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Hussain S, Rajput SA, Khan KM, Naz F, Ambreen N, Choudhary MI. Benzimidazole derivatives protect pancreatic β-cells against cytokine-induced apoptosis. Bioorg Chem 2025; 160:108472. [PMID: 40252368 DOI: 10.1016/j.bioorg.2025.108472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 03/20/2025] [Accepted: 04/11/2025] [Indexed: 04/21/2025]
Abstract
This study describes the synthesis of a series of benzimidazoles 1-30 by treating 1,2-phenylenediamines with aromatic aldehydes. To further investigate the potential of benzimidazole derivatives in safeguarding the INS-1E β-cell line against apoptosis induced by cytokines, the cellular ATP levels were measured after 48 h of incubation with a cytokine cocktail of IL-1b, INF-c, and TNF-a. Eight out of thirty derivatives demonstrated protection against cytokine effects compound 7 exhibiting significant restoration of β-cell ATP levels. Structure-activity relationship (SAR) analysis revealed that hydroxyl and methoxy groups on the phenyl ring influenced activity, with a parallel arrangement of both groups showing the highest activity. Additionally, the position of these groups played a crucial role, with the ortho position being favorable. Compounds 7, 13, and 25 exhibited excellent to moderate activity, containing hydroxyl and methoxy groups in the ortho position and a fluoro group at position 6 of the fused benzimidazole moiety. Further analysis showed that compounds reducing nitrite production in the presence of cytokines also restored glucose-stimulated insulin secretion (GSIS). Compounds 7, 13, and 25 emerged as the most potent derivatives, displaying dose-dependent increases in cellular ATP levels, inhibition of caspase-3 activity, decreased nitrite production, and restored glucose-stimulated insulin secretion (GSIS). These findings suggest the potential of benzimidazoles in protecting pancreatic β-cells against cytokine-induced apoptosis, warranting further investigation into their specific mechanisms and potential use as antidiabetic agents.
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Affiliation(s)
- Shafqat Hussain
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan; Department of Chemistry, University of Baltistan, Skardu, Pakistan
| | - Sajid Ali Rajput
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan; Institute of Biotechnology and Genetic Engineering, Allama I. I. Kazi Campus, University of Sindh, Jamshoro, Pakistan
| | - Khalid Mohammed Khan
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan; Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P. O. Box 31441, Dammam, Saudi Arabia.
| | - Fouzia Naz
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Nida Ambreen
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan; Department of Chemistry, Abdul Wali Khan University, Mardan, Khyber Pakhtunkhwa, Pakistan
| | - M Iqbal Choudhary
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan; Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan; Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
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Rampy J, Torres-Manzo AP, Hoffsmith K, Loberg MA, Sheng Q, Salas-Lucia F, Bianco AC, Arrojo E Drigo R, Wang H, Weiss VL, Carrasco N. Overnutrition directly impairs thyroid hormone biosynthesis and utilization, causing hypothyroidism, despite remarkable thyroidal adaptations. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.31.645596. [PMID: 40236234 PMCID: PMC11996416 DOI: 10.1101/2025.03.31.645596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Thyroid hormones (THs: T 3 and T 4 ) are key regulators of metabolic rate and nutrient metabolism. They are controlled centrally and peripherally in a coordinated manner to elegantly match T 3 -mediated energy expenditure (EE) to energy availability. Hypothyroidism reduces EE and has long been blamed for obesity; however, emerging evidence suggests that, instead, obesity may drive thyroid dysfunction. Thus, we used a mouse model of diet-induced obesity to determine its direct effects on thyroid histopathology and function, deiodinase activity, and T 3 action. Strikingly, overnutrition induced hypothyroidism within 3 weeks. Levels of thyroidal THs and their precursor protein thyroglobulin decreased, and ER stress was induced, indicating that thyroid function was directly impaired. We also observed pronounced histological and vascular expansion in the thyroid. Overnutrition additionally suppressed T 4 activation, rendering the mice resistant to T 4 and reducing EE. Our findings collectively show that overnutrition deals a double strike to TH biosynthesis and action, despite large efforts to adapt-but, fortunately, thyroid dysfunction in mice can be reversed by weight loss. In humans, BMI correlated with thyroidal vascularization, importantly demonstrating initial translatability. These studies lay the groundwork for novel obesity therapies that tackle hypothyroidism-which are much-needed, as no current obesity treatment works for everyone.
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Luo Y, Li JE, Zeng H, Zhang Y, Yang S, Liu J. Semaglutide alleviates the pancreatic β cell function via the METTL14 signaling and modulating gut microbiota in type 2 diabetes mellitus mice. Life Sci 2025; 361:123328. [PMID: 39719165 DOI: 10.1016/j.lfs.2024.123328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 12/09/2024] [Accepted: 12/19/2024] [Indexed: 12/26/2024]
Abstract
AIMS Semaglutide, a novel long-acting GLP-1RA, stimulates insulin and suppresses islet-secreted glucagon to reduce glucose levels. It has been unveiled that m6A mRNA modification plays a pivotal role in regulating β cell function. However, it remains unclear whether semaglutide can elicit protective effects through manipulating m6A modification and the underlying mechanism. We aimed to elucidate the role played by semaglutide in m6A modification, and to explore its specific regulatory targets. Furthermore, we also delve into its effects on gut microbiota. MAIN METHODS Five-week-old male C57BL/6 mice were assigned to two dietary groups and fed a control or high-fat diet for 4 weeks. Then T2DM was induced in high-fat diet-fed mice via streptozotocin (STZ), the main groups were resampled to include treatment with semaglutide (SEM, 40 μg/kg) for another 4 weeks, totaling three groups: Control, Model (T2DM), T2DM + SEM. Additionally, we elucidated specific regulatory targets and signaling pathways in palmitic acid (PA)-stimulated beta-TC-6 cells. Immunofluorescence, Western blot, and RT-qPCR were used in the study. KEY FINDINGS Semaglutide mitigated pancreatic damage, enhanced islet cell proliferation, and restored islet size and alpha- and beta-cell masses. It also improved the expression of METTL14, pancreatic duodenal homeobox 1 (PDX-1), and protecting mitochondria, and modulated the PDX1 expression in an m6A-dependent manner. Concurrently, semaglutide significantly decreases the abundance of Firmicutes, Actinobacteriota, and Lactobacillus, while increasing the Bacteroides and norank_f_Muribaculaceae content, and the production of short-chain fatty acids (SCFA). SIGNIFICANCE Semaglutide positively influences by regulating m6A modifications to alleviate pancreatic beta cell dysfunction and modulate the gut microbiome.
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Affiliation(s)
- Yunfei Luo
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, China
| | - Jin-E Li
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, China
| | - Haixia Zeng
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, China
| | - Yuying Zhang
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, China
| | - Shiqi Yang
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, China
| | - Jianping Liu
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, China; Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang City, Jiangxi Province, China; Branch of National Clinical Research Center for Metabolic Diseases, Nanchang City, Jiangxi Province, China.
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Li J, Zhu J, Deng Y, Reck EC, Walker EM, Sidarala V, Hubers DL, Pasmooij MB, Shin CS, Bandesh K, Motakis E, Nargund S, Kursawe R, Basrur V, Nesvizhskii AI, Stitzel ML, Chan DC, Soleimanpour SA. LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.03.597215. [PMID: 38895283 PMCID: PMC11185607 DOI: 10.1101/2024.06.03.597215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Proteotoxicity is a contributor to the development of type 2 diabetes (T2D), but it is unknown whether protein misfolding in T2D is generalized or has special features. Here, we report a robust accumulation of misfolded proteins within the mitochondria of human pancreatic islets in T2D and elucidate its impact on β cell viability. Surprisingly, quantitative proteomics studies of protein aggregates reveal that human islets from donors with T2D have a signature more closely resembling mitochondrial rather than ER protein misfolding. The matrix protease LonP1 and its chaperone partner mtHSP70 were among the proteins enriched in protein aggregates. Deletion of LONP1 in mice yields mitochondrial protein misfolding and reduced respiratory function, ultimately leading to β cell apoptosis and hyperglycemia. Intriguingly, LONP1 gain of function ameliorates mitochondrial protein misfolding and restores human β cell survival following glucolipotoxicity via a protease-independent effect requiring LONP1-mtHSP70 chaperone activity. Thus, LONP1 promotes β cell survival and prevents hyperglycemia by facilitating mitochondrial protein folding. These observations may open novel insights into the nature of impaired proteostasis on β cell loss in the pathogenesis of T2D that could be considered as future therapeutic targets.
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Zhang X, Zhang D, Huo L, Zhou X, Zhang J, Li M, Su D, Sun P, Chen F, Liang X. Upregulation of α-ENaC induces pancreatic β-cell dysfunction, ER stress, and SIRT2 degradation. J Biomed Res 2024; 38:241-255. [PMID: 38769731 PMCID: PMC11144933 DOI: 10.7555/jbr.37.20230128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 11/05/2023] [Accepted: 11/11/2023] [Indexed: 05/22/2024] Open
Abstract
Islet beta cells (β-cells) produce insulin in response to high blood glucose levels, which is essential for preserving glucose homeostasis. Voltage-gated ion channels in β-cells, including Na +, K +, and Ca 2+ channels, aid in the release of insulin. The epithelial sodium channel alpha subunit (α-ENaC), a voltage-independent sodium ion channel, is also expressed in human pancreatic endocrine cells. However, there is no reported study on the function of ENaC in the β-cells. In the current study, we found that α-ENaC was expressed in human pancreatic glandule and pancreatic islet β-cells. In the pancreas of db/db mice and high-fat diet-induced mice, and in mouse islet β-cells (MIN6 cells) treated with palmitate, α-ENaC expression was increased. When α-ENaC was overexpressed in MIN6 cells, insulin content and glucose-induced insulin secretion were significantly reduced. On the other hand, palmitate injured islet β-cells and suppressed insulin synthesis and secretion, but increased α-ENaC expression in MIN6 cells. However, α-ENaC knockout ( Scnn1a -/-) in MIN6 cells attenuated β-cell disorder induced by palmitate. Furthermore, α-ENaC regulated the ubiquitylation and degradation of sirtuin 2 in β-cells. α-ENaC also modulated β-cell function in correlation with the inositol-requiring enzyme 1 alpha/X-box binding protein 1 (IRE1α/XBP1) and protein kinase RNA-like endoplasmic reticulum kinase/C/EBP homologous protein (PERK/CHOP) endoplasmic reticulum stress pathways. These results suggest that α-ENaC may play a novel role in insulin synthesis and secretion in the β-cells, and the upregulation of α-ENaC promotes islet β-cell dysfunction. In conclusion, α-ENaC may be a key regulator involved in islet β-cell damage and a potential therapeutic target for type 2 diabetes mellitus.
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Affiliation(s)
- Xue Zhang
- Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
- Department of Pathology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210009, China
| | - Dan Zhang
- Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
- Department of Pathology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210009, China
| | - Lei Huo
- Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Xin Zhou
- Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Jia Zhang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Min Li
- Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Dongming Su
- Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Peng Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Fang Chen
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Xiubin Liang
- Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
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Leenders F, de Koning EJP, Carlotti F. Pancreatic β-Cell Identity Change through the Lens of Single-Cell Omics Research. Int J Mol Sci 2024; 25:4720. [PMID: 38731945 PMCID: PMC11083883 DOI: 10.3390/ijms25094720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/12/2024] [Accepted: 04/17/2024] [Indexed: 05/13/2024] Open
Abstract
The main hallmark in the development of both type 1 and type 2 diabetes is a decline in functional β-cell mass. This decline is predominantly attributed to β-cell death, although recent findings suggest that the loss of β-cell identity may also contribute to β-cell dysfunction. This phenomenon is characterized by a reduced expression of key markers associated with β-cell identity. This review delves into the insights gained from single-cell omics research specifically focused on β-cell identity. It highlights how single-cell omics based studies have uncovered an unexpected level of heterogeneity among β-cells and have facilitated the identification of distinct β-cell subpopulations through the discovery of cell surface markers, transcriptional regulators, the upregulation of stress-related genes, and alterations in chromatin activity. Furthermore, specific subsets of β-cells have been identified in diabetes, such as displaying an immature, dedifferentiated gene signature, expressing significantly lower insulin mRNA levels, and expressing increased β-cell precursor markers. Additionally, single-cell omics has increased insight into the detrimental effects of diabetes-associated conditions, including endoplasmic reticulum stress, oxidative stress, and inflammation, on β-cell identity. Lastly, this review outlines the factors that may influence the identification of β-cell subpopulations when designing and performing a single-cell omics experiment.
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Affiliation(s)
| | | | - Françoise Carlotti
- Department of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (F.L.); (E.J.P.d.K.)
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Zeng W, Cai N, Liu J, Liu K, Lin S, Zeng L. Caveolin-1 deficiency alleviates palmitate-induced intracellular lipid accumulation and inflammation in pancreatic β cells. J Physiol Biochem 2024; 80:175-188. [PMID: 38032518 DOI: 10.1007/s13105-023-00995-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 10/31/2023] [Indexed: 12/01/2023]
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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Affiliation(s)
- Wen Zeng
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China
- Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China
- Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China
- Medical Center for Comprehensive Weight Control, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China
| | - Nan Cai
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China
- Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China
- Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China
- Medical Center for Comprehensive Weight Control, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China
| | - Jia Liu
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China
- Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China
- Medical Center for Comprehensive Weight Control, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China
| | - Kunying Liu
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China
- Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China
| | - Shuo Lin
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China.
- Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China.
- Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China.
- Medical Center for Comprehensive Weight Control, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China.
| | - Longyi Zeng
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China.
- Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China.
- Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China.
- Medical Center for Comprehensive Weight Control, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China.
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Hsu C, Templin AT, Prosswimmer T, Shea D, Li J, Brooks‐Worrell B, Kahn SE, Daggett V. Human islet amyloid polypeptide-induced β-cell cytotoxicity is linked to formation of α-sheet structure. Protein Sci 2024; 33:e4854. [PMID: 38062941 PMCID: PMC10823758 DOI: 10.1002/pro.4854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 11/10/2023] [Accepted: 12/04/2023] [Indexed: 01/30/2024]
Abstract
Type 2 diabetes (T2D) results from insulin secretory dysfunction arising in part from the loss of pancreatic islet β-cells. Several factors contribute to β-cell loss, including islet amyloid formation, which is observed in over 90% of individuals with T2D. The amyloid is comprised of human islet amyloid polypeptide (hIAPP). Here we provide evidence that early in aggregation, hIAPP forms toxic oligomers prior to formation of amyloid fibrils. The toxic oligomers contain α-sheet secondary structure, a nonstandard secondary structure associated with toxic oligomers in other amyloid diseases. De novo, synthetic α-sheet compounds designed to be nontoxic and complementary to the α-sheet structure in the toxic oligomers inhibit hIAPP aggregation and neutralize oligomer-mediated cytotoxicity in cell-based assays. In vivo administration of an α-sheet design to mice for 4 weeks revealed no evidence of toxicity nor did it elicit an immune response. Furthermore, the α-sheet designs reduced endogenous islet amyloid formation and mitigation of amyloid-associated β-cell loss in cultured islets isolated from an hIAPP transgenic mouse model of islet amyloidosis. Characterization of the involvement of α-sheet in early aggregation of hIAPP and oligomer toxicity contributes to elucidation of the molecular mechanisms underlying amyloid-associated β-cell loss.
