C9orf72 controls hepatic lipid metabolism by regulating SREBP1 transport.

ABSTRACT

Sterol regulatory element binding transcription factors (SREBPs) play a crucial role in lipid homeostasis. They are processed and transported to the nucleus via COPII, where they induce the expression of lipogenic genes. COPII maintains the homeostasis of organelles and plays an essential role in the protein secretion pathways in eukaryotes. The formation of COPII begins at endoplasmic reticulum exit sites (ERES), and is regulated by SEC16A, which provides a platform for the assembly of COPII. However, there have been few studies on the changes in SEC16A protein levels. The repetitive expansion of the hexanucleotide sequence GGGGCC within the chromosome 9 open reading frame 72 (C9orf72) gene is a prevalent factor in the development of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we found that the absence of C9orf72 leads to a decrease in SEC16A protein levels, resulting in reduced localization of the guanine nucleotide exchange factor SEC12 at the ERES. Consequently, the small GTP binding protein SAR1 is unable to bind the endoplasmic reticulum normally, impairing the assembly of COPII. Ultimately, the disruption of SREBPs transport decreases de novo lipogenesis. These results suggest that C9orf72 acts as a novel role in regulating lipid homeostasis and may serve as a potential therapeutic target for obesity.