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Hepatic AKAP1 deficiency exacerbates diet-induced MASLD by enhancing GPAT1-mediated lysophosphatidic acid synthesis

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Listed:
  • Linjie He

    (Fourth Military Medical University)

  • Xiaojuan She

    (Fourth Military Medical University
    Yan’an University)

  • Lifei Guo

    (Fourth Military Medical University
    Northwest University)

  • Mingshu Gao

    (Northwest University
    Fourth Military Medical University)

  • Shuangbin Wang

    (Fourth Military Medical University
    Medical College of Yan’an University)

  • Zhenxing Lu

    (Fourth Military Medical University)

  • Haitao Guo

    (Fourth Military Medical University)

  • Renlong Li

    (Fourth Military Medical University)

  • Yongzhan Nie

    (Fourth Military Medical University)

  • Jinliang Xing

    (Fourth Military Medical University)

  • Lele Ji

    (Fourth Military Medical University)

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), closely associated with obesity, can progress to metabolic dysfunction-associated steatohepatitis when the liver undergoes overt inflammatory damage. A-kinase anchoring protein 1 (AKAP1) has been shown to control lipid accumulation in brown adipocytes. However, the role of AKAP1 signaling in hepatic lipid metabolism and MASLD remains poorly understood. Here, we showed that hepatocyte-specific AKAP1 deficiency exacerbated hepatic steatosis and steatohepatitis in male mice subjected to a high-fat diet and fast-food diet, respectively. Mechanistically, AKAP1 directly phosphorylated and inactivated glycerol-3-phosphate acyltransferase 1 (GPAT1) in a PKA-dependent manner, thus suppressing lysophosphatidic acid (LPA) production. Increased endogenous LPA in hepatocytes promoted hepatocellular triglyceride (TG) synthesis and initiated pronounced inflammatory response in Kupffer cells. Restoring hepatic AKAP1 or repressing LPA levels via GPAT1 knockdown alleviated MASLD exacerbation. Overall, AKAP1 plays a protective role against MASLD by inhibiting GPAT1 activity, highlighting the potential of targeting AKAP1/PKA/GPAT1 signalosome for MASLD therapy.

Suggested Citation

  • Linjie He & Xiaojuan She & Lifei Guo & Mingshu Gao & Shuangbin Wang & Zhenxing Lu & Haitao Guo & Renlong Li & Yongzhan Nie & Jinliang Xing & Lele Ji, 2025. "Hepatic AKAP1 deficiency exacerbates diet-induced MASLD by enhancing GPAT1-mediated lysophosphatidic acid synthesis," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58790-7
    DOI: 10.1038/s41467-025-58790-7
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