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

Liang, Rui; Liu, Na; Cao, Jinglin; Liu, Tengli; Sun, Peng; Cai, Xiangheng; Zhang, Lanqiu; Liu, Yaojuan; Zou, Jiaqi; Wang, Le; Ding, Xuejie; Zhang, Boya; Shen, Zhongyang; Yoshida, Sei; Dou, Jianmin; Wang, Shusen

doi:10.1016/j.bbadis.2022.166356

Cited by 17 publications

(15 citation statements)

References 57 publications

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“…This suggested that the execution of FKBP5 function in β cells depends on FOXO1 signaling. In addition, earlier studies, including ours, have reported FOXO1's crucial role in promoting β cell survival via activating autophagy in both human and rodent β cells under different stresses, such as hypoxia and lipo-toxicity [11,42] . In this study, we further expanded our understanding on the regulatory role of FOXO1 in β cells survival against in ammation factors.…”

Section: Discussionsupporting

confidence: 49%

“…Human islets were prepared in HIRC, China, from the pancreases from organ donors with informed research consent. Human islets were isolated by Collagenase NB1 (SERVA, Heidelberg, Germany) and Neutral Protease NB (SERVA, Heidelberg, Germany) digestion and continuous density puri cation, according to our earlier documents [10,11] . High purity islets (>80%) were collected and cultured in CMRL-1066 medium (Corning, Manassas, VA, USA), supplemented with 10% Human Serum Albumin (Baxter, Vienna, Austria), 100 U/mL penicillin, and 100 mg/mL streptomycin, at 37 ℃ in 5% CO2.…”

Section: Human Pancreas Tissue Sections and Human Isletsmentioning

confidence: 99%

“…3.4 FKBP5 inhibition activates Akt/Foxo1 signaling in β cells FKBP5 is a multi-functional protein [20][21][22] , yet SAFit2 speci cally antagonizes its interaction with PHLPP and hence inhibits the downstream dephosphorylation of AKT at Serine 473(Ser 473 ), resulting in the accumulation AKT-Ser 473 and the subsequent Serine 256 phosphorylation (Ser 256 ) of FOXO1, its classic downstream effector. FOXO1 is not only a critical transcription factor for insulin gene in β cells, but also plays a key role in β cell survival under stresses, such as oxidative stress [23,24] and hypoxia [11] . Here, using siRNAs and achieved a 54% knockdown of FKBP5 expression in primary human islets (Fig.…”

Section: Fkbp5 Inhibition Improves β Cell Function In Ex Vivo Culture...mentioning

confidence: 99%

“…Cell autophagy was detected using Cyto-ID Autophagy Detection Kit (Enzo Life Sciences, NY, USA) and propidium iodide (PI) staining was also used to exclude the apoptotic cells. Chloroquine (CQ) was used to block the autophagosome degradation, and the concentration of CQ was selected according to the previous study [11,12] . Autophagy level was evaluated by ow cytometry, as described previously [13,14] .…”

Section: Apoptosis and Autophagy Analysismentioning

confidence: 99%

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The inhibition of FKBP5 protects β cell survival under inflammation stress via AKT/FOXO1 signaling.

Liu

Cao

et al. 2023

Preprint

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The FK506-binding protein 51 (FKBP51, encoded by FKBP5 gene) has emerged as a critical regulator of mammalian endocrine stress responses and as a potential pharmacological target for metabolic disorders, including type 2 diabetes (T2D). However, in β cells, which secrete the only glucose-lowering hormone—insulin, the expression and function of FKBP5 has not been documented. Here, using human pancreatic tissue and primary human islets, we demonstrated the abundant expression of FKBP5 in β cells, which displayed an responsive induction upon acute inflammatory stress mimicked by in vitro treatment with a cocktail of inflammatory cytokines (IL-1β, IFN-γ, and TNF-α). To explore its function, siRNAs targeting FKBP5 and pharmacological inhibitor SAFit2 were applied both in clonal βTC-6 cells and primary human/mice islets. We found that FKBP5 inhibition promoted β cell survival, improved insulin secretion, and upregulated β cell functional gene expressions (Pdx1 and NKX6.1) in acute-inflammation stressed β cells. In primary human and mice islets, which constitutively suffer from inflammation stress during isolation and culture, FKBP5 inhibition also presented decent performance in improving islet function, in accordance with its protective effect against inflammation. Molecular studies found that FKBP5 is an important regulator for FOXO1 phosphorylation at Serine 256 and the subsequent nuclear translocation; Combining with the abundant expression of FKBP5 in β cells, this finding explains, as least partially, the unique constitutively cytoplasmic sub-cellular localization of FOXO1 protein. Meanwhile, silencing of FOXO1 abrogated the protective effect of FKBP5 inhibition, suggesting that it is the key downstream effector of FKBP5 in β cells. At last, taking advantage of pancreatic specimens from T2D patients and non-diabetic organ donors, we found a reduction of FKBP5 expression in β cells in T2D, which may indicate a FKBP5-inhibition mediated pro-survival mechanism against the complex stresses in T2D milieus.