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Affiliation(s)
- Cheng‐Chieh Hsu
- Department of BioengineeringUniversity of WashingtonSeattleWashingtonUSA
- Molecular Engineering ProgramUniversity of WashingtonSeattleWashingtonUSA
| | - Andrew T. Templin
- Division of Metabolism, Endocrinology and Nutrition, Department of MedicineVA Puget Sound Health Care System and University of WashingtonSeattleWashingtonUSA
| | - Tatum Prosswimmer
- Molecular Engineering ProgramUniversity of WashingtonSeattleWashingtonUSA
| | - Dylan Shea
- Molecular Engineering ProgramUniversity of WashingtonSeattleWashingtonUSA
| | - Jinzheng Li
- Department of BiochemistryUniversity of WashingtonSeattleWashingtonUSA
| | - Barbara Brooks‐Worrell
- Division of Metabolism, Endocrinology and Nutrition, Department of MedicineVA Puget Sound Health Care System and University of WashingtonSeattleWashingtonUSA
| | - Steven E. Kahn
- Division of Metabolism, Endocrinology and Nutrition, Department of MedicineVA Puget Sound Health Care System and University of WashingtonSeattleWashingtonUSA
| | - Valerie Daggett
- Department of BioengineeringUniversity of WashingtonSeattleWashingtonUSA
- Molecular Engineering ProgramUniversity of WashingtonSeattleWashingtonUSA
- Department of BiochemistryUniversity of WashingtonSeattleWashingtonUSA
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Sue N, Thai LM, Saito A, Boyer CK, Fordham AM, Yan C, Davenport A, Tao J, Bensellam M, Cantley J, Shi YC, Stephens SB, Imaizumi K, Biden TJ. Independent activation of CREB3L2 by glucose fills a regulatory gap in mouse β-cells by co-ordinating insulin biosynthesis with secretory granule formation. Mol Metab 2024; 79:101845. [PMID: 38013154 PMCID: PMC10755490 DOI: 10.1016/j.molmet.2023.101845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 11/22/2023] [Accepted: 11/23/2023] [Indexed: 11/29/2023] Open
Abstract
OBJECTIVE Although individual steps have been characterized, there is little understanding of the overall process whereby glucose co-ordinates the biosynthesis of insulin with its export out of the endoplasmic reticulum (ER) and incorporation into insulin secretory granules (ISGs). Here we investigate a role for the transcription factor CREB3L2 in this context. METHODS MIN6 cells and mouse islets were analysed by immunoblotting after treatment with glucose, fatty acids, thapsigargin and various inhibitors. Knockdown of CREB3L2 was achieved using si or sh constructs by transfection, or viral delivery. In vivo metabolic phenotyping was conducted after deletion of CREB3L2 in β-cells of adult mice using Ins1-CreER+. Islets were isolated for RNAseq and assays of glucose-stimulated insulin secretion (GSIS). Trafficking was monitored in islet monolayers using a GFP-tagged proinsulin construct that allows for synchronised release from the ER. RESULTS With a Km ≈3.5 mM, glucose rapidly (T1/2 0.9 h) increased full length (FL) CREB3L2 followed by a slower rise (T1/2 2.5 h) in its transcriptionally-active cleavage product, P60 CREB3L2. Glucose stimulation repressed the ER stress marker, CHOP, and this was partially reverted by knockdown of CREB3L2. Activation of CREB3L2 by glucose was not due to ER stress, however, but a combination of O-GlcNAcylation, which impaired proteasomal degradation of FL-CREB3L2, and mTORC1 stimulation, which enhanced its conversion to P60. cAMP generation also activated CREB3L2, but independently of glucose. Deletion of CREB3L2 inhibited GSIS ex vivo and, following a high-fat diet (HFD), impaired glucose tolerance and insulin secretion in vivo. RNAseq revealed that CREB3L2 regulated genes controlling trafficking to-and-from the Golgi, as well as a broader cohort associated with β-cell compensation during a HFD. Although post-Golgi trafficking appeared intact, knockdown of CREB3L2 impaired the generation of both nascent ISGs and proinsulin condensates in the Golgi, implying a defect in ER export of proinsulin and/or its processing in the Golgi. CONCLUSION The stimulation of CREB3L2 by glucose defines a novel, rapid and direct mechanism for co-ordinating the synthesis, packaging and storage of insulin, thereby minimizing ER overload and optimizing β-cell function under conditions of high secretory demand. Upregulation of CREB3L2 also potentially contributes to the benefits of GLP1 agonism and might in itself constitute a novel means of treating β-cell failure.
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Affiliation(s)
- Nancy Sue
- Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia
| | - Le May Thai
- Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia
| | - Atsushi Saito
- Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Cierra K Boyer
- Fraternal Order of Eagles Diabetes Research Center, Department of Internal Medicine, University of Iowa, Iowa City, IA 52246, USA
| | - Ashleigh M Fordham
- Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia
| | - Chenxu Yan
- Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia
| | - Aimee Davenport
- Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia
| | - Jiang Tao
- Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia
| | - Mohammed Bensellam
- Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia
| | - James Cantley
- Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia
| | - Yan-Chuan Shi
- Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia
| | - Samuel B Stephens
- Fraternal Order of Eagles Diabetes Research Center, Department of Internal Medicine, University of Iowa, Iowa City, IA 52246, USA
| | - Kazunori Imaizumi
- Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Trevor J Biden
- Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia.
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Thomas P, Gallagher MT, Da Silva Xavier G. Beta cell lipotoxicity in the development of type 2 diabetes: the need for species-specific understanding. Front Endocrinol (Lausanne) 2023; 14:1275835. [PMID: 38144558 PMCID: PMC10739424 DOI: 10.3389/fendo.2023.1275835] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 11/13/2023] [Indexed: 12/26/2023] Open
Abstract
The propensity to develop type 2 diabetes (T2D) is known to have both environmental and hereditary components. In those with a genetic predisposition to T2D, it is widely believed that elevated concentrations of circulatory long-chain fatty acids (LC-FFA) significantly contribute towards the demise of insulin-producing pancreatic β-cells - the fundamental feature of the development of T2D. Over 25 years of research support that LC-FFA are deleterious to β-cells, through a process termed lipotoxicity. However, the work underpinning the theory of β-cell lipotoxicity is mostly based on rodent studies. Doubts have been raised as to whether lipotoxicity also occurs in humans. In this review, we examine the evidence, both in vivo and in vitro, for the pathogenic effects of LC-FFA on β-cell viability and function in humans, highlighting key species differences. In this way, we aim to uncover the role of lipotoxicity in the human pathogenesis of T2D and motivate the need for species-specific understanding.
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Affiliation(s)
- Patricia Thomas
- Centre for Systems Modelling and Quantitative Biomedicine, University of Birmingham, Birmingham, United Kingdom
- Institute for Metabolism and Systems Research, Birmingham Medical School, University of Birmingham, Birmingham, United Kingdom
| | - Meurig T. Gallagher
- Centre for Systems Modelling and Quantitative Biomedicine, University of Birmingham, Birmingham, United Kingdom
- Institute for Metabolism and Systems Research, Birmingham Medical School, University of Birmingham, Birmingham, United Kingdom
| | - Gabriela Da Silva Xavier
- Institute for Metabolism and Systems Research, Birmingham Medical School, University of Birmingham, Birmingham, United Kingdom
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11
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Vanheer L, Fantuzzi F, To SK, Schiavo A, Van Haele M, Ostyn T, Haesen T, Yi X, Janiszewski A, Chappell J, Rihoux A, Sawatani T, Roskams T, Pattou F, Kerr-Conte J, Cnop M, Pasque V. Inferring regulators of cell identity in the human adult pancreas. NAR Genom Bioinform 2023; 5:lqad068. [PMID: 37435358 PMCID: PMC10331937 DOI: 10.1093/nargab/lqad068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 06/17/2023] [Accepted: 06/28/2023] [Indexed: 07/13/2023] Open
Abstract
Cellular identity during development is under the control of transcription factors that form gene regulatory networks. However, the transcription factors and gene regulatory networks underlying cellular identity in the human adult pancreas remain largely unexplored. Here, we integrate multiple single-cell RNA-sequencing datasets of the human adult pancreas, totaling 7393 cells, and comprehensively reconstruct gene regulatory networks. We show that a network of 142 transcription factors forms distinct regulatory modules that characterize pancreatic cell types. We present evidence that our approach identifies regulators of cell identity and cell states in the human adult pancreas. We predict that HEYL, BHLHE41 and JUND are active in acinar, beta and alpha cells, respectively, and show that these proteins are present in the human adult pancreas as well as in human induced pluripotent stem cell (hiPSC)-derived islet cells. Using single-cell transcriptomics, we found that JUND represses beta cell genes in hiPSC-alpha cells. BHLHE41 depletion induced apoptosis in primary pancreatic islets. The comprehensive gene regulatory network atlas can be explored interactively online. We anticipate our analysis to be the starting point for a more sophisticated dissection of how transcription factors regulate cell identity and cell states in the human adult pancreas.
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Affiliation(s)
- Lotte Vanheer
- Department of Development and Regeneration; KU Leuven - University of Leuven; Single-cell Omics Institute and Leuven Stem Cell Institute, Herestraat 49, B-3000 Leuven, Belgium
| | - Federica Fantuzzi
- ULB Center for Diabetes Research; Université Libre de Bruxelles; Route de Lennik 808, B-1070 Brussels, Belgium
| | - San Kit To
- Department of Development and Regeneration; KU Leuven - University of Leuven; Single-cell Omics Institute and Leuven Stem Cell Institute, Herestraat 49, B-3000 Leuven, Belgium
| | - Andrea Schiavo
- ULB Center for Diabetes Research; Université Libre de Bruxelles; Route de Lennik 808, B-1070 Brussels, Belgium
| | - Matthias Van Haele
- Department of Imaging and Pathology; Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven; Herestraat 49, B-3000 Leuven, Belgium
| | - Tessa Ostyn
- Department of Imaging and Pathology; Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven; Herestraat 49, B-3000 Leuven, Belgium
| | - Tine Haesen
- Department of Development and Regeneration; KU Leuven - University of Leuven; Single-cell Omics Institute and Leuven Stem Cell Institute, Herestraat 49, B-3000 Leuven, Belgium
| | - Xiaoyan Yi
- ULB Center for Diabetes Research; Université Libre de Bruxelles; Route de Lennik 808, B-1070 Brussels, Belgium
| | - Adrian Janiszewski
- Department of Development and Regeneration; KU Leuven - University of Leuven; Single-cell Omics Institute and Leuven Stem Cell Institute, Herestraat 49, B-3000 Leuven, Belgium
| | - Joel Chappell
- Department of Development and Regeneration; KU Leuven - University of Leuven; Single-cell Omics Institute and Leuven Stem Cell Institute, Herestraat 49, B-3000 Leuven, Belgium
| | - Adrien Rihoux
- Department of Development and Regeneration; KU Leuven - University of Leuven; Single-cell Omics Institute and Leuven Stem Cell Institute, Herestraat 49, B-3000 Leuven, Belgium
| | - Toshiaki Sawatani
- ULB Center for Diabetes Research; Université Libre de Bruxelles; Route de Lennik 808, B-1070 Brussels, Belgium
| | - Tania Roskams
- Department of Imaging and Pathology; Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven; Herestraat 49, B-3000 Leuven, Belgium
| | - Francois Pattou
- University of Lille, Inserm, CHU Lille, Institute Pasteur Lille, U1190-EGID, F-59000 Lille, France
- European Genomic Institute for Diabetes, F-59000 Lille, France
- University of Lille, F-59000 Lille, France
| | - Julie Kerr-Conte
- University of Lille, Inserm, CHU Lille, Institute Pasteur Lille, U1190-EGID, F-59000 Lille, France
- European Genomic Institute for Diabetes, F-59000 Lille, France
- University of Lille, F-59000 Lille, France
| | - Miriam Cnop
- ULB Center for Diabetes Research; Université Libre de Bruxelles; Route de Lennik 808, B-1070 Brussels, Belgium
- Division of Endocrinology; Erasmus Hospital, Université Libre de Bruxelles; Route de Lennik 808, B-1070 Brussels, Belgium
| | - Vincent Pasque
- Department of Development and Regeneration; KU Leuven - University of Leuven; Single-cell Omics Institute and Leuven Stem Cell Institute, Herestraat 49, B-3000 Leuven, Belgium
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12
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Ahmed OM, Abdel Fattah AA, Abdul-Hamid M, Abdel-Aziz AM, Sakr HI, Damanhory AA, Abdel-Kawi SH, Ghaboura N, Awad MMY. Antidiabetic and Liver Histological and Ultrastructural Effects of Cynara scolymus Leaf and Flower Head Hydroethanolic Extracts in Nicotinamide/Streptozotocin-Induced Diabetic Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2023; 2023:4223026. [PMID: 37163198 PMCID: PMC10164244 DOI: 10.1155/2023/4223026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 02/25/2023] [Accepted: 04/01/2023] [Indexed: 05/11/2023]
Abstract
This study aims to investigate the effect of hydroethanolic extracts of Cynara scolymus (C. scolymus) leaf (CLHE) and C. scolymus flower (CFHE) on the hepatic histopathological lesions and functional biochemical changes induced by type 2 diabetes mellitus (T2DM). The rat model of T2DM was induced by intraperitoneal injection of streptozotocin (STZ) in a dose of 60 mg/kg for 15 minutes following nicotinamide (NA) (60 mg/kg). The rats were allocated into four groups: group 1 (negative control), group 2 (diabetic control), group 3 (diabetic rats supplemented with 100 mg/kg/day CLHE), and group 4 (diabetic rats supplemented with 100 mg/kg/day CFHE). Treatment with CLHE and CFHE, for the study duration of 28 days, significantly improved the deteriorated hepatic glycogen content, glycogen phosphorylase, glucose-6-phosphatase activities, serum fructosamine levels, lipid profile, aspartate transaminase activities, and alanine transaminase activities as well as serum insulin and C-peptide levels. The elevated liver lipid peroxidation and the decreased activities of superoxide dismutase and glutathione peroxidase were significantly alleviated. The elevated expression of the proinflammatory cytokine tumor necrosis factor-α in the liver of diabetic rats was significantly reduced by treatments with CLHE and CFHE. NA/STZ-induced T2DM exhibited hepatic histopathological changes in the form of disordered hepatocytes, cytoplasm dissolution, and mononuclear leukocytic infiltration. The electron microscopic ultrastructure study revealed damaged mitochondria with ill-defined cristae and fragmentation of the rough endoplasmic reticulum. Treatments with CLHE and CFHE remarkably amended these histopathological and EM ultrastructural changes. In conclusion, both CLHE and CFHE may have antidiabetic and improvement effects on the liver function and structural integrity, which may be mediated, at least in part, via suppression of inflammation and oxidative stress and enhancement of the antioxidant defence system.
