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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.

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Fig. 1: The body weights of C9orf72-knockout rats decreased.
Fig. 2: Loss of C9orf72 inhibits HFD-induced hepatic steatosis.
Fig. 3: Loss of C9orf72 inhibits in the Srebp1 translocation into the nucleus.
Fig. 4: C9orf72 deficiency in HepG2 cells inhibits SREBP1 pathways.
Fig. 5: Reintroduction of C9orf72 rescues the phenotype of HepG2 cells.
Fig. 6: SEC16A is degraded by the ubiquitin proteasome pathway.
Fig. 7: Model of C9orf72 mediated regulation of SREBP1 transport into the nucleus.

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The paper and its supplementary information contain all data supporting the study findings. Additional information is available upon reasonable request to the authors. Source data accompany this paper.

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Acknowledgements

We express our gratitude to the Large Instrument and Equipment Sharing Platform of the School of Pharmaceutical Sciences, Wuhan University, as well as the Center for Animal Experiment/Animal Biosafety Level-III Laboratory of Wuhan University.

Funding

This work was supported by grants from the National Key Research and Development Program of China (2019YFA0904300), Wuhan Science and Technology Major Project (2023020302020708), Shenzhen Key Laboratory of Microbiology in Genomic Modification & Editing and Application (Shenzhen Science and Technology Program, ZDSYS202306263000006), and the Fundamental Research Funds for the Central Universities of China.

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S Chen and L Wang conceived the study and supervised the project. Y Wu designed and performed the experiments. Y Wu, W Zheng, G Xu, L Zhu, Z Li, J Chen, S Chen and L Wang analyzed the data. Y Wu, S Chen and L Wang wrote the manuscript. All the authors discussed the results and commented on the manuscript.

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Correspondence to Lianrong Wang or Shi Chen.

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All experimental protocols were approved by the Institutional Animal Care and Use Committee at Wuhan University (IACUC NO. SQ20200283).

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Wu, Y., Zheng, W., Xu, G. et al. C9orf72 controls hepatic lipid metabolism by regulating SREBP1 transport. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01312-7

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