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Section: Discussionsupporting

confidence: 49%

Section: Human Pancreas Tissue Sections and Human Isletsmentioning

confidence: 99%

Section: Fkbp5 Inhibition Improves β Cell Function In Ex Vivo Culture...mentioning

confidence: 99%

Section: Apoptosis and Autophagy Analysismentioning

confidence: 99%

See 2 more Smart Citations

The inhibition of FKBP5 protects β cell survival under inflammation stress via AKT/FOXO1 signaling.

Liu

Cao

et al. 2023

Preprint

Self Cite

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“…This process acts as a metabolic regulator, dynamically responding to nutrient availability and energy status, while also protecting against various stressors like oxidative stress, endoplasmic reticulum (ER) stress, and infections 5 . A substantial body of evidence indicates that impaired autophagy is associated with a spectrum of metabolic imbalances, including IR, 6 T2DM, 7–9 and sarcopenic obesity 5 . This review offers a current understanding of the intricate relationship between autophagy and cellular metabolism and explores the pivotal role of autophagy in the development of T2DM.…”

Section: Introductionmentioning

confidence: 99%

The role of autophagy in insulin resistance and glucolipid metabolism and potential use of autophagy modulating natural products in the treatment of type 2 diabetes mellitus

Yang,

Ding,

Chen

et al. 2024

Diabetes Metabolism Res

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Type 2 diabetes mellitus (T2DM) is a severe, long‐term condition characterised by disruptions in glucolipid and energy metabolism. Autophagy, a fundamental cellular process, serves as a guardian of cellular health by recycling and renewing cellular components. To gain a comprehensive understanding of the vital role that autophagy plays in T2DM, we conducted an extensive search for high‐quality publications across databases such as Web of Science, PubMed, Google Scholar, and SciFinder and used keywords like ‘autophagy’, ‘insulin resistance’, and ‘type 2 diabetes mellitus’, both individually and in combinations. A large body of evidence underscores the significance of activating autophagy in alleviating T2DM symptoms. An enhanced autophagic activity, either by activating the adenosine monophosphate‐activated protein kinase and sirtuin‐1 signalling pathways or inhibiting the mechanistic target of rapamycin complex 1 signalling pathway, can effectively improve insulin resistance and balance glucolipid metabolism in key tissues like the hypothalamus, skeletal muscle, liver, and adipose tissue. Furthermore, autophagy can increase β‐cell mass and functionality in the pancreas. This review provides a narrative summary of autophagy regulation with an emphasis on the intricate connection between autophagy and T2DM symptoms. It also discusses the therapeutic potentials of natural products with autophagy activation properties for the treatment of T2DM conditions. Our findings suggest that autophagy activation represents an innovative approach of treating T2DM.

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Contribution of HIF-1α to Heat Shock Response by Transcriptional Regulation of HSF1/HSP70 Signaling Pathway in Pacific Oyster, Crassostrea gigas

Tian

et al. 2023

Mar Biotechnol

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

Cited by 17 publications

References 57 publications

The inhibition of FKBP5 protects β cell survival under inflammation stress via AKT/FOXO1 signaling.

The inhibition of FKBP5 protects β cell survival under inflammation stress via AKT/FOXO1 signaling.

The role of autophagy in insulin resistance and glucolipid metabolism and potential use of autophagy modulating natural products in the treatment of type 2 diabetes mellitus

Contribution of HIF-1α to Heat Shock Response by Transcriptional Regulation of HSF1/HSP70 Signaling Pathway in Pacific Oyster, Crassostrea gigas

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