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Affiliation(s)
- Osama M. Ahmed
- Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. 62521, Beni-Suef, Egypt
| | - Asmaa A. Abdel Fattah
- Cell Biology, Histology and Genetics Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. 62521, Beni-Suef, Egypt
| | - Manal Abdul-Hamid
- Cell Biology, Histology and Genetics Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. 62521, Beni-Suef, Egypt
| | - Ayman M. Abdel-Aziz
- Zoology Department, Faculty of Science, Fayoum University, Fayoum 63514, Egypt
| | - Hader I. Sakr
- Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
- Department of Medical Physiology, Medicine Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia
| | - Ahmed A. Damanhory
- Department of Biochemistry, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
- Department of Biochemistry, Medicine Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia
| | - Samraa H. Abdel-Kawi
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Nehmat Ghaboura
- Department of Pharmacy Practice, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Moaaz M. Y. Awad
- Department of Anatomy, Medicine Program, Batterjee Medical College, Jeddah, Saudi Arabia
- Department of Anatomy, Damietta Faculty of Medicine, Al-Azhar University, Damietta, Egypt
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13
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Protopanaxadiol ameliorates palmitate-induced lipotoxicity and pancreatic β-cell dysfunction in INS-1 cells. J Ginseng Res 2023. [DOI: 10.1016/j.jgr.2023.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/27/2023] Open
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14
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Celik C, Lee SYT, Yap WS, Thibault G. Endoplasmic reticulum stress and lipids in health and diseases. Prog Lipid Res 2023; 89:101198. [PMID: 36379317 DOI: 10.1016/j.plipres.2022.101198] [Citation(s) in RCA: 84] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 11/03/2022] [Accepted: 11/09/2022] [Indexed: 11/14/2022]
Abstract
The endoplasmic reticulum (ER) is a complex and dynamic organelle that regulates many cellular pathways, including protein synthesis, protein quality control, and lipid synthesis. When one or multiple ER roles are dysregulated and saturated, the ER enters a stress state, which, in turn, activates the highly conserved unfolded protein response (UPR). By sensing the accumulation of unfolded proteins or lipid bilayer stress (LBS) at the ER, the UPR triggers pathways to restore ER homeostasis and eventually induces apoptosis if the stress remains unresolved. In recent years, it has emerged that the UPR works intimately with other cellular pathways to maintain lipid homeostasis at the ER, and so does at cellular levels. Lipid distribution, along with lipid anabolism and catabolism, are tightly regulated, in part, by the ER. Dysfunctional and overwhelmed lipid-related pathways, independently or in combination with ER stress, can have reciprocal effects on other cellular functions, contributing to the development of diseases. In this review, we summarize the current understanding of the UPR in response to proteotoxic stress and LBS and the breadth of the functions mitigated by the UPR in different tissues and in the context of diseases.
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Affiliation(s)
- Cenk Celik
- School of Biological Sciences, Nanyang Technological University, Singapore
| | | | - Wei Sheng Yap
- School of Biological Sciences, Nanyang Technological University, Singapore
| | - Guillaume Thibault
- School of Biological Sciences, Nanyang Technological University, Singapore; Mechanobiology Institute, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, A*STAR, Singapore.
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15
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Sajadimajd S, Deravi N, Forouhar K, Rahimi R, Kheirandish A, Bahramsoltani R. Endoplasmic reticulum as a therapeutic target in type 2 diabetes: Role of phytochemicals. Int Immunopharmacol 2023; 114:109508. [PMID: 36495694 DOI: 10.1016/j.intimp.2022.109508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 11/23/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disorders characterized by insulin resistance and β-cell dysfunction with an increasing worldwide incidence. Several studies have revealed that long-term glucotoxicity results in β-cell failure and death through induction of endoplasmic reticulum (ER) stress. Owing to the chronic progression of T2DM and the low effectiveness of antidiabetic drugs in long-term use, medicinal plants and their secondary metabolites seem to be the promising alternatives. Here we have provided a comprehensive review regarding the role of phytochemicals to alleviate ER stress in T2DM. Ginsenoside compound K, baicalein, quercetin, isopulegol, kaempferol, liquiritigenin, aspalathin, and tyrosol have demonstrated remarkable improvement of T2DM via modulation of ER stress. Arctigenin and total glycosides of peony have been shown to be effective in the treatment of diabetic retinopathy through modulation of ER stress. The effectiveness of grape seed proanthocyanidins and wolfberry is also shown in the relief of diabetic neuropathy and retinopathy. Resveratrol is involved in the prevention of atherosclerosis via ER stress modulation. Taken together, the data described herein revealed the capability of herbal constituents to prevent different complications of T2DM via a decrease in ER stress which open new doors to the treatment of diabetes.
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Affiliation(s)
- Soraya Sajadimajd
- Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran
| | - Niloofar Deravi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kimia Forouhar
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Roja Rahimi
- Derpartment of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran; PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Ali Kheirandish
- Department of Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Roodabeh Bahramsoltani
- Derpartment of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran; PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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16
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Sekhon AS, He B, Iovieno A, Yeung SN. Pathophysiology of Corneal Endothelial Cell Loss in Dry Eye Disease and Other Inflammatory Ocular Disorders. Ocul Immunol Inflamm 2023; 31:21-31. [PMID: 34678119 DOI: 10.1080/09273948.2021.1980808] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE Dry eye disease (DED) and other inflammatory ocular disorders have been reported to be associated with decreased corneal endothelial cell density (CECD), however the mechanism of underlying endothelial cell loss remains unknown. METHODS We conducted a comprehensive literature search of English-written publications on dry eye disease, corneal endothelial cell loss, Sjögren's syndrome, and Graft Vs Host Disease (GVHD), to review the effects of DED and other inflammatory ocular surface conditions on CECD. RESULTS A total of 78 studies were included in our study. Loss of corneal neurotrophic support, cytotoxic stress, and a heightened immune response, all of which may occur secondarily to a common causative agent such as inflammation, are major contributors to reduced CECD. CONCLUSION More studies are needed to determine how the interrelated pathways of altered corneal nerve function and upregulated expression of inflammatory activity influence corneal endothelial cell loss.
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Affiliation(s)
- Amardeep S Sekhon
- Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - Bonnie He
- Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Alfonso Iovieno
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada
| | - Sonia N Yeung
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada
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17
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Effects of adrenergic-stimulated lipolysis and cytokine production on in vitro mouse adipose tissue-islet interactions. Sci Rep 2022; 12:15831. [PMID: 36138030 PMCID: PMC9499973 DOI: 10.1038/s41598-022-18262-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/08/2022] [Indexed: 11/08/2022] Open
Abstract
Inflammatory cytokines and non-esterified fatty acids (NEFAs) are obesity-linked factors that disturb insulin secretion. The aim of this study was to investigate whether pancreatic adipose tissue (pWAT) is able to generate a NEFA/cytokine overload within the pancreatic environment and as consequence to impact on insulin secretion. Pancreatic fat is a minor fat depot, therefore we used high-fat diet (HFD) feeding to induce pancreatic steatosis in mice. Relative Adipoq and Lep mRNA levels were higher in pWAT of HFD compared to chow diet mice. Regardless of HFD, Adipoq and Lep mRNA levels of pWAT were at least 10-times lower than those of epididymal fat (eWAT). Lipolysis stimulating receptors Adrb3 and Npr1 were expressed in pWAT and eWAT, and HFD reduced their expression in eWAT only. In accordance, HFD impaired lipolysis in eWAT but not in pWAT. Despite expression of Npr mRNA, lipolysis was stimulated solely by the adrenergic agonists, isoproterenol and adrenaline. Short term co-incubation of islets with CD/HFD pWAT did not alter insulin secretion. In the presence of CD/HFD eWAT, glucose stimulated insulin secretion only upon isoproterenol-induced lipolysis, i.e. in the presence of elevated NEFA. Isoproterenol augmented Il1b and Il6 mRNA levels both in pWAT and eWAT. These results suggest that an increased sympathetic activity enhances NEFA and cytokine load of the adipose microenvironment, including that of pancreatic fat, and by doing so it may alter beta-cell function.
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18
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Chan TT, Tse YK, Lui RNS, Wong GLH, Chim AML, Kong APS, Woo J, Yeung DKW, Abrigo JM, Chu WCW, Wong VWS, Tang RSY. Fatty Pancreas Is Independently Associated With Subsequent Diabetes Mellitus Development: A 10-Year Prospective Cohort Study. Clin Gastroenterol Hepatol 2022; 20:2014-2022.e4. [PMID: 34571257 DOI: 10.1016/j.cgh.2021.09.027] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/12/2021] [Accepted: 09/16/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Although the association between fatty pancreas and metabolic syndrome has been suggested in retrospective studies, long-term prospective data on the effect of fatty pancreas on various metabolic outcomes are lacking. We aimed to prospectively investigate the association between fatty pancreas and the development of major metabolic outcomes. METHODS A total of 631 subjects from a population study using fat-water magnetic resonance imaging to quantify pancreatic and liver fat content during 2008 to 2010 were followed up prospectively until December 2020 (mean follow-up time, 11.1 ± 1.1 y). Subjects with significant alcohol intake and diabetes mellitus (DM) at baseline were excluded. Incidence of newly diagnosed DM, hypertension, dyslipidemia, ischemic heart disease, cardiovascular accidents, pancreatic cancer, and mortality were evaluated. RESULTS Among the 631 subjects (mean age, 48 ± 11 y), 93 (14.7%) had fatty pancreas. The fatty pancreas group had a higher incidence of DM (33.3% vs 10.4%; P < .001), hypertension (37.7% vs 22.7%; P = .003), and dyslipidemia (37.7% vs 14.6%; P < .001) during long-term follow-up evaluation. Individuals with both fatty liver and pancreas had the highest DM incidence, followed by fatty liver only and fatty pancreas only groups (P < .001). Fatty pancreas was associated independently with DM (adjusted hazard ratio, 1.81; 95% CI, 1.10-3.00; P = .020), but not hypertension or dyslipidemia on multivariate analysis. Each percentage increase of pancreatic fat increased the risk of incident DM by 7% (adjusted hazard ratio, 1.07; 95% CI, 1.01-1.13; P = .016). No participants developed pancreatic cancer during the follow-up period. CONCLUSIONS Fatty pancreas is associated independently with subsequent DM development, but not hypertension or dyslipidemia.
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Affiliation(s)
- Ting Ting Chan
- Department of Medicine and Therapeutics, Hong Kong Special Administrative Region, China; Institute of Digestive Disease, Hong Kong Special Administrative Region, China
| | - Yee Kit Tse
- Department of Medicine and Therapeutics, Hong Kong Special Administrative Region, China; Medical Data Analytic Centre, Hong Kong Special Administrative Region, China
| | - Rashid Nok-Shun Lui
- Department of Medicine and Therapeutics, Hong Kong Special Administrative Region, China; Institute of Digestive Disease, Hong Kong Special Administrative Region, China
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, Hong Kong Special Administrative Region, China; Institute of Digestive Disease, Hong Kong Special Administrative Region, China; Medical Data Analytic Centre, Hong Kong Special Administrative Region, China
| | - Angel Mei-Ling Chim
- Department of Medicine and Therapeutics, Hong Kong Special Administrative Region, China; Institute of Digestive Disease, Hong Kong Special Administrative Region, China
| | - Alice Pik-Shan Kong
- Department of Medicine and Therapeutics, Hong Kong Special Administrative Region, China
| | - Jean Woo
- Department of Medicine and Therapeutics, Hong Kong Special Administrative Region, China
| | - David Ka-Wai Yeung
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Jill M Abrigo
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Winnie Chiu-Wing Chu
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, Hong Kong Special Administrative Region, China; Institute of Digestive Disease, Hong Kong Special Administrative Region, China; Medical Data Analytic Centre, Hong Kong Special Administrative Region, China.
| | - Raymond Shing-Yan Tang
- Department of Medicine and Therapeutics, Hong Kong Special Administrative Region, China; Institute of Digestive Disease, Hong Kong Special Administrative Region, China.
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19
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Lv C, Sun Y, Zhang ZY, Aboelela Z, Qiu X, Meng ZX. β-cell dynamics in type 2 diabetes and in dietary and exercise interventions. J Mol Cell Biol 2022; 14:6656373. [PMID: 35929791 PMCID: PMC9710517 DOI: 10.1093/jmcb/mjac046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 05/07/2022] [Accepted: 08/03/2022] [Indexed: 01/14/2023] Open
Abstract
Pancreatic β-cell dysfunction and insulin resistance are two of the major causes of type 2 diabetes (T2D). Recent clinical and experimental studies have suggested that the functional capacity of β-cells, particularly in the first phase of insulin secretion, is a primary contributor to the progression of T2D and its associated complications. Pancreatic β-cells undergo dynamic compensation and decompensation processes during the development of T2D, in which metabolic stresses such as endoplasmic reticulum stress, oxidative stress, and inflammatory signals are key regulators of β-cell dynamics. Dietary and exercise interventions have been shown to be effective approaches for the treatment of obesity and T2D, especially in the early stages. Whilst the targeted tissues and underlying mechanisms of dietary and exercise interventions remain somewhat vague, accumulating evidence has implicated the improvement of β-cell functional capacity. In this review, we summarize recent advances in the understanding of the dynamic adaptations of β-cell function in T2D progression and clarify the effects and mechanisms of dietary and exercise interventions on β-cell dysfunction in T2D. This review provides molecular insights into the therapeutic effects of dietary and exercise interventions on T2D, and more importantly, it paves the way for future research on the related underlying mechanisms for developing precision prevention and treatment of T2D.
