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Mup3 ameliorates the dysregulation of glucose and lipid metabolism in MAFLD

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Major urinary protein 3 (Mup3), belonging to the Mup family, is involved in metabolic regulation, but the exact regulatory pathways remain to be elucidated. In this study we investigated the function of Mup3 in regulating hepatic glucose and lipid metabolism. We established four mouse models of metabolic disorders, i.e. db/db and ob/ob obese mice, high-fat diet (HFD)-induced obese (DIO) mice and mice with methionine-choline-deficient (MCD) diet-induced metabolic-associated steatohepatitis (MASH). We found that the expression levels of Mup3 were significantly reduced in the livers of all the four model mice. Moreover, upregulation of Mup3 levels in the liver of HFD-induced obese mice and db/db mice via adeno-associated virus notably decreased blood glucose levels and hepatic triglyceride (TG) content, and improved glucose tolerance and insulin sensitivity. Conversely, Mup3 gene knockout exacerbated HFD-induced hyperglycemia and hepatic lipid accumulation and worsened glucose intolerance and insulin resistance (IR). Restoring the expression of Mup3 reversed these effects in the livers of Mup3-/-. By conducting RNA sequencing (RNA-seq) analysis we revealed that Mup3 primarily modulated gluconeogenesis and the PI3K/AKT signaling cascades. We demonstrated that Mup3 downregulated the genes associated with hepatic gluconeogenesis and lipid synthesis while attenuating hepatic inflammation. These results suggest that Mup3 plays a central role in regulating glucose and lipid balance, highlighting its significance as a prospective treatment target for metabolic disorders, including diabetes and metabolic dysfunction-associated fatty liver disease (MAFLD).

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Fig. 1: Downregulation of Mup3 expression in metabolic disease models.
Fig. 2: Mup3 markedly suppresses gluconeogenesis in primary mouse hepatocytes.
Fig. 3: Mup3 overexpression alleviates HFD-induced hyperglycemia and insulin resistance.
Fig. 4: Mup3 overexpression ameliorates HFD-induced hepatic steatosis and inflammation.
Fig. 5: Mup3 is involved in multiple metabolic pathways in the livers of HFD-induced obese mice.
Fig. 6: Mup3 deficiency exacerbates HFD-induced metabolic disorders in mice.
Fig. 7: Mup3 knockout exacerbates HFD-induced hepatic steatosis and inflammation.
Fig. 8: Re-expression of Mup3 in the liver of Mup3-/- restores glycemic and lipid control in HFD-fed mice.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82370878, 81870402, 82200975 and 82300659), Key Research and Development Program of Anhui Province (2022i01020023), Anhui Science Fund for Distinguished Young Scholars (2208085J45), Research Fund of Anhui Institute of Translational Medicine (2022zhyx-C12), and Natural Science Foundation of Anhui Province (2308085QH247).

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Author notes

  1. These authors contributed equally: Xiao-min Zhang, Jing-ya Gao, Dong Wang

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei, 230032, China

    Xiao-min Zhang, Jing-ya Gao, Li Lin, Xin-rui Xie, Han Gao, Xiu-yun Wang & Hua-bing Zhang

  2. Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China

    Dong Wang, Hong-ting Hua, Chao-bing Gao & Hua-bing Zhang

  3. Department of Hyperbaric Oxygen, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, 230011, China

    Xiang Wei

  4. Department of Endocrinology, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China

    Yong-xia Xu

  5. Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510000, China

    Lei Zhang

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Contributions

XMZ, JYG, and DW contributed equally to this work. HBZ, CBG, and LZ conceived and designed the experiments. XMZ, JYG, DW, LL, XW, XRX, and HG performed the laboratory experiments. HTH, XYW, and YXX completed the data analysis RNA sequencing. HBZ provided funding. XMZ and JYG drafted the original manuscript. All authors contributed to and have approved the final manuscript.

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Correspondence to Lei Zhang, Chao-bing Gao or Hua-bing Zhang.

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Zhang, Xm., Gao, Jy., Wang, D. et al. Mup3 ameliorates the dysregulation of glucose and lipid metabolism in MAFLD. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01668-7

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