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

Wenfeng Zhang1,2, Chaoying Wu1, Rui Ni1

  • 1Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China.

Plos Genetics
|December 23, 2021
PubMed

Insights

Formimidoyltransferase cyclodeaminase (FTCD) prevents liver hypertrophy during starvation. A zebrafish study found FTCD mutation causes liver dysfunction by preventing mTORC1 downregulation, highlighting FTCD

Area of Science:

  • Metabolic regulation
  • Hepatology
  • Zebrafish genetics

Background:

  • The liver is central to energy homeostasis, particularly during starvation.
  • Downregulation of mammalian target of rapamycin complex 1 (mTORC1) is key in starvation response, but upstream regulators are unclear.
  • Understanding these mechanisms is vital for addressing liver energy disorders.

Purpose of the Study:

  • To identify genetic factors regulating liver energy metabolism during starvation.
  • To elucidate the upstream mechanisms controlling mTORC1 activity in the liver under fasting conditions.
  • To characterize the function of formimidoyltransferase cyclodeaminase (FTCD) in hepatic starvation response.

Main Methods:

  • Zebrafish forward genetic screen to identify liver energy disorder mutants.
  • Positional cloning to identify the causative gene mutation.
  • Analysis of liver phenotype (hypertrophy, cell size) under feeding and fasting.
  • Biochemical assays measuring mTORC1 pathway activity (phosphorylated ribosomal S6 protein).
  • Pharmacological inhibition of mTORC1 using rapamycin.

Main Results:

  • A zebrafish mutant (liver hulk, lvh) displayed liver hypertrophy and dysfunction specifically under fasting conditions.
  • Positional cloning identified the mutation in the lvh mutant to be in the ftcd gene, encoding formimidoyltransferase cyclodeaminase (FTCD).
  • The lvh mutant showed sustained high levels of phosphorylated ribosomal S6 protein (a marker of mTORC1 activity) during starvation, unlike wild-type.
  • Rapamycin treatment rescued the liver hypertrophy and dysfunction in the lvh mutant.

Conclusions:

  • FTCD is a critical upstream regulator of mTORC1 signaling in the liver during starvation.
  • Loss of FTCD function leads to impaired mTORC1 downregulation, resulting in liver hypertrophy and dysfunction.
  • FTCD plays a protective role in preventing hepatic energy imbalance and maintaining liver function under starvation.

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