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Affiliation(s)
- Chengan Lv
- Department of Pathology and Pathophysiology and Metabolic Research Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Yuchen Sun
- Department of Pathology and Pathophysiology and Metabolic Research Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China,Zhejiang University–University of Edinburgh Institute (ZJE), Zhejiang University, Haining 314400, China
| | - Zhe Yu Zhang
- Department of Pathology and Pathophysiology and Metabolic Research Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Zeyad Aboelela
- Department of Pathology and Pathophysiology and Metabolic Research Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China,Bachelors of Surgery, Bachelors of Medicine (MBBS), Zhejiang University School of Medicine, Hangzhou 310003, China
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20
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He X, Wang C, Zhu Y, Jiang X, Qiu Y, Yin F, Xiong W, Liu B, Huang Y. Spirulina compounds show hypoglycemic activity and intestinal flora regulation in type 2 diabetes mellitus mice. ALGAL RES 2022. [DOI: 10.1016/j.algal.2022.102791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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21
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Xu G, Chen J, Jo S, Grayson TB, Ramanadham S, Koizumi A, Germain-Lee EL, Lee SJ, Shalev A. Deletion of Gdf15 Reduces ER Stress-induced Beta-cell Apoptosis and Diabetes. Endocrinology 2022; 163:6548945. [PMID: 35290443 PMCID: PMC9272264 DOI: 10.1210/endocr/bqac030] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Indexed: 01/12/2023]
Abstract
Endoplasmic reticulum (ER) stress contributes to pancreatic beta-cell apoptosis in diabetes, but the factors involved are still not fully elucidated. Growth differentiation factor 15 (GDF15) is a stress response gene and has been reported to be increased and play an important role in various diseases. However, the role of GDF15 in beta cells in the context of ER stress and diabetes is still unclear. In this study, we have discovered that GDF15 promotes ER stress-induced beta-cell apoptosis and that downregulation of GDF15 has beneficial effects on beta-cell survival in diabetes. Specifically, we found that GDF15 is induced by ER stress in beta cells and human islets, and that the transcription factor C/EBPβ is involved in this process. Interestingly, ER stress-induced apoptosis was significantly reduced in INS-1 cells with Gdf15 knockdown and in isolated Gdf15 knockout mouse islets. In vivo, we found that Gdf15 deletion attenuates streptozotocin-induced diabetes by preserving beta cells and insulin levels. Moreover, deletion of Gdf15 significantly delayed diabetes development in spontaneous ER stress-prone Akita mice. Thus, our findings suggest that GDF15 contributes to ER stress-induced beta-cell apoptosis and that inhibition of GDF15 may represent a novel strategy to promote beta-cell survival and treat diabetes.
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Affiliation(s)
- Guanlan Xu
- Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Correspondence: Guanlan Xu, PhD, Comprehensive Diabetes Center, University of Alabama at Birmingham, 1825 University Blvd, Shelby Bldg 1272, Birmingham, AL 35294-2182, USA. E-mail:
| | - Junqin Chen
- Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - SeongHo Jo
- Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Truman B Grayson
- Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Sasanka Ramanadham
- Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Akio Koizumi
- Institute of Public Health and Social Welfare Public Interest Incorporation Associations, Kyoto Hokenkai, Ukyo-ku Kyoto 615-8577, Japan
| | - Emily L Germain-Lee
- Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT 06030, USA
- Connecticut Children’s Center for Rare Bone Disorders, Farmington, CT 06032, USA
| | - Se-Jin Lee
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
- University of Connecticut School of Medicine, Department of Genetics and Genome Sciences, Farmington, CT 06030, USA
| | - Anath Shalev
- Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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22
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Byun JH, Lebeau PF, Platko K, Carlisle RE, Faiyaz M, Chen J, MacDonald ME, Makda Y, Yousof T, Lynn EG, Dickhout JG, Krepinsky JC, Weaver F, Igdoura SA, Seidah NG, Austin RC. Inhibitory Antibodies against PCSK9 Reduce Surface CD36 and Mitigate Diet-Induced Renal Lipotoxicity. KIDNEY360 2022; 3:1394-1410. [PMID: 36176646 PMCID: PMC9416829 DOI: 10.34067/kid.0007022021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 04/26/2022] [Indexed: 01/11/2023]
Abstract
Background PCSK9 modulates the uptake of circulating lipids through a range of receptors, including the low-density lipoprotein receptor (LDLR) and CD36. In the kidney, CD36 is known to contribute to renal injury through pro-inflammatory and -fibrotic pathways. In this study, we sought to investigate the role of PCSK9 in modulating renal lipid accumulation and injury through CD36 using a high fat diet (HFD)-induced murine model. Methods The effect of PCSK9 on the expression of CD36 and intracellular accumulation of lipid was examined in cultured renal cells and in the kidneys of male C57BL/6J mice. The effect of these findings was subsequently explored in a model of HFD-induced renal injury in Pcsk9 -/- and Pcsk9 +/+ littermate control mice on a C57BL/6J background. Results In the absence of PCSK9, we observed heightened CD36 expression levels, which increased free fatty acid (FFA) uptake in cultured renal tubular cells. As a result, PCSK9 deficiency was associated with an increase in long-chain saturated FFA-induced ER stress. Consistent with these observations, Pcsk9-/- mice fed a HFD displayed elevated ER stress, inflammation, fibrosis, and renal injury relative to HFD-fed control mice. In contrast to Pcsk9-/- mice, pretreatment of WT C57BL/6J mice with evolocumab, an anti-PCSK9 monoclonal antibody (mAb) that binds to and inhibits the function of circulating PCSK9, protected against HFD-induced renal injury in association with reducing cell surface CD36 expression on renal epithelia. Conclusions We report that circulating PCSK9 modulates renal lipid uptake in a manner dependent on renal CD36. In the context of increased dietary fat consumption, the absence of circulating PCSK9 may promote renal lipid accumulation and subsequent renal injury. However, although the administration of evolocumab blocks the interaction of PCSK9 with the LDLR, this evolocumab/PCSK9 complex can still bind CD36, thereby protecting against HFD-induced renal lipotoxicity.
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Affiliation(s)
- Jae Hyun Byun
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe’s Hamilton and The Hamilton Centre for Kidney Research, Hamilton, Canada
| | - Paul F. Lebeau
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe’s Hamilton and The Hamilton Centre for Kidney Research, Hamilton, Canada
| | - Khrystyna Platko
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe’s Hamilton and The Hamilton Centre for Kidney Research, Hamilton, Canada
| | - Rachel E. Carlisle
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe’s Hamilton and The Hamilton Centre for Kidney Research, Hamilton, Canada
| | - Mahi Faiyaz
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe’s Hamilton and The Hamilton Centre for Kidney Research, Hamilton, Canada
| | - Jack Chen
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe’s Hamilton and The Hamilton Centre for Kidney Research, Hamilton, Canada
| | - Melissa E. MacDonald
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe’s Hamilton and The Hamilton Centre for Kidney Research, Hamilton, Canada
| | - Yumna Makda
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe’s Hamilton and The Hamilton Centre for Kidney Research, Hamilton, Canada
| | - Tamana Yousof
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe’s Hamilton and The Hamilton Centre for Kidney Research, Hamilton, Canada
| | - Edward G. Lynn
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe’s Hamilton and The Hamilton Centre for Kidney Research, Hamilton, Canada
| | - Jeffrey G. Dickhout
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe’s Hamilton and The Hamilton Centre for Kidney Research, Hamilton, Canada
| | - Joan C. Krepinsky
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe’s Hamilton and The Hamilton Centre for Kidney Research, Hamilton, Canada
| | - Fiona Weaver
- Department of Biology and Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
| | - Suleiman A. Igdoura
- Department of Biology and Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
| | - Nabil G. Seidah
- Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Canada
| | - Richard C. Austin
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe’s Hamilton and The Hamilton Centre for Kidney Research, Hamilton, Canada
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23
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Zheng X, Ho QWC, Chua M, Stelmashenko O, Yeo XY, Muralidharan S, Torta F, Chew EGY, Lian MM, Foo JN, Jung S, Wong SH, Tan NS, Tong N, Rutter GA, Wenk MR, Silver DL, Berggren PO, Ali Y. Destabilization of β Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes. Proc Natl Acad Sci U S A 2022; 119:e2113074119. [PMID: 35254894 PMCID: PMC8931238 DOI: 10.1073/pnas.2113074119] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 01/29/2022] [Indexed: 02/05/2023] Open
Abstract
SignificanceWith obesity on the rise, there is a growing appreciation for intracellular lipid droplet (LD) regulation. Here, we show how saturated fatty acids (SFAs) reduce fat storage-inducing transmembrane protein 2 (FIT2)-facilitated, pancreatic β cell LD biogenesis, which in turn induces β cell dysfunction and death, leading to diabetes. This mechanism involves direct acylation of FIT2 cysteine residues, which then marks the FIT2 protein for endoplasmic reticulum (ER)-associated degradation. Loss of β cell FIT2 and LDs reduces insulin secretion, increases intracellular ceramides, stimulates ER stress, and exacerbates diet-induced diabetes in mice. While palmitate and stearate degrade FIT2, unsaturated fatty acids such as palmitoleate and oleate do not, results of which extend to nutrition and diabetes.
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Affiliation(s)
- Xiaofeng Zheng
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, S308232, Singapore
- Singapore Eye Research Institute, Singapore General Hospital, S168751, Singapore
- Department of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China
| | - Qing Wei Calvin Ho
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, S308232, Singapore
| | - Minni Chua
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, S308232, Singapore
| | - Olga Stelmashenko
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, S308232, Singapore
- Singapore Eye Research Institute, Singapore General Hospital, S168751, Singapore
| | - Xin Yi Yeo
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, S138667, Singapore
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, S119228, Singapore
| | - Sneha Muralidharan
- Singapore Lipidomics Incubator, Department of Medicine, National University of Singapore, S117456, Singapore
| | - Federico Torta
- Singapore Lipidomics Incubator, Department of Biochemistry, Life Sciences Institute and Yong Loo Lin School of Medicine, National University of Singapore, S117456, Singapore
| | - Elaine Guo Yan Chew
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, S308232, Singapore
- Human Genetics, A*STAR, Genome Institute of Singapore, S138672, Singapore
| | - Michelle Mulan Lian
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, S308232, Singapore
- Human Genetics, A*STAR, Genome Institute of Singapore, S138672, Singapore
| | - Jia Nee Foo
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, S308232, Singapore
- Human Genetics, A*STAR, Genome Institute of Singapore, S138672, Singapore
| | - Sangyong Jung
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, S138667, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, S117593, Singapore
| | - Sunny Hei Wong
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, S308232, Singapore
| | - Nguan Soon Tan
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, S308232, Singapore
- School of Biological Sciences, Nanyang Technological University Singapore, S637551, Singapore
| | - Nanwei Tong
- Department of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China
| | - Guy A. Rutter
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, S308232, Singapore
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology, and Metabolism, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London SW7 2AZ, United Kingdom
- Le Centre de recherche du Centre hospitalier de l’Université de Montréal (CR-CHUM), University of Montréal, Montréal, QC H2X 0A9, Canada
| | - Markus R. Wenk
- Singapore Lipidomics Incubator, Department of Biochemistry, Life Sciences Institute and Yong Loo Lin School of Medicine, National University of Singapore, S117456, Singapore
| | - David L. Silver
- Signature Research Program in Cardiovascular and Metabolic Disorders, Duke–National University of Singapore Graduate Medical School, S169857, Singapore
| | - Per-Olof Berggren
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, S308232, Singapore
- Singapore Eye Research Institute, Singapore General Hospital, S168751, Singapore
- Department of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Yusuf Ali
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, S308232, Singapore
- Singapore Eye Research Institute, Singapore General Hospital, S168751, Singapore
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24
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Ma J, Zeng P, Liu L, Zhu M, Zheng J, Wang C, Zhao X, Hu W, Yang X, Duan Y, Han J, Miao QR, Chen Y. Peroxisome Proliferator-Activated Receptor-Gamma Reduces ER Stress and Inflammation via Targeting NGBR Expression. Front Pharmacol 2022; 12:817784. [PMID: 35111067 PMCID: PMC8801792 DOI: 10.3389/fphar.2021.817784] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 12/27/2021] [Indexed: 01/01/2023] Open
Abstract
Increased Nogo-B receptor (NGBR) expression in the liver improves insulin sensitivity by reducing endoplasmic reticulum stress (ER stress) and activating the AMPK pathway, although it remains elusive the mechanisms by which NGBR is induced. In this study, we found that PPARγ ligands (rosiglitazone or pioglitazone) increased NGBR expression in hepatic cells and HUVECs. Furthermore, promoter analysis defined two PPREs (PPARγ-responsive elements) in the promoter region of NGBR, which was further confirmed by the ChIP assay. In vivo, using liver-specific PPARγ deficient (PPARγLKO) mice, we identified the key role of PPARγ expression in pioglitazone-induced NGBR expression. Meanwhile, the basal level of ER stress and inflammation was slightly increased by NGBR knockdown. However, the inhibitory effect of rosiglitazone on inflammation was abolished while rosiglitazone-inhibited ER stress was weakened by NGBR knockdown. Taken together, these findings show that NGBR is a previously unrecognized target of PPARγ activation and plays an essential role in PPARγ-reduced ER stress and inflammation.
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Affiliation(s)
- Jialing Ma
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Peng Zeng
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Lipei Liu
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Mengmeng Zhu
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Juan Zheng
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Chengyi Wang
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Xiaokang Zhao
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Wenquan Hu
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China
| | - Xiaoxiao Yang
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Yajun Duan
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Jihong Han
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.,College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Qing R Miao
- Diabetes and Obesity Research Center, New York University Long Island School of Medicine, New York, NY, United States
| | - Yuanli Chen
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
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25
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Divergent effects of HIV reverse transcriptase inhibitors on pancreatic beta-cell function and survival: Potential role of oxidative stress and mitochondrial dysfunction. Life Sci 2022; 294:120329. [PMID: 35090905 DOI: 10.1016/j.lfs.2022.120329] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 01/04/2022] [Accepted: 01/10/2022] [Indexed: 11/23/2022]
Abstract
Antiretroviral therapy (ART), a life-saving treatment strategy in HIV/AIDS, has been implicated in increasing the risk of type 2 diabetes mellitus (T2DM). Direct damaging effects on beta-cell function and survival by either non-nucleoside reverse transcriptase inhibitors (NNRTIs) or nucleoside/tide reverse transcriptase inhibitors (NRTIs) may predispose individuals to developing T2DM or if already type 2 diabetic, to insulin dependency. The aim of this study was to investigate the effects of the NNRTIs efavirenz, rilpivirine and doravirine, and the NRTIs tenofovir disoproxil fumarate and emtricitabine, on beta-cell function and survival while suggesting potential cellular and molecular mechanism(s). Our results show contrasting effects within the NNRTI class as doravirine did not cause damaging effects in the rat insulinoma INS-1E cells while efavirenz and rilpivirine reduced insulin release and cell viability, and induced apoptosis in INS-1E cells. Additionally, efavirenz and rilpivirine increased ROS generation, disrupted Δψm and upregulated the mRNA and protein expression of CHOP and GRP78, key markers of endoplasmic reticulum stress. In silico docking studies predict a possible inhibition of the mitochondrial ATP synthase by rilpivirine. On the contrary, both the NRTIs tenofovir disoproxil fumarate and emtricitabine did not affect GSIS, cell viability and apoptosis/necrosis levels in INS-1E cells. The deleterious effects observed in beta-cells exposed to efavirenz or rilpivirine may be, at least partially, mediated by oxidative stress and mitochondrial toxicity. These findings provide potential mechanism(s) by which efavirenz and rilpivirine may contribute to the pathogenesis of T2DM and the progression of T2DM to insulin dependency in HIV-infected type 2 diabetics.
