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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<jats:italic>liver hulk (lvh)<\/jats:italic>mutant with normal liver under feeding, but exhibiting liver hypertrophy under fasting. The hepatomegaly in<jats:italic>lvh<\/jats:italic>is caused by enlarged hepatocyte size and leads to liver dysfunction as well as limited tolerance to starvation. Positional cloning reveals that<jats:italic>lvh<\/jats:italic>phenotypes are caused by mutation in the<jats:italic>ftcd<\/jats:italic>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<jats:italic>lvh<\/jats:italic>. Inhibition of mTORC1 by rapamycin rescues the hepatomegaly and liver dysfunction of<jats:italic>lvh<\/jats:italic>. 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.<\/jats:p>","DOI":"10.1371\/journal.pgen.1009980","type":"journal-article","created":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T18:52:52Z","timestamp":1640285572000},"page":"e1009980","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Formimidoyltransferase cyclodeaminase prevents the starvation-induced liver hepatomegaly and dysfunction through downregulating mTORC1"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5976-2259","authenticated-orcid":true,"given":"Wenfeng","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4525-9513","authenticated-orcid":true,"given":"Chaoying","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6135-816X","authenticated-orcid":true,"given":"Rui","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qifen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5318-8137","authenticated-orcid":true,"given":"Lingfei","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianbo","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,12,23]]},"reference":[{"issue":"2","key":"pgen.1009980.ref001","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S0012-1606(02)00017-9","article-title":"Formation of the digestive system in zebrafish. 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