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

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 co...

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Bibliographic Details
Published in:Genes & development 2018-11, Vol.32 (21-22), p.1380-1397
Main Authors: Liu, Yang, Wang, Tao, Ji, Yon Ju, Johnson, Kenji, Liu, Honghe, Johnson, Kaitlin, Bailey, Scott, Suk, Yongwon, Lu, Yu-Ning, Liu, Mingming, Wang, Jiou
Format: Article
Language:English
Subjects:
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - metabolism
Animals
C9orf72 Protein - genetics
C9orf72 Protein - metabolism
C9orf72 Protein - physiology
Cells, Cultured
Fatty Acids - metabolism
Frontotemporal Dementia - genetics
Frontotemporal Dementia - metabolism
Glucose - physiology
HEK293 Cells
Humans
Lipid Metabolism
Lysosomes - metabolism
Mice
Protein-Arginine N-Methyltransferases - metabolism
Protein-Arginine N-Methyltransferases - physiology
Research Paper
Stress, Physiological
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Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.315564.118