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26
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Pancreatic Steatosis Is Associated with Both Metabolic Syndrome and Pancreatic Stiffness Detected by Ultrasound Elastography. Dig Dis Sci 2022; 67:293-304. [PMID: 33651254 DOI: 10.1007/s10620-021-06844-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 01/10/2021] [Indexed: 12/16/2022]
Abstract
INTRODUCTION There is increasing evidence that pancreatic steatosis (PS) is associated with metabolic syndrome (MS). However, it is not known whether it is associated with PS grade and pancreatic stiffness, or not. We aimed to evaluate the relationship between PS and its grade detected by transabdominal ultrasound, and pancreatic stiffness determined by two-dimensional shearwave elastography (2D-SWE), whether it has clinical significance and its relationship with MS. METHODS Patients with and without PS were evaluated prospectively. RESULTS Patients with PS had higher odds ratio for MS (OR 5.49). Also, ultrasonographic grade of PS was associated with MS parameters and hepatosteatosis. Pancreatic SWE value was significantly higher in PS group and positively correlated with PS grade, liver fat, MS, number of MS criteria. DISCUSSION/CONCLUSION PS and its grade were associated with MS. In this first comprehensive PS-SWE study, we found that pancreas stiffness increased in the presence of PS, in correlation with PS grade and MS.
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27
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Berger Z, Orellana F, Cocio R, Torres F, Simian D, Araneda G, Toledo P. Pancreatic steatosis: A frequent finding in a Chilean population. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2021; 88:118-124. [PMID: 34974993 DOI: 10.1016/j.rgmxen.2021.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 06/02/2021] [Indexed: 12/13/2022]
Abstract
INTRODUCTION AND AIMS Pancreatic steatosis is an incidental radiologic finding in asymptomatic patients, and its clinical importance is unclear. Primary aim: to study the prevalence of pancreatic steatosis (PS) in consecutive patients registered at our hospital, that underwent computed axial tomography (CAT) scanning of the abdomen and pelvis, excluding known pancreatic diseases. Secondary aim: to review the association of PS with the demographic and clinical data of the patients, as well as with hepatic steatosis (HS). MATERIALS AND METHODS An observational study was conducted on adult patients that had CAT scans of the abdomen and pelvis. DEFINITIONS a) tissue density was measured in Hounsfield units (HU) in five 1 cm2 areas of the pancreas, three areas of the spleen, and in segments VI and VII of the liver; b) fatty pancreas: a difference < -10 HU between the mean pancreas and mean spleen densities; and c) fatty liver: density < 40 HU. We registered the epidemiologic and laboratory data of the patients. The association of those factors with the presence of PS was analyzed using SPSS version 24.0 software, and statistical significance was set at a p < 0.05. RESULTS Of the 203 patients, PS was found in 61 (30%). The patients with PS were significantly older and had a higher body mass index. We found no significant association with the rest of the parameters studied, nor with HS (55 patients). None of the patients had symptoms attributable to a disease of the exocrine pancreas. CONCLUSIONS Fatty infiltration of the pancreas is a frequent finding in CAT scans, and its clinical importance is unclear. Aging of the population and the increase in obesity underline the need for future studies on PS.
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Affiliation(s)
- Z Berger
- Sección de Gastroenterología, Departamento de Medicina, Hospital Clínico Universidad de Chile, Santiago, Chile.
| | - F Orellana
- Sección de Gastroenterología, Departamento de Medicina, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - R Cocio
- Departamento de Imagenología, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - F Torres
- Sección de Gastroenterología, Departamento de Medicina, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - D Simian
- Sección de Gastroenterología, Departamento de Medicina, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - G Araneda
- Sección de Gastroenterología, Departamento de Medicina, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - P Toledo
- Sección de Gastroenterología, Departamento de Medicina, Hospital Clínico Universidad de Chile, Santiago, Chile
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28
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Mukherjee N, Lin L, Contreras CJ, Templin AT. β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances. Metabolites 2021; 11:796. [PMID: 34822454 PMCID: PMC8620854 DOI: 10.3390/metabo11110796] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/15/2021] [Accepted: 11/18/2021] [Indexed: 12/19/2022] Open
Abstract
β-cell death is regarded as a major event driving loss of insulin secretion and hyperglycemia in both type 1 and type 2 diabetes mellitus. In this review, we explore past, present, and potential future advances in our understanding of the mechanisms that promote β-cell death in diabetes, with a focus on the primary literature. We first review discoveries of insulin insufficiency, β-cell loss, and β-cell death in human diabetes. We discuss findings in humans and mouse models of diabetes related to autoimmune-associated β-cell loss and the roles of autoreactive T cells, B cells, and the β cell itself in this process. We review discoveries of the molecular mechanisms that underlie β-cell death-inducing stimuli, including proinflammatory cytokines, islet amyloid formation, ER stress, oxidative stress, glucotoxicity, and lipotoxicity. Finally, we explore recent perspectives on β-cell death in diabetes, including: (1) the role of the β cell in its own demise, (2) methods and terminology for identifying diverse mechanisms of β-cell death, and (3) whether non-canonical forms of β-cell death, such as regulated necrosis, contribute to islet inflammation and β-cell loss in diabetes. We believe new perspectives on the mechanisms of β-cell death in diabetes will provide a better understanding of this pathological process and may lead to new therapeutic strategies to protect β cells in the setting of diabetes.
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Affiliation(s)
- Noyonika Mukherjee
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Lilly Diabetes Center of Excellence, Indiana Biosciences Research Institute, Indianapolis, IN 46202, USA; (L.L.); (C.J.C.)
| | - Li Lin
- Lilly Diabetes Center of Excellence, Indiana Biosciences Research Institute, Indianapolis, IN 46202, USA; (L.L.); (C.J.C.)
| | - Christopher J. Contreras
- Lilly Diabetes Center of Excellence, Indiana Biosciences Research Institute, Indianapolis, IN 46202, USA; (L.L.); (C.J.C.)
- Department of Medicine, Roudebush Veterans Affairs Medical Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Andrew T. Templin
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Lilly Diabetes Center of Excellence, Indiana Biosciences Research Institute, Indianapolis, IN 46202, USA; (L.L.); (C.J.C.)
- Department of Medicine, Roudebush Veterans Affairs Medical Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Center for Diabetes and Metabolic Diseases, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
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29
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Takeda Y, Ishibashi K, Kuroda Y, Atsumi GI. Exposure to Stearate Activates the IRE1α/XBP-1 Pathway in 3T3-L1 Adipocytes. Biol Pharm Bull 2021; 44:1752-1758. [PMID: 34719651 DOI: 10.1248/bpb.b21-00478] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In the endoplasmic reticulum (ER), accumulation of abnormal proteins with malformed higher-order structures activates signaling pathways (inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP-1) pathway, protein kinase RNA-activated-like endoplasmic reticulum kinase (PERK)/CCAAT/enhancer binding protein-homologous protein (CHOP) pathway and activating transcription factor 6α (ATF6α) pathway) that result in a cellular response suppressing the production of abnormal proteins or inducing apoptosis. These responses are collectively known as the unfolded protein response (UPR). Recently, it has been suggested that the UPR induced by saturated fatty acids in hepatocytes and pancreatic β cells is involved in the development of metabolic diseases such as diabetes. The effect of palmitate, a saturated fatty acid, on the UPR has also been investigated in adipocytes, which are associated with the development of metabolic disorders, but the results were inconclusive. Therefore, as the major saturated fatty acids present in the daily diet are palmitate and stearate, we examined the effects of these saturated fatty acids on UPR in adipocytes. Here, we show that saturated fatty acids caused limited activation of the UPR in adipocytes. Exposure to stearate for several hours elevated the ratio of spliced XBP-1 mRNA, and this effect was stronger than that of palmitate. Moreover, the phosphorylation level of IRE1α, upstream of XBP-1 and expression levels of its downstream targets such as DNAJB9 and Pdia6 were elevated in 3T3-L1 adipocytes exposed to stearate. On the other hand, stearate did not affect the phosphorylation of PERK, its activation of CHOP, or the cleavage of ATF6α. Thus, in adipocytes, exposure to stearate activates the UPR via the IRE1α/XBP-1 pathway, but not the PERK/CHOP and ATF6α pathway.
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Affiliation(s)
- Yoshihiro Takeda
- Department of Molecular Physiology and Pathology, Faculty of Pharma-Science, Teikyo University
| | - Kenichi Ishibashi
- Department of Molecular Physiology and Pathology, Faculty of Pharma-Science, Teikyo University
| | - Yumi Kuroda
- Department of Molecular Physiology and Pathology, Faculty of Pharma-Science, Teikyo University
| | - Gen-Ichi Atsumi
- Department of Molecular Physiology and Pathology, Faculty of Pharma-Science, Teikyo University
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Chen SM, Hee SW, Chou SY, Liu MW, Chen CH, Mochly-Rosen D, Chang TJ, Chuang LM. Activation of Aldehyde Dehydrogenase 2 Ameliorates Glucolipotoxicity of Pancreatic Beta Cells. Biomolecules 2021; 11:biom11101474. [PMID: 34680107 PMCID: PMC8533366 DOI: 10.3390/biom11101474] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/28/2021] [Accepted: 09/29/2021] [Indexed: 01/12/2023] Open
Abstract
Chronic hyperglycemia and hyperlipidemia hamper beta cell function, leading to glucolipotoxicity. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies reactive aldehydes, such as methylglyoxal (MG) and 4-hydroxynonenal (4-HNE), derived from glucose and lipids, respectively. We aimed to investigate whether ALDH2 activators ameliorated beta cell dysfunction and apoptosis induced by glucolipotoxicity, and its potential mechanisms of action. Glucose-stimulated insulin secretion (GSIS) in MIN6 cells and insulin secretion from isolated islets in perifusion experiments were measured. The intracellular ATP concentrations and oxygen consumption rates of MIN6 cells were assessed. Furthermore, the cell viability, apoptosis, and mitochondrial and intracellular reactive oxygen species (ROS) levels were determined. Additionally, the pro-apoptotic, apoptotic, and anti-apoptotic signaling pathways were investigated. We found that Alda-1 enhanced GSIS by improving the mitochondrial function of pancreatic beta cells. Alda-1 rescued MIN6 cells from MG- and 4-HNE-induced beta cell death, apoptosis, mitochondrial dysfunction, and ROS production. However, the above effects of Alda-1 were abolished in Aldh2 knockdown MIN6 cells. In conclusion, we reported that the activator of ALDH2 not only enhanced GSIS, but also ameliorated the glucolipotoxicity of beta cells by reducing both the mitochondrial and intracellular ROS levels, thereby improving mitochondrial function, restoring beta cell function, and protecting beta cells from apoptosis and death.
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Affiliation(s)
- Shiau-Mei Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan; (S.-M.C.); (S.-W.H.); (S.-Y.C.); (M.-W.L.); (L.-M.C.)
| | - Siow-Wey Hee
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan; (S.-M.C.); (S.-W.H.); (S.-Y.C.); (M.-W.L.); (L.-M.C.)
| | - Shih-Yun Chou
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan; (S.-M.C.); (S.-W.H.); (S.-Y.C.); (M.-W.L.); (L.-M.C.)
| | - Meng-Wei Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan; (S.-M.C.); (S.-W.H.); (S.-Y.C.); (M.-W.L.); (L.-M.C.)
| | - Che-Hong Chen
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; (C.-H.C.); (D.M.-R.)
| | - Daria Mochly-Rosen
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; (C.-H.C.); (D.M.-R.)
| | - Tien-Jyun Chang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan; (S.-M.C.); (S.-W.H.); (S.-Y.C.); (M.-W.L.); (L.-M.C.)
- School of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- Correspondence: ; Tel.: +886-2-23123456 (ext. 66217)
| | - Lee-Ming Chuang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan; (S.-M.C.); (S.-W.H.); (S.-Y.C.); (M.-W.L.); (L.-M.C.)
- School of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
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Lu H, Guo R, Zhang Y, Su S, Zhao Q, Yu Y, Shi H, Sun H, Zhang Y, Li S, Shi D, Chu X, Sun C. Inhibition of lncRNA TCONS_00077866 Ameliorates the High Stearic Acid Diet-Induced Mouse Pancreatic β-Cell Inflammatory Response by Increasing miR-297b-5p to Downregulate SAA3 Expression. Diabetes 2021; 70:2275-2288. [PMID: 34261739 DOI: 10.2337/db20-1079] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 07/06/2021] [Indexed: 11/13/2022]
Abstract
Long-term consumption of a high-fat diet increases the circulating concentration of stearic acid (SA), which has a potent toxic effect on β-cells, but the underlying molecular mechanisms of this action have not been fully elucidated. Here, we evaluated the role of long noncoding (lnc)RNA TCONS_00077866 (lnc866) in SA-induced β-cell inflammation. lnc866 was selected for study because lncRNA high-throughput sequencing analysis demonstrated it to have the largest fold-difference in expression of five lncRNAs that were affected by SA treatment. Knockdown of lnc866 by virus-mediated shRNA expression in mice or by Smart Silencer in mouse pancreatic β-TC6 cells significantly inhibited the SA-induced reduction in insulin secretion and β-cell inflammation. According to lncRNA-miRNAs-mRNA coexpression network analysis and luciferase reporter assays, lnc866 directly bound to miR-297b-5p, thereby preventing it from reducing the expression of its target serum amyloid A3 (SAA3). Furthermore, overexpression of miR-297b-5p or inhibition of SAA3 also had marked protective effects against the deleterious effects of SA in β-TC6 cells and mouse islets. In conclusion, lnc866 silencing ameliorates SA-induced β-cell inflammation by targeting the miR-297b-5p/SAA3 axis. lnc866 inhibition may represent a new strategy to protect β-cells against the effects of SA during the development of type 2 diabetes.
