underlying the downregulation of mTORC1 remain incompletely understood. In a zebrafish genetic screen aiming to characterize factors important for starvation response in the liver, we identify an ftcd mutation that causes liver hypertrophy and dysfunction under fasting. FTCD acts upstream to inactivate mTORC1 in response to starvation. Our work reveals previously unappreciated roles of FTCD in the responses to energy stress through modulating mTORC1 activities, moreover implicates a potential liver disorder risk of FTCD deficiency under the circumstances of starvation.