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Int J Biol Sci 2024; 20(6):2219-2235. doi:10.7150/ijbs.92337 This issue Cite

Research Paper

NUP85 alleviates lipid metabolism and inflammation by regulating PI3K/AKT signaling pathway in nonalcoholic fatty liver disease

Yin-cui Wu^1,2,*, Qi Yan^3,*, Si-qing Yue^1,2, Lin-xin Pan⁴, Da-shuai Yang^1,2, Liang-song Tao^1,2, Ze-yuan Wei^1,2, Fan Rong^1,2, Cheng Qian⁵, Meng-qi Han^1,2, Fu-cheng Zuo^1,2, Jun-fa Yang^1,2, Jia-jia Xu¹, Zheng-rong Shi⁶, Jian Du^3✉, Zhao-lin Chen^7,8✉, Tao Xu^1,2✉

1. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
2. Institute for Liver Diseases of Anhui Medical University, Hefei 230032, China.
3. School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China.
4. College of life sciences, Anhui Medical University, Hefei 230032, China.
5. Research and Experiment center, Anhui Medical University, Hefei 230032, China.
6. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
7. Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Hospital, Hefei, Anhui, 230001, China.
8. Anhui Provincial Key Laboratory of Precision Pharmaceutical Preparations and Clinical Pharmacy, Hefei, Anhui, 230001, China.
*They contribute equally to this work.

✉ Corresponding author: Jian Du, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, 230032, China. E-mail: dujianedu.cn. Zhaolin Chen, Department of Pharmacy, The First Affiliated Hospital of USTC, Hefei, Anhui Province, 230032, China. Email: czl0808edu.cn. Tao Xu, School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, Anhui Province, 230032, China. Tel/fax: +86 0551-65172131; E-mail: xutaoedu.cn. More

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the common causes of chronic liver disease in the world. The problem of NAFLD had become increasingly prominent. However, its pathogenesis is still indistinct. As we all know, NAFLD begins with the accumulation of triglyceride (TG), leading to fatty degeneration, inflammation and other liver tissues damage. Notably, structure of nucleoporin 85 (NUP85) is related to lipid metabolism and inflammation of liver diseases. In this study, the results of researches indicated that NUP85 played a critical role in NAFLD. Firstly, the expression level of NUP85 in methionine-choline-deficient (MCD)-induced mice increased distinctly, as well as the levels of fat disorder and inflammation. On the contrary, knockdown of NUP85 had the opposite effects. In vitro, AML-12 cells were stimulated with 2 mm free fatty acids (FFA) for 24 h. Results also proved that NUP85 significantly increased in model group, and increased lipid accumulation and inflammation level. Besides, NUP85 protein could interact with C-C motif chemokine receptor 2 (CCR2). Furthermore, when NUP85 protein expressed at an extremely low level, the expression level of CCR2 protein also decreased, accompanied with an inhibition of phosphorylation of phosphoinositol-3 kinase (PI3K)-protein kinase B (AKT) signaling pathway. What is more, trans isomer (ISRIB), a targeted inhibitor of NUP85, could alleviate NAFLD. In summary, our findings suggested that NUP85 functions as an important regulator in NAFLD through modulation of CCR2.

Keywords: NUP85, Nonalcoholic fatty liver disease, PI3K/AKT, CCR2, ISRIB

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