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MESH Headings
- Animals
- Cells, Cultured
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/pathology
- Diabetes Mellitus, Type 2/prevention & control
- Diet, High-Fat/adverse effects
- Down-Regulation/drug effects
- Gene Expression Regulation/drug effects
- HEK293 Cells
- Humans
- Inflammation/etiology
- Inflammation/genetics
- Inflammation/pathology
- Inflammation/prevention & control
- Insulin Secretion/drug effects
- Insulin-Secreting Cells/drug effects
- Insulin-Secreting Cells/metabolism
- Insulin-Secreting Cells/pathology
- Male
- Mice
- Mice, Inbred C57BL
- MicroRNAs/genetics
- Palmitic Acid/adverse effects
- Palmitic Acid/pharmacology
- Pancreatitis/etiology
- Pancreatitis/genetics
- Pancreatitis/pathology
- Pancreatitis/prevention & control
- RNA, Long Noncoding/antagonists & inhibitors
- RNA, Long Noncoding/genetics
- RNA, Small Interfering/pharmacology
- Serum Amyloid A Protein/genetics
- Stearic Acids/adverse effects
- Stearic Acids/pharmacology
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Affiliation(s)
- Huimin Lu
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
| | - Rui Guo
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
| | - Yunjin Zhang
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
| | - Shenghan Su
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
| | - Qingrui Zhao
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
| | - Yue Yu
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
| | - Hongbo Shi
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Haoran Sun
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Yongjian Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Tumor Hospital of Harbin Medical University, Harbin, China
| | - Shenglong Li
- Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dan Shi
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
| | - Xia Chu
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
| | - Changhao Sun
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
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Guo R, Zhang Y, Yu Y, Su S, Zhao Q, Chu X, Li S, Lu H, Sun C. TCONS_00230836 silencing restores stearic acid-induced β cell dysfunction through alleviating endoplasmic reticulum stress rather than apoptosis. GENES AND NUTRITION 2021; 16:8. [PMID: 34022799 PMCID: PMC8140511 DOI: 10.1186/s12263-021-00685-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 03/19/2021] [Indexed: 08/07/2023]
Abstract
BACKGROUND Chronic exposure of pancreatic β cells to high levels of stearic acid (C18:0) leads to impaired insulin secretion, which accelerates the progression of type 2 diabetes mellitus (T2DM). Recently, long noncoding RNAs (lncRNAs) were found to participate in saturated fatty acid-induced metabolism dysfunction. However, their contribution to stearic acid-induced β-cell dysfunction remains largely unknown. This study evaluated the possible role of the lncRNA TCONS_00230836 in stearic acid-stimulated lipotoxicity to β cells. METHOD Using high-throughput RNA-sequencing, TCONS_00230836 was screened out as being exclusively differentially expressed in stearic acid-treated mouse β-TC6 cells. Co-expression network was constructed to reveal the potential mRNAs targeted for lncRNA TCONS_00230836. Changes in this lncRNA's and candidate mRNAs' levels were further assessed by real-time PCR in stearic acid-treated β-TC6 cells and islets of mice fed a high-stearic-acid diet (HSD). The localization of TCONS_00230836 was detected by fluorescent in situ hybridization. The endogenous lncRNA TCONS_00230836 in β-TC6 cells was abrogated by its Smart Silencer. RESULTS TCONS_00230836 was enriched in mouse islets and mainly localized in the cytoplasm. Its expression was significantly increased in stearic acid-treated β-TC6 cells and HSD-fed mouse islets. Knockdown of TCONS_00230836 significantly restored stearic acid-impaired glucose-stimulated insulin secretion through alleviating endoplasmic reticulum stress. However, stearic acid-induced β cell apoptosis was not obviously recovered. CONCLUSION Our findings suggest the involvement of TCONS_00230836 in stearic acid-induced β-cell dysfunction, which provides novel insight into stearic acid-induced lipotoxicity to β cells. Anti-lncRNA TCONS_00230836 might be a new therapeutic strategy for alleviating stearic acid-induced β-cell dysfunction in the progression of T2DM.
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Affiliation(s)
- Rui Guo
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, Hei Longjiang province, 150081, People's Republic of China
| | - Yunjin Zhang
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, Hei Longjiang province, 150081, People's Republic of China
| | - Yue Yu
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, Hei Longjiang province, 150081, People's Republic of China
| | - Shenghan Su
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, Hei Longjiang province, 150081, People's Republic of China
| | - Qingrui Zhao
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, Hei Longjiang province, 150081, People's Republic of China
| | - Xia Chu
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, Hei Longjiang province, 150081, People's Republic of China
| | - Shenglong Li
- General Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Huimin Lu
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, Hei Longjiang province, 150081, People's Republic of China.
| | - Changhao Sun
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, Hei Longjiang province, 150081, People's Republic of China.
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Shabbir S, Raza MH, Arshad M, Khan MJ. The interplay between the immune system and SARS-CoV-2 in COVID-19 patients. Arch Virol 2021; 166:2109-2117. [PMID: 33950288 PMCID: PMC8097254 DOI: 10.1007/s00705-021-05091-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 03/01/2021] [Indexed: 12/20/2022]
Abstract
Millions of people across the globe have been affected by coronavirus disease 2019 (COVID-19), which began in Wuhan, China, and is caused by SARS-CoV-2. COVID-19 has a variety of clinical characteristics and triggers immune responses required for the elimination of the viral agent. Currently, no effective treatment options are available for targeting SARS-CoV-2 infection. Repurposing of drugs such as chloroquine, thalidomide, and leflunomide alongside convalescent plasma is being employed as a therapeutic strategy. Clinical studies have shown that both asymptomatic and symptomatic patients can have an extremely active immune response that is largely attributable to immune system modulations. This includes cytokine storm syndrome (CSS), which affects the adaptive immune system, leading to exhaustion of natural killer (NK) cells and thrombocytopenia in some cases. This review examines the interaction of SARS-CoV-2 with the host immune system and the potential for the development of appropriate immunotherapy for the treatment of COVID-19.
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Affiliation(s)
- Sana Shabbir
- Department of Biosciences, COMSATS University Islamabad, Park Road, Chak Shahzad, Islamabad, 45550, Pakistan
| | - Muhammad Hassan Raza
- Department of Biological Sciences, International Islamic University Islamabad, Sri Nagar Highway, H10, Islamabad, 45550, Pakistan
| | - Muhammad Arshad
- Department of Biological Sciences, International Islamic University Islamabad, Sri Nagar Highway, H10, Islamabad, 45550, Pakistan.
| | - Muhammad Jawad Khan
- Department of Biosciences, COMSATS University Islamabad, Park Road, Chak Shahzad, Islamabad, 45550, Pakistan.
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Šrámek J, Němcová-Fürstová V, Kovář J. Molecular Mechanisms of Apoptosis Induction and Its Regulation by Fatty Acids in Pancreatic β-Cells. Int J Mol Sci 2021; 22:4285. [PMID: 33924206 PMCID: PMC8074590 DOI: 10.3390/ijms22084285] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/09/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic β-cell failure and death contribute significantly to the pathogenesis of type 2 diabetes. One of the main factors responsible for β-cell dysfunction and subsequent cell death is chronic exposure to increased concentrations of FAs (fatty acids). The effect of FAs seems to depend particularly on the degree of their saturation. Saturated FAs induce apoptosis in pancreatic β-cells, whereas unsaturated FAs are well tolerated and are even capable of inhibiting the pro-apoptotic effect of saturated FAs. Molecular mechanisms of apoptosis induction by saturated FAs in β-cells are not completely elucidated. Saturated FAs induce ER stress, which in turn leads to activation of all ER stress pathways. When ER stress is severe or prolonged, apoptosis is induced. The main mediator seems to be the CHOP transcription factor. Via regulation of expression/activity of pro- and anti-apoptotic Bcl-2 family members, and potentially also through the increase in ROS production, CHOP switches on the mitochondrial pathway of apoptosis induction. ER stress signalling also possibly leads to autophagy signalling, which may activate caspase-8. Saturated FAs activate or inhibit various signalling pathways, i.e., p38 MAPK signalling, ERK signalling, ceramide signalling, Akt signalling and PKCδ signalling. This may lead to the activation of the mitochondrial pathway of apoptosis, as well. Particularly, the inhibition of the pro-survival Akt signalling seems to play an important role. This inhibition may be mediated by multiple pathways (e.g., ER stress signalling, PKCδ and ceramide) and could also consequence in autophagy signalling. Experimental evidence indicates the involvement of certain miRNAs in mechanisms of FA-induced β-cell apoptosis, as well. In the rather rare situations when unsaturated FAs are also shown to be pro-apoptotic, the mechanisms mediating this effect in β-cells seem to be the same as for saturated FAs. To conclude, FA-induced apoptosis rather appears to be preceded by complex cross talks of multiple signalling pathways. Some of these pathways may be regulated by decreased membrane fluidity due to saturated FA incorporation. Few data are available concerning molecular mechanisms mediating the protective effect of unsaturated FAs on the effect of saturated FAs. It seems that the main possible mechanism represents a rather inhibitory intervention into saturated FA-induced pro-apoptotic signalling than activation of some pro-survival signalling pathway(s) or metabolic interference in β-cells. This inhibitory intervention may be due to an increase of membrane fluidity.
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Affiliation(s)
- Jan Šrámek
- Department of Biochemistry, Cell and Molecular Biology & Center for Research of Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Ruská 87, 100 00 Prague, Czech Republic;
| | - Vlasta Němcová-Fürstová
- Department of Biochemistry, Cell and Molecular Biology & Center for Research of Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Ruská 87, 100 00 Prague, Czech Republic;
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35
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Pietrobon CB, Lisboa PC, Bertasso IM, Peixoto TC, Soares PN, de Oliveira E, Rabelo K, de Carvalho JJ, Manhães AC, de Moura EG. Pancreatic steatosis in adult rats induced by nicotine exposure during breastfeeding. Endocrine 2021; 72:104-115. [PMID: 33420949 DOI: 10.1007/s12020-020-02579-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 11/27/2020] [Indexed: 12/19/2022]
Abstract
PURPOSE Maternal nicotine exposure negatively impacts offspring's health and metabolism, leading to obesity and insulin resistance. Here we investigated the pancreatic islet function, glycemic homeostasis, and insulin signaling in adult rat offspring that were nicotine-exposed during breastfeeding. METHODS For this, lactating Wistar rat dams were divided into two groups: Nicotine (implanted with osmotic minipumps containing 6 mg/Kg, NIC) and Control (saline, CON). Solutions were released from postnatal (PN) day 2-16. At PN110 and PN170, 10 offspring per litter/sex/group were submitted to the oral glucose tolerance test (OGTT). PN180 offspring were killed and glycemia, insulinemia, adiponectinemia, pancreas morphology as well as pancreatic islet protein expression (related to insulin secretion) and skeletal muscle (related to insulin action) were evaluated. Males and females were compared to their respective controls. RESULTS Adult NIC offspring of both sexes showed glucose intolerance in the OGTT. Despite normoglycemia, NIC males showed hyperinsulinemia while females, although normoinsulinemic, had hyperglycemia. Both sexes showed increased IRI, reduced adiponectin/visceral fat mass ratio and higher ectopic deposition of lipids in the pancreatic tissue adipocytes. In pancreatic islets, NIC males showed lower PDX-1 expression while females had higher PDX-1 and GLUT2 expressions plus lower α2 adrenergic receptor. In the muscle, NIC offspring of both sexes showed reduction of GLUT4 expression; NIC males also had lower insulin receptor and pAKT expressions. CONCLUSIONS Thus, glycemic homeostasis and peripheral insulin signaling in adult offspring of both sexes are affected by nicotine exposure through the milk, increasing the risk for type 2 diabetes development.
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Affiliation(s)
- Carla Bruna Pietrobon
- Laboratory of Endocrine Physiology, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Patrícia Cristina Lisboa
- Laboratory of Endocrine Physiology, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Iala Milene Bertasso
- Laboratory of Endocrine Physiology, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Thamara Cherem Peixoto
- Laboratory of Endocrine Physiology, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Patrícia Novaes Soares
- Laboratory of Endocrine Physiology, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Elaine de Oliveira
- Laboratory of Endocrine Physiology, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Kíssila Rabelo
- Laboratory of Ultrastructure and Tissue Biology, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Jorge José de Carvalho
- Laboratory of Ultrastructure and Tissue Biology, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Alex Christian Manhães
- Neurophysiology Laboratory, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Egberto Gaspar de Moura
- Laboratory of Endocrine Physiology, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
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Haider HF, Hoare DJ, Ribeiro SF, Ribeiro D, Caria H, Trigueiros N, Borrego LM, Szczepek AJ, Papoila AL, Elarbed A, da Luz Martins M, Paço J, Sereda M. Evidence for biological markers of tinnitus: A systematic review. PROGRESS IN BRAIN RESEARCH 2021; 262:345-398. [PMID: 33931188 DOI: 10.1016/bs.pbr.2021.01.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Subjective tinnitus is a phantom sound heard only by the affected person and may be a symptom of various diseases. Tinnitus diagnosis and monitoring is based on subjective audiometric and psychometric methods. This review aimed to synthesize evidence for tinnitus presence or its severity. We searched several electronic databases, citation searches of the included primary studies through Web of Science, and further hand searches. At least two authors performed all systematic review steps. Sixty-two records were included and were categorized according the biological variable. Evidence for possible tinnitus biomarkers come from oxidative stress, interleukins, steroids and neurotransmitters categories. We found conflicting evidence for full blood count, vitamins, lipid profile, neurotrophic factors, or inorganic ions. There was no evidence for an association between tinnitus and the remaining categories. The current review evidences that larger studies, with stricter exclusion criteria and powerful harmonized methodological design are needed. Protocol published on PROSPERO (CRD42017070998).
