HIF-1α/FOXO1 轴调节的自噬对人胰岛缺氧条件下的 β 细胞存活具有保护作用,Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

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HIF-1α/FOXO1 轴调节的自噬对人胰岛缺氧条件下的 β 细胞存活具有保护作用
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 4.2 ) Pub Date : 2022-02-04 , DOI: 10.1016/j.bbadis.2022.166356
Rui Liang ₁ , Na Liu ₂ , Jinglin Cao ₃ , Tengli Liu ₁ , Peng Sun ₁ , Xiangheng Cai ₄ , Lanqiu Zhang ₅ , Yaojuan Liu ₁ , Jiaqi Zou ₁ , Le Wang ₁ , Xuejie Ding ₁ , Boya Zhang ₁ , Zhongyang Shen ₆ , Sei Yoshida ₇ , Jian Dou ₃ , Shusen Wang ₈

Affiliation

Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin 300192, PR China; NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300384, PR China.
NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300384, PR China; Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, Tianjin 300192, PR China.
Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, PR China.
School of Medicine, Nankai University, Tianjin 300071, PR China.
Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin, 300100, PR China.
Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin 300192, PR China; NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300384, PR China; Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, Tianjin 300192, PR China.
State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Center for Cell Responses, Nankai University, Tianjin 300071, PR China.
Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin 300192, PR China; NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300384, PR China; Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, Tianjin 300192, PR China; School of Medicine, Nankai University, Tianjin 300071, PR China.

β细胞由于快速的代谢率来提供胰岛素产生而遭受缺氧。缺氧条件下 β 细胞存活的机制研究可能会揭示 2 型糖尿病 (T2DM) 中 β 细胞质量的损失。在这里，我们发现 LC3 和 p62/SQSTM1 这两种关键的自噬调节因子在非糖尿病和 T2DM 人胰腺的 β 细胞中的表达显着高于非 β 内分泌细胞，并且自噬过程加速离体氯化钴 (CoCl2) 处理培养的初级人类胰岛。同时，CoCl2 诱导人胰岛中 FOXO1 的上调，其中 HIF-1α 起关键作用。CoCl2 处理导致 β 细胞凋亡增加，但通过氯喹或 FOXO1 敲低抑制自噬进一步加重细胞凋亡，表明 FOXO1 调节的自噬对缺氧条件下的 β 细胞存活具有保护作用。免疫荧光染色显示，2型糖尿病患者LC3和p62/SQSTM1表达明显降低，且与HbA1c呈负相关，提示β细胞自噬能力随着疾病进展而受损。我们的研究表明，HIF-1α/FOXO1 调节的自噬有益于缺氧条件下的 β 细胞存活，而自噬失调可能是 T2DM 中 β 细胞质量损失的原因。

简要总结

我们的研究表明，HIF-1α/FOXO1 调节的自噬有益于缺氧条件下的 β 细胞存活，而自噬失调可能是 T2DM 中 β 细胞质量损失的原因。

"点击查看英文标题和摘要"

HIF-1α/FOXO1 axis regulated autophagy is protective for β cell survival under hypoxia in human islets

β cells suffer from hypoxia due to the rapid metabolic rate to supply insulin production. Mechanistic study of β cell survival under hypoxia may shed light on the β cell mass loss in type 2 diabetes mellitus (T2DM). Here, we found that the expressions of LC3 and p62/SQSTM1, two key autophagy regulators, were significantly higher in β cells than that in non-β endocrine cells in both non-diabetic and T2DM human pancreases, and the autophagy process was accelerated upon Cobalt Chloride (CoCl2) treatment in ex vivo cultured primary human islets. Meanwhile, CoCl2 induced the upregulation of FOXO1 in human islets, where HIF-1α played a key role. CoCl2 treatment caused the increase of β cell apoptosis, yet inhibiting autophagy by Chloroquine or by FOXO1 knockdown further aggravated apoptosis, suggesting that FOXO1-regulated autophagy is protective for β cell survival under hypoxia. Immunofluorescence staining showed that LC3 and p62/SQSTM1 expressions were significantly decreased in T2DM patients and negatively correlated with HbA1c, indicating that the autophagy capacity of β cells is impaired along with the progression of the disease. Our study revealed that HIF-1α/FOXO1 regulated autophagy benefits β cell survival under hypoxia and autophagy dysregulation may account for β cell mass loss in T2DM.

Brief summary

Our study revealed that HIF-1α/FOXO1 regulated autophagy benefits β cell survival under hypoxia and autophagy dysregulation may account for β cell mass loss in T2DM.

更新日期：2022-02-11

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