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Caveolin-1 deficiency alleviates palmitate-induced intracellular lipid accumulation and inflammation in pancreatic β cells

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Abstract

Lipotoxicity-induced pancreatic β cell damage is a strong predictor of type 2 diabetes mellitus (T2DM). Our previous work showed that Caveolin-1 (Cav-1) depletion decreased β-cell apoptosis and improved β-cell viability. Further microarray analysis indicated significant changes in the expression of genes related to fatty acid metabolism and inflammation. The objective of this study was to explore the role of Cav-1 in intracellular lipid accumulation and inflammation in β cells under lipotoxic conditions. Here, we established a β-cell-specific Cav-1 knockout (β-Cav-1 KO) mouse model and a CAV-1 depleted β cell line (NIT-1). We found that Cav-1 silencing significantly reduced palmitate (PA)-induced intracellular triglyceride (TG) accumulation and decreased proinflammatory factor expression in both the mouse and cell models. Further mechanistic investigation revealed that amelioration of lipid metabolism was achieved through the downregulation of lipogenic markers (SREBP-1c, FAS and ACC) and upregulation of a fatty acid oxidation marker (CPT-1). Meanwhile, decrease of inflammatory cytokines (IL-6, TNF-α, and IL-1β) secretion was found with the involvement of the IKKβ/NF-κB signaling pathways. Our findings suggest that Cav-1 is of considerable importance in regulating lipotoxicity-induced β-cell intracellular lipid accumulation and inflammation.

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The data are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Dr. Jiansong Tang for editing and critically revising this manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (grant numbers: 81070661 and 51873071), the Natural Science Foundation of Guangdong Province (grant number: 2018B030311012), the Medical Scientific Research Foundation of Guangdong Province (grant number: A2021168), the Science and Technology Planning Project of Guangzhou (grant number: 202102010146) and the Science and Technology Planning Project Fundamental and Applied Fundamental Research Topics of Guangzhou (assignment number: 2023A04J1088).

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Author notes

  1. Wen Zeng and Nan Cai contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China

    Wen Zeng, Nan Cai, Jia Liu, Kunying Liu, Shuo Lin & Longyi Zeng

  2. Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China

    Wen Zeng, Nan Cai, Kunying Liu, Shuo Lin & Longyi Zeng

  3. Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China

    Wen Zeng, Nan Cai, Jia Liu, Shuo Lin & Longyi Zeng

  4. Medical Center for Comprehensive Weight Control, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China

    Wen Zeng, Nan Cai, Jia Liu, Shuo Lin & Longyi Zeng

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  1. Wen Zeng
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Contributions

Wen Zeng wrote the manuscript. Wen Zeng and Nan Cai organized the literature and figures. Wen Zeng, Nan Cai, Jia Liu and Kunying Liu performed the experiments. Shuo Lin and Longyi Zeng conceived the project, led and supervised the study, and reviewed/edited the manuscript. Wen Zeng and Nan Cai contributed to this study equally. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Shuo Lin or Longyi Zeng.

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This manuscript does not contain clinical studies or patient data. All of the animal procedures were carried out in accordance with National Institutes of Health guidelines and approved by the Institute Animal Care and Use Committee (IACUC) at the Animal Ethics Committees of the Sun Yat-Sen University.

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Key points

• β-cell-specific CAV-1 knockout decreased blood lipid levels in HFD-fed mice and downregulated the expression of inflammatory mediators in PA-treated β cells.

• The reduction in intracellular lipid accumulation by Cav-1 depletion was found to occur through the inhibition of lipogenesis-related gene expression and facilitation of lipolysis-related gene expression.

• The suppression of the inflammatory response after Cav-1 depletion was found to involve the IKKβ/NF-κB signaling pathway.

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Zeng, W., Cai, N., Liu, J. et al. Caveolin-1 deficiency alleviates palmitate-induced intracellular lipid accumulation and inflammation in pancreatic β cells. J Physiol Biochem 80, 175–188 (2024). https://doi.org/10.1007/s13105-023-00995-9

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