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Affiliation(s)
- Haúla F Haider
- ENT Department, Hospital Cuf Tejo-Nova Medical School, Lisbon, Portugal; CUF Academic and Research Medical Center, Lisbon, Portugal; Comprehensive Health Research Centre (CHRC), Lisbon, Portugal.
| | - Derek J Hoare
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Hearing Sciences, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Sara F Ribeiro
- ENT Department, Hospital Cuf Tejo-Nova Medical School, Lisbon, Portugal; CUF Academic and Research Medical Center, Lisbon, Portugal
| | - Diogo Ribeiro
- ENT Department, Hospital Cuf Tejo-Nova Medical School, Lisbon, Portugal; CUF Academic and Research Medical Center, Lisbon, Portugal
| | - Helena Caria
- Deafness Research Group, BTR Unit, BioISI, Faculty of Sciences, University of Lisbon (FCUL), Portugal; ESS/IPS-Biomedical Sciences Department, School of Health, Polytechnic Institute of Setubal, Portugal
| | - Nuno Trigueiros
- ENT Department, Hospital Pedro Hispano, Matosinhos, Portugal
| | - Luís Miguel Borrego
- Department of Immunology, Chronic Diseases Research Center (CEDOC), Faculty of Medical Sciences, NOVA Medical School, Lisbon, Portugal; Department of Immunoallergy, LUZ SAUDE, Hospital da Luz, Lisbon, Portugal
| | - Agnieszka J Szczepek
- Department of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Ana Luísa Papoila
- Bioestatistics Department, Faculty of Medical Sciences, NOVA Medical School, Lisbon, Portugal
| | - Asma Elarbed
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Hearing Sciences, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Maria da Luz Martins
- ENT Department, Hospital Cuf Tejo-Nova Medical School, Lisbon, Portugal; CUF Academic and Research Medical Center, Lisbon, Portugal
| | - João Paço
- ENT Department, Hospital Cuf Tejo-Nova Medical School, Lisbon, Portugal; CUF Academic and Research Medical Center, Lisbon, Portugal
| | - Magdalena Sereda
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Hearing Sciences, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, United Kingdom
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Benito-Vicente A, Jebari-Benslaiman S, Galicia-Garcia U, Larrea-Sebal A, Uribe KB, Martin C. Molecular mechanisms of lipotoxicity-induced pancreatic β-cell dysfunction. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 359:357-402. [PMID: 33832653 DOI: 10.1016/bs.ircmb.2021.02.013] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes (T2D), a heterogeneous disorder derived from metabolic dysfunctions, leads to a glucose overflow in the circulation due to both defective insulin secretion and peripheral insulin resistance. One of the critical risk factor for T2D is obesity, which represents a global epidemic that has nearly tripled since 1975. Obesity is characterized by chronically elevated free fatty acid (FFA) levels, which cause deleterious effects on glucose homeostasis referred to as lipotoxicity. Here, we review the physiological FFA roles onto glucose-stimulated insulin secretion (GSIS) and the pathological ones affecting many steps of the mechanisms and modulation of GSIS. We also describe in vitro and in vivo experimental evidences addressing lipotoxicity in β-cells and the role of saturation and chain length of FFA on the potency of GSIS stimulation. The molecular mechanisms underpinning lipotoxic-β-cell dysfunction are also reviewed. Among them, endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction, inflammation, impaired autophagy and β-cell dedifferentiation. Finally therapeutic strategies for the β-cells dysfunctions such as the use of metformin, glucagon-like peptide 1, thiazolidinediones, anti-inflammatory drugs, chemical chaperones and weight are discussed.
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Affiliation(s)
- Asier Benito-Vicente
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Shifa Jebari-Benslaiman
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Unai Galicia-Garcia
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Molecular Biophysics, Fundación Biofísica Bizkaia, Leioa, Spain
| | - Asier Larrea-Sebal
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Molecular Biophysics, Fundación Biofísica Bizkaia, Leioa, Spain
| | - Kepa B Uribe
- Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Donostia San Sebastián, Spain
| | - Cesar Martin
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Leioa, Spain.
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Diaz-Ganete A, Quiroga-de-Castro A, Mateos RM, Medina F, Segundo C, Lechuga-Sancho AM. Toxicity Induced by Cytokines, Glucose, and Lipids Increase Apoptosis and Hamper Insulin Secretion in the 1.1E7 Beta Cell-Line. Int J Mol Sci 2021; 22:ijms22052559. [PMID: 33806355 PMCID: PMC7961802 DOI: 10.3390/ijms22052559] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/01/2021] [Accepted: 03/02/2021] [Indexed: 12/27/2022] Open
Abstract
Basic research on types 1 and 2 diabetes mellitus require early stage studies using beta cells or cell lines, ideally of human origin and with preserved insulin secretion in response to glucose. The 1.1E7 cells are a hybrid cell line resulting from the electrofusion of dispersed human islets and PANC-1 cells, capable of secreting insulin in response to glucose, but their survival and function under toxic conditions remains untested. This characterization is the purpose of the present study. We treated these cells with a cytokine mix, high glucose, palmitate, and the latter two combined. Under these conditions, we measured cell viability and apoptosis (MTT, Caspase Glo and TUNEL assays, as well as caspase-8 and -9 levels by Western blotting), endoplasmic reticulum stress markers (EIF2AK3, HSPA4, EIF2a, and HSPA5) by real-time PCR, and insulin secretion with a glucose challenge. All of these stimuli (i) induce apoptosis and ER stress markers expression, (ii) reduce mRNA amounts of 2–5 components of genes involved in the insulin secretory pathway, and (iii) abrogate the insulin release capability of 1.1E7 cells in response to glucose. The most pronounced effects were observed with cytokines and with palmitate and high glucose combined. This characterization may well serve as the starting point for those choosing this cell line for future basic research on certain aspects of diabetes.
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Affiliation(s)
- Antonia Diaz-Ganete
- Inflammation, Nutrition, Metabolism and Oxidative Stress Study Group (INMOX), Biomedical Research and Innovation Institute of Cádiz (INiBICA), Research Unit, Puerta del Mar University Hospital, 11009 Cádiz, Spain; (A.D.-G.); (R.M.M.); (F.M.)
| | - Aranzazu Quiroga-de-Castro
- Area of Pediatrics, Department of Child and Mother Health and Radiology, Medical School, University of Cádiz, 11002 Cádiz, Spain;
| | - Rosa M. Mateos
- Inflammation, Nutrition, Metabolism and Oxidative Stress Study Group (INMOX), Biomedical Research and Innovation Institute of Cádiz (INiBICA), Research Unit, Puerta del Mar University Hospital, 11009 Cádiz, Spain; (A.D.-G.); (R.M.M.); (F.M.)
- Area of Biochemistry and Molecular Biology, Department of Biomedicine, Biotechnology and Public Health, University of Cádiz, 11519 Cádiz, Spain
| | - Francisco Medina
- Inflammation, Nutrition, Metabolism and Oxidative Stress Study Group (INMOX), Biomedical Research and Innovation Institute of Cádiz (INiBICA), Research Unit, Puerta del Mar University Hospital, 11009 Cádiz, Spain; (A.D.-G.); (R.M.M.); (F.M.)
- Salus Infirmorum Faculty of Nursing, Cadiz University, 11001 Cadiz, Spain
| | - Carmen Segundo
- Inflammation, Nutrition, Metabolism and Oxidative Stress Study Group (INMOX), Biomedical Research and Innovation Institute of Cádiz (INiBICA), Research Unit, Puerta del Mar University Hospital, 11009 Cádiz, Spain; (A.D.-G.); (R.M.M.); (F.M.)
- Salus Infirmorum Faculty of Nursing, Cadiz University, 11001 Cadiz, Spain
- Correspondence: (C.S.); (A.M.L.-S.)
| | - Alfonso M. Lechuga-Sancho
- Inflammation, Nutrition, Metabolism and Oxidative Stress Study Group (INMOX), Biomedical Research and Innovation Institute of Cádiz (INiBICA), Research Unit, Puerta del Mar University Hospital, 11009 Cádiz, Spain; (A.D.-G.); (R.M.M.); (F.M.)
- Area of Pediatrics, Department of Child and Mother Health and Radiology, Medical School, University of Cádiz, 11002 Cádiz, Spain;
- Pediatric Endocrinology, Department of Pediatrics, Puerta del Mar University Hospital, 11009 Cádiz, Spain
- Correspondence: (C.S.); (A.M.L.-S.)
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Pluquet O, Abbadie C. Cellular senescence and tumor promotion: Role of the Unfolded Protein Response. Adv Cancer Res 2021; 150:285-334. [PMID: 33858599 DOI: 10.1016/bs.acr.2021.01.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Senescence is a cellular state which can be viewed as a stress response phenotype implicated in various physiological and pathological processes, including cancer. Therefore, it is of fundamental importance to understand why and how a cell acquires and maintains a senescent phenotype. Direct evidence has pointed to the homeostasis of the endoplasmic reticulum whose control appears strikingly affected during senescence. The endoplasmic reticulum is one of the sensing organelles that transduce signals between different pathways in order to adapt a functional proteome upon intrinsic or extrinsic challenges. One of these signaling pathways is the Unfolded Protein Response (UPR), which has been shown to be activated during senescence. Its exact contribution to senescence onset, maintenance, and escape, however, is still poorly understood. In this article, we review the mechanisms through which the UPR contributes to the appearance and maintenance of characteristic senescent features. We also discuss whether the perturbation of the endoplasmic reticulum proteostasis or accumulation of misfolded proteins could be possible causes of senescence, and-as a consequence-to what extent the UPR components could be considered as therapeutic targets allowing for the elimination of senescent cells or altering their secretome to prevent neoplastic transformation.
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Affiliation(s)
- Olivier Pluquet
- Univ Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France.
| | - Corinne Abbadie
- Univ Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
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Zhang K, Wang T, Liu X, Yuan Q, Xiao T, Yuan X, Zhang Y, Yuan L, Wang Y. CASK, APBA1, and STXBP1 collaborate during insulin secretion. Mol Cell Endocrinol 2021; 520:111076. [PMID: 33159991 DOI: 10.1016/j.mce.2020.111076] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 11/01/2020] [Accepted: 11/03/2020] [Indexed: 01/09/2023]
Abstract
Calcium/calmodulin-dependent serine protein kinase (CASK) knockdown reduces insulin vesicle docking to cell membranes. Here, we explored CASK interactions with other proteins during insulin secretion. Using co-immunoprecipitation, liquid chromatography-mass spectrometry and bioinformatic analysis, we identified that CASK, Adapter protein X11 alpha (APBA1), and Syntaxin binding protein 1 (STXBP1) formed tripartite complex during insulin secretion. CASK enhanced APBA1-STXBP1 interaction and mediated their traffic from cytoplasm to plasma membrane during insulin release. High fatty acid stimulation decreased insulin secretion along with CASK, APBA1, and STXBP1 expression; Cask overexpression enhanced CASK/APBA1/STXBP1 tripartite complex function, and may thereby rescue lipotoxicity-induced insulin-release defects. Collectively, our results illustrated the function of CASK in insulin granules exocytosis, which broadens the underlying mechanism of insulin secretion and highlights the clinical potential of CASK as a drug target of type 2 Diabetes Mellitus (T2DM).
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Affiliation(s)
- Kai Zhang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, 210009, China
| | - Tianyuan Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, 210009, China
| | - Xingjing Liu
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, 210009, China
| | - Qingzhao Yuan
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, 210009, China
| | - Tin Xiao
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, 210009, China
| | - Xiangjiang Yuan
- Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210009, China
| | - Yijian Zhang
- Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210009, China
| | - Li Yuan
- Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210009, China
| | - Yao Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, 210009, China.
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Rajput SA, Mirza MR, Choudhary MI. Bergenin protects pancreatic beta cells against cytokine-induced apoptosis in INS-1E cells. PLoS One 2020; 15:e0241349. [PMID: 33347462 PMCID: PMC7751853 DOI: 10.1371/journal.pone.0241349] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 10/13/2020] [Indexed: 12/13/2022] Open
Abstract
Beta cell apoptosis induced by proinflammatory cytokines is one of the hallmarks of diabetes. Small molecules which can inhibit the cytokine-induced apoptosis could lead to new drug candidates that can be used in combination with existing therapeutic interventions against diabetes. The current study evaluated several effects of bergenin, an isocoumarin derivative, in beta cells in the presence of cytokines. These included (i) increase in beta cell viability (by measuring cellular ATP levels) (ii) suppression of beta cell apoptosis (by measuring caspase activity), (iii) improvement in beta cell function (by measuring glucose-stimulated insulin secretion), and (iv) improvement of beta cells mitochondrial physiological functions. The experiments were carried out using rat beta INS-1E cell line in the presence or absence of bergenin and a cocktail of proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon- gamma) for 48 hr. Bergenin significantly inhibited beta cell apoptosis, as inferred from the reduction in the caspase-3 activity (IC50 = 7.29 ± 2.45 μM), and concurrently increased cellular ATP Levels (EC50 = 1.97 ± 0.47 μM). Bergenin also significantly enhanced insulin secretion (EC50 = 6.73 ± 2.15 μM) in INS-1E cells, presumably because of the decreased nitric oxide production (IC50 = 6.82 ± 2.83 μM). Bergenin restored mitochondrial membrane potential (EC50 = 2.27 ± 0.83 μM), decreased ROS production (IC50 = 14.63 ± 3.18 μM), and improved mitochondrial dehydrogenase activity (EC50 = 1.39 ± 0.62 μM). This study shows for the first time that bergenin protected beta cells from cytokine-induced apoptosis and restored insulin secretory function by virtue of its anti-inflammatory, antioxidant and anti-apoptotic properties. To sum up, the above mentioned data highlight bergenin as a promising anti-apoptotic agent in the context of diabetes.
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Affiliation(s)
- Sajid Ali Rajput
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi, Sindh, Pakistan
| | - Munazza Raza Mirza
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi, Sindh, Pakistan
| | - M. Iqbal Choudhary
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi, Sindh, Pakistan
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Sindh, Pakistan
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
- * E-mail:
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Piñeros AR, Gao H, Wu W, Liu Y, Tersey SA, Mirmira RG. Single-Cell Transcriptional Profiling of Mouse Islets Following Short-Term Obesogenic Dietary Intervention. Metabolites 2020; 10:metabo10120513. [PMID: 33353164 PMCID: PMC7765825 DOI: 10.3390/metabo10120513] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/14/2020] [Accepted: 12/17/2020] [Indexed: 12/22/2022] Open
Abstract
Obesity is closely associated with adipose tissue inflammation and insulin resistance. Dysglycemia and type 2 diabetes results when islet β cells fail to maintain appropriate insulin secretion in the face of insulin resistance. To clarify the early transcriptional events leading to β-cell failure in the setting of obesity, we fed male C57BL/6J mice an obesogenic, high-fat diet (60% kcal from fat) or a control diet (10% kcal from fat) for one week, and islets from these mice (from four high-fat- and three control-fed mice) were subjected to single-cell RNA sequencing (sc-RNAseq) analysis. Islet endocrine cell types (α cells, β cells, δ cells, PP cells) and other resident cell types (macrophages, T cells) were annotated by transcript profiles and visualized using Uniform Manifold Approximation and Projection for Dimension Reduction (UMAP) plots. UMAP analysis revealed distinct cell clusters (11 for β cells, 5 for α cells, 3 for δ cells, PP cells, ductal cells, endothelial cells), emphasizing the heterogeneity of cell populations in the islet. Collectively, the clusters containing the majority of β cells showed the fewest gene expression changes, whereas clusters harboring the minority of β cells showed the most changes. We identified that distinct β-cell clusters downregulate genes associated with the endoplasmic reticulum stress response and upregulate genes associated with insulin secretion, whereas others upregulate genes that impair insulin secretion, cell proliferation, and cell survival. Moreover, all β-cell clusters negatively regulate genes associated with immune response activation. Glucagon-producing α cells exhibited patterns similar to β cells but, again, in clusters containing the minority of α cells. Our data indicate that an early transcriptional response in islets to an obesogenic diet reflects an attempt by distinct populations of β cells to augment or impair cellular function and/or reduce inflammatory responses as possible harbingers of ensuing insulin resistance.
