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Amyloid Precursor Protein Promotes MASH Progression by Upregulating Death Receptor 6-Mediated Hepatocyte Apoptosis
Background: Metabolic dysfunction-associated steatohepatitis (MASH) is a complicated process that contributes to end-stage liver disease and, eventually, hepatocellular carcinoma (HCC). Hepatocyte apoptosis, a well-defined form of cell death in MASH, is considered the primary cause of liver inflammation and fibrosis. However, the mechanisms underlying the regulation of hepatocyte apoptosis in MASH remain largely unclear. We explored the pro-apoptotic effect of hepatocyte amyloid precursor protein (APP) in MASH.
Methods: C57BL/6J mice were fed a western diet plus sugar water, a high-fat high-fructose diet or a methionine and choline deficiency diet induce MASH. APP expression was analyzed in murine MASH specimens. App−/− mice and mice with adeno-associated virus-mediated APP overexpression were established to study the role of APP in MASH. Palmitic acid was used to mimic lipotoxicity induced MASH in AML-12 cells.
Finds: We identified a dramatic increase in APP expression in hepatocytes of patients with MASH and three different mouse models. Suppression of APP attenuated hepatic steatosis, inflammation, and fibrosis in MASH mice, whereas its restoration activated MASH pathogenesis. Furthermore, increased death receptor 6 (DR6) was observed in MASH mouse livers. Mechanistically, APP interacted with DR6, a tumor necrosis factor receptor, to facilitate DR6 expression and activation. Activated DR6 increased apoptosis in hepatocytes, which was associated with an increase in pro-apoptotic effectors (cleaved-caspase 3/7).
Interpretation: Our results highlight the role of the APP/DR6 axis in hepatocyte apoptosis, inflammation activation and fibrosis formation in murine MASH model, providing new insights into therapeutic strategies for MASH.
Funding: This work was supported by the National Key Research and Development Program (2018YFA0109800), the National Natural Science Foundation of China (82070585 and 82270602), the Natural Science Foundation of Zhejiang Province (No. LY21H030001), Excellent Postdoctoral Program of Jiangsu Province (2023ZB699) and the Natural Science Foundation of Jiangsu Province (BK20241115).
Declaration of Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Ethical Approval: All animal experiments were approved by the Animal Care and Use Committee of the First Affiliated Hospital, Zhejiang University School of Medicine (reference number: 2022-8).
Guo, Yanjun and Huang, Hangkai and Yang, Ling and Liu, Zhening and Wang, Qinqiu and Chen, Shenghui and Pan, Jiaqi and Zhai, Haoliang and Li, Youming and Xu, Lei and Yu, Chaohui and Xu, Cheng-Fu, Amyloid Precursor Protein Promotes MASH Progression by Upregulating Death Receptor 6-Mediated Hepatocyte Apoptosis. Available at SSRN: https://ssrn.com/abstract=4971462 or http://dx.doi.org/10.2139/ssrn.4971462
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