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

Linjie He, Xiaojuan She, Lifei Guo, Mingshu Gao, Shuangbin Wang, Zhenxing Lu, Haitao Guo, Renlong Li, Yongzhan Nie, Jinliang Xing () and Lele Ji ()
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Linjie He: Fourth Military Medical University
Xiaojuan She: Fourth Military Medical University
Lifei Guo: Fourth Military Medical University
Mingshu Gao: Northwest University
Shuangbin Wang: Fourth Military Medical 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

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58790-7

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