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Affiliation(s)
- Annie R. Piñeros
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (A.R.P.); (W.W.)
| | - Hongyu Gao
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (H.G.); (Y.L.)
| | - Wenting Wu
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (A.R.P.); (W.W.)
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (H.G.); (Y.L.)
| | - Yunlong Liu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (H.G.); (Y.L.)
| | - Sarah A. Tersey
- Kolver Diabetes Center and Department of Medicine, The University of Chicago, Chicago, IL 60637, USA;
| | - Raghavendra G. Mirmira
- Kolver Diabetes Center and Department of Medicine, The University of Chicago, Chicago, IL 60637, USA;
- Correspondence:
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Al-Mrabeh A. Pathogenesis and remission of type 2 diabetes: what has the twin cycle hypothesis taught us? Cardiovasc Endocrinol Metab 2020; 9:132-142. [PMID: 33225228 PMCID: PMC7673778 DOI: 10.1097/xce.0000000000000201] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 03/23/2020] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes has been regarded a complex multifactorial disease that lead to serious health complications including high cardiovascular risks. The twin cycle hypothesis postulated that both hepatic insulin resistance and dysfunction rather than death of beta (β) cell determine diabetes onset. Several studies were carried out to test this hypothesis, and all demonstrated that chronic excess calorie intake and ectopic fat accumulation within the liver and pancreas are fundamental to the development of this disease. However, these recent research advances cannot determine the exact cause of this disease. In this review, the major factors that contribute to the pathogenesis and remission of type 2 diabetes will be outlined. Importantly, the effect of disordered lipid metabolism, characterized by altered hepatic triglyceride export will be discussed. Additionally, the observed changes in pancreas morphology in type 2 diabetes will be highlighted and discussed in relation to β cell function.
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Affiliation(s)
- Ahmad Al-Mrabeh
- Magnetic Resonance Centre, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Beta Cell Physiological Dynamics and Dysfunctional Transitions in Response to Islet Inflammation in Obesity and Diabetes. Metabolites 2020; 10:metabo10110452. [PMID: 33182622 PMCID: PMC7697558 DOI: 10.3390/metabo10110452] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 10/02/2020] [Accepted: 10/10/2020] [Indexed: 02/07/2023] Open
Abstract
Beta cells adapt their function to respond to fluctuating glucose concentrations and variable insulin demand. The highly specialized beta cells have well-established endoplasmic reticulum to handle their high metabolic load for insulin biosynthesis and secretion. Beta cell endoplasmic reticulum therefore recognize and remove misfolded proteins thereby limiting their accumulation. Beta cells function optimally when they sense glucose and, in response, biosynthesize and secrete sufficient insulin. Overnutrition drives the pathogenesis of obesity and diabetes, with adverse effects on beta cells. The interleukin signaling system maintains beta cell physiology and plays a role in beta cell inflammation. In pre-diabetes and compromised metabolic states such as obesity, insulin resistance, and glucose intolerance, beta cells biosynthesize and secrete more insulin, i.e., hyperfunction. Obesity is entwined with inflammation, characterized by compensatory hyperinsulinemia, for a defined period, to normalize glycemia. However, with chronic hyperglycemia and diabetes, there is a perpetual high demand for insulin, and beta cells become exhausted resulting in insufficient insulin biosynthesis and secretion, i.e., they hypofunction in response to elevated glycemia. Therefore, beta cell hyperfunction progresses to hypofunction, and may progressively worsen towards failure. Preserving beta cell physiology, through healthy nutrition and lifestyles, and therapies that are aligned with beta cell functional transitions, is key for diabetes prevention and management.
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Mashek DG. Hepatic lipid droplets: A balancing act between energy storage and metabolic dysfunction in NAFLD. Mol Metab 2020; 50:101115. [PMID: 33186758 PMCID: PMC8324678 DOI: 10.1016/j.molmet.2020.101115] [Citation(s) in RCA: 126] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 10/21/2020] [Accepted: 11/06/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is defined by the abundance of lipid droplets (LDs) in hepatocytes. While historically considered simply depots for energy storage, LDs are increasingly recognized to impact a wide range of biological processes that influence cellular metabolism, signaling, and function. While progress has been made toward understanding the factors leading to LD accumulation (i.e. steatosis) and its progression to advanced stages of NAFLD and/or systemic metabolic dysfunction, much remains to be resolved. SCOPE OF REVIEW This review covers many facets of LD biology. We provide a brief overview of the major pathways of lipid accretion and degradation that contribute to steatosis and how they are altered in NAFLD. The major focus is on the relationship between LDs and cell function and the detailed mechanisms that couple or uncouple steatosis from the severity and progression of NAFLD and systemic comorbidities. The importance of specific lipids and proteins within or on LDs as key components that determine whether LD accumulation is linked to cellular and metabolic dysfunction is presented. We discuss emerging areas of LD biology and future research directions that are needed to advance our understanding of the role of LDs in NAFLD etiology. MAJOR CONCLUSIONS Impairments in LD breakdown appear to contribute to disease progression, but inefficient incorporation of fatty acids (FAs) into LD-containing triacylglycerol (TAG) and the consequential changes in FA partitioning also affect NAFLD etiology. Increased LD abundance in hepatocytes does not necessarily equate to cellular dysfunction. While LD accumulation is the prerequisite step for most NAFLD cases, the protein and lipid composition of LDs are critical factors in determining the progression from simple steatosis. Further defining the detailed molecular mechanisms linking LDs to metabolic dysfunction is important for designing effective therapeutic approaches targeting NAFLD and its comorbidities.
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Affiliation(s)
- Douglas G Mashek
- Department of Biochemistry, Molecular Biology, and Biophysics, Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, University of Minnesota, Suite 6-155, 321 Church St. SE, Minneapolis, MN, 55455, USA.
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Endo N, Toyama T, Naganuma A, Saito Y, Hwang GW. Hydrogen Peroxide Causes Cell Death via Increased Transcription of HOXB13 in Human Lung Epithelial A549 Cells. TOXICS 2020; 8:78. [PMID: 32998228 PMCID: PMC7712356 DOI: 10.3390/toxics8040078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 09/23/2020] [Accepted: 09/27/2020] [Indexed: 02/05/2023]
Abstract
Although homeobox protein B13 (HOXB13) is an oncogenic transcription factor, its role in stress response has rarely been examined. We previously reported that knockdown of HOXB13 reduces the cytotoxicity caused by various oxidative stress inducers. Here, we studied the role of HOXB13 in cytotoxicity caused by hydrogen peroxide in human lung epithelial A549 cells. The knockdown of HOXB13 reduced hydrogen peroxide-induced cytotoxicity; however, this phenomenon was largely absent in the presence of antioxidants (Trolox or N-acetyl cysteine (NAC)). This suggests that HOXB13 may be involved in the cytotoxicity caused by hydrogen peroxide via the production of reactive oxygen species (ROS). Hydrogen peroxide also increased both the mRNA and protein levels of HOXB13. However, these increases were rarely observed in the presence of a transcriptional inhibitor, which suggests that hydrogen peroxide increases protein levels via increased transcription of HOXB13. Furthermore, cell death occurred in A549 cells that highly expressed HOXB13. However, this cell death was mostly inhibited by treatment with antioxidants. Taken together, our findings indicate that HOXB13 may be a novel factor involved in the induction of oxidative stress, which causes cell death via intracellular ROS production.
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Affiliation(s)
- Naoki Endo
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan; (N.E.); (T.T.); (A.N.)
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan;
- Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., 1848, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0014, Japan
| | - Takashi Toyama
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan; (N.E.); (T.T.); (A.N.)
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan;
| | - Akira Naganuma
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan; (N.E.); (T.T.); (A.N.)
| | - Yoshiro Saito
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan;
| | - Gi-Wook Hwang
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan; (N.E.); (T.T.); (A.N.)
- Laboratory of Environmental and Health Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan
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Zhao T, Ma J, Li L, Teng W, Tian Y, Ma Y, Wang W, Yan W, Jiao P. MKP-5 Relieves Lipotoxicity-Induced Islet β-Cell Dysfunction and Apoptosis via Regulation of Autophagy. Int J Mol Sci 2020; 21:ijms21197161. [PMID: 32998359 PMCID: PMC7582937 DOI: 10.3390/ijms21197161] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 09/16/2020] [Accepted: 09/25/2020] [Indexed: 01/28/2023] Open
Abstract
Mitogen-activated protein kinase phosphatase-5 (MKP-5) is a regulator of extracellular signaling that is known to regulate lipid metabolism. In this study, we found that obesity caused by a high-fat diet (HFD) decreased the expression of MKP-5 in the pancreas and primary islet cells derived from mice. Then, we further investigated the role of MKP-5 in the protection of islet cells from lipotoxicity by modulating MKP-5 expression. As a critical inducer of lipotoxicity, palmitic acid (PA) was used to treat islet β-cells. We found that MKP-5 overexpression restored PA-mediated autophagy inhibition in Rin-m5f cells and protected these cells from PA-induced apoptosis and dysfunction. Consistently, a lack of MKP-5 aggravated the adverse effects of lipotoxicity. Islet cells from HFD-fed mice were infected using recombinant adenovirus expressing MKP-5 (Ad-MKP-5), and we found that Ad-MKP-5 was able to alleviate HFD-induced apoptotic protein activation and relieve the HFD-mediated inhibition of functional proteins. Notably, HFD-mediated impairments in autophagic flux were restored by Ad-MKP-5 transduction. Furthermore, the autophagy inhibitor 3-methyladenine (3-MA) was used to treat Rin-m5f cells, confirming that the MKP-5 overexpression suppressed apoptosis, dysfunction, inflammatory response, and oxidative stress induced by PA via improving autophagic signaling. Lastly, employing c-Jun amino-terminal kinas (JNK), P38, or extracellular-regulated kinase (ERK) inhibitors, we established that the JNK and P38 MAPK pathways were involved in the MKP-5-mediated apoptosis, dysfunction, and autophagic inhibition observed in islet β cells in response to lipotoxicity.
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Affiliation(s)
| | | | | | | | | | | | | | - Weiqun Yan
- Correspondence: (W.Y.); (P.J.); Tel.: +86-431-8561-9289 (P.J.)
| | - Ping Jiao
- Correspondence: (W.Y.); (P.J.); Tel.: +86-431-8561-9289 (P.J.)
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48
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Haque SKM, Ashwaq O, Sarief A, Azad John Mohamed AK. A comprehensive review about SARS-CoV-2. Future Virol 2020; 15:625-648. [PMID: 33224265 PMCID: PMC7664148 DOI: 10.2217/fvl-2020-0124] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 09/21/2020] [Indexed: 12/16/2022]
Abstract
The coronavirus disease (COVID-19) was first identified in China, December 2019. Since then, it has spread the length and breadth of the world at an unprecedented, alarming rate. Severe acute respiratory syndrome coronavirus (SARS-CoV)-2, which causes COVID-19, has much in common with its closest homologs, SARS-CoV and Middle East respiratory syndrome-CoV. The virus-host interaction of SARS-CoV-2 uses the same receptor, ACE2, which is similar to that of SARS-CoV, which spreads through the respiratory tract. Patients with COVID-19 report symptoms including mild-to-severe fever, cough and fatigue; very few patients report gastrointestinal infections. There are no specific antiviral strategies. A few strong medications are under investigation, so we have to focus on proposals which ought to be taken to forestall this infection in a living host.
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Affiliation(s)
- SK Manirul Haque
- Department of Chemical & Process Engineering Technology, Jubail Industrial College, P. O. Box 10099, Jubail Industrial City 31961, Saudi Arabia
| | - Omar Ashwaq
- Department of Chemical & Process Engineering Technology, Jubail Industrial College, P. O. Box 10099, Jubail Industrial City 31961, Saudi Arabia
| | - Abdulla Sarief
- Department of Chemical & Process Engineering Technology, Jubail Industrial College, P. O. Box 10099, Jubail Industrial City 31961, Saudi Arabia
| | - Abdul Kalam Azad John Mohamed
- Department of Chemical & Process Engineering Technology, Jubail Industrial College, P. O. Box 10099, Jubail Industrial City 31961, Saudi Arabia
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49
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Santerre M, Arjona SP, Allen CN, Shcherbik N, Sawaya BE. Why do SARS-CoV-2 NSPs rush to the ER? J Neurol 2020; 268:2013-2022. [PMID: 32870373 PMCID: PMC7461160 DOI: 10.1007/s00415-020-10197-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/15/2020] [Accepted: 08/27/2020] [Indexed: 12/18/2022]
Abstract
SARS-CoV-2, which led to the 2020 global pandemic, is responsible for the Coronavirus Disease 2019 (COVID-19), a respiratory illness, and presents a tropism for the central nervous system. Like most members of this family, the virus is composed of structural and non-structural proteins (NSPs). The non-structural proteins are critical elements of the replication and transcription complex (RTC), as well as immune system evasion. Through hijacking the endoplasmic reticulum (ER) membrane, NSPs help the virus establish the RTC, inducing ER stress after membrane rearrangement and causing severe neuronal disturbance. In this review, we focus on the role of Nsp3, 4, and 6 in intracellular membrane rearrangement and evaluate the potential disruption of the central nervous system and the neurodegeneration which it could trigger. Studies of these NSPs will not only bring to light their specific role in viral infection but also facilitate the discovery of novel targeted drugs.
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Affiliation(s)
- Maryline Santerre
- Molecular Studies of Neurodegenerative