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Arf1-deficiency-induced neuronal surplus fatty acid synthesis evokes neurodegeneration through mtDNA releasing and inflammatory activating in microglia

ABSTRACT: The crucial role of lipid metabolism disorders and neuronal inflammation has been revealed in many studies of neurodegenerative diseases. However, the pathological connection between lipid droplets and neuronal immune circuits remains poorly understood. We have previously reported a neuronal-specific Arf1-knockout mouse as an ideal lipid metabolism disorder-induced neurodegeneration model. Here, we found that Arf1-deficiency first induced surplus fatty acid synthesis and lipid droplets (LDs) accumulation through the AKT-mTORC1-SREBP1-FASN axis, which further triggered endoplasmic reticulum (ER)-mitochondrial stress cascade via calcium flux. The organelle stress cascade further induced mitochondrial DNA (mtDNA) to be released into the cytoplasm. Meanwhile, the FASN-driven fatty acid synthesis in the Arf1-deficient neurons also induced lysosomal sphingolipids accumulation that caused dysfunction of autophagy and lysosomes, which enables the neuronal mtDNA to transfer to microglia via extracellular vesicles (EVs) and activates the inflammatory pathways to aggravate neurodegeneration. Furthermore, inhibition of FASN or boosting autophagy in vivo reversed neuronal degeneration disease in Arf1-knockout mice. Our study suggests a unified pathological function of LD in NDs and proves that inhibition of fatty acid synthesis-induced inflammation might be a therapeutic route to neuronal degeneration disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE273284 | GEO | 2025/04/30

REPOSITORIES: GEO

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Project description:Metabolic reprogramming is a typical feature of tumors, in which biological macromolecules and energy produced in abnormal metabolism meet the requirements of highly proliferative tumor cells and participate in multiple stages of tumor development. High mobility group A1 (HMGA1) is a structural transcription factor, which plays a carcinogenic role in regulating the transcription of oncogenes. Bioinformatics analysis showed that HMGA1 was overexpressed in human CRC. However, the mechanisms by which HMGA1 promotes the tumorigenesis of CRC remains unknown. Herein, we applied intestinal epithelium conditional knockout (Hmga1△IEC) and knock-in (Hmga1IEC-OE/+) mice of HMGA1 to induce CRC, and identified that HMGA1 promotes colorectal cancer growth by increasing lipid synthesis. Single-cell sequencing (scRNA seq) and immunohistochemical staining showed that HMGA1 was highly expressed in the epithelial cells of CRC. HMGA1 promoted the CRC cell proliferation and accelerated CRC development in HMGA1-knock-in (Hmga1IEC-OE/+) mice. Knockout of HMGA1 (Hmga1△IEC) in intestinal epithelial cells of mice reduced the lipid accumulation and inhibited the occurrence and development of CRC. We further characterized that HMGA1 upregulated the level of fatty acid synthase (FASN) through enhancing the transcriptional binding of sterol regulatory element-binding protein 1 (SREBP1) to the promoter of FASN, leading to an increase in lipid synthesis in intestinal epithelial cells. High fat diet (HFD) aggravated the malignant progression of CRC in Hmga1△IEC mice and reversed the inhibitory effect of HMGA1 depletion on CRC. Administration Orlistat (50 mg/kg), an inhibitor of FASN-mediated lipid synthesis, into Hmga1-knock-in (Hmga1IEC-OE/+) mice markedly reduced lipid accumulation in intestinal epithelial cells and decreased the tumorigenesis of CRC. Taken together, our data suggest that HMGA1 promotes the tumorigenesis of colorectal cancer by up-regulating FASN-mediated de novo fatty acid synthesis. Our findings provide strong evidence supporting therapeutic intervention of lipid accumulation for the prevention and treatment of CRC

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Arf1-deficiency-induced neuronal surplus fatty acid synthesis evokes neurodegeneration through mtDNA releasing and inflammatory activating in microglia

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