A C9orf72–CARM1 axis regulates lipid metabolism under glucose starvation-induced nutrient stress

Yang Liu, Tao Wang, Yon Ju Ji, Kenji Johnson, Honghe Liu, Kaitlin Johnson, Scott Bailey, Yongwon Suk, Yu Ning Lu, Mingming Liu, Jiou Wang

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Cells undergo metabolic adaptation during environmental changes by using evolutionarily conserved stress response programs. This metabolic homeostasis is exquisitely regulated, and its imbalance could underlie human pathological conditions. We report here that C9orf72, which is linked to the most common forms of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is a key regulator of lipid metabolism under stress. Loss of C9orf72 leads to an overactivation of starvation-induced lipid metabolism that is mediated by dysregulated autophagic digestion of lipids and increased de novo fatty acid synthesis. C9orf72 acts by promoting the lysosomal degradation of coactivator-associated arginine methyltransferase 1 (CARM1), which in turn regulates autophagy–lysosomal functions and lipid metabolism. In ALS/FTD patient-derived neurons or tissues, a reduction in C9orf72 function is associated with dysregulation in the levels of CARM1, fatty acids, and NADPH oxidase NOX2. These results reveal a C9orf72–CARM1 axis in the control of stress-induced lipid metabolism and implicates epigenetic dysregulation in relevant human diseases.

Original languageEnglish (US)
Pages (from-to)1380-1397
Number of pages18
JournalGenes and Development
Issue number21-22
StatePublished - Nov 1 2018


  • ALS
  • Autophagy
  • C9orf72
  • CARM1
  • FTD
  • Lipid metabolism
  • NOX2

ASJC Scopus subject areas

  • General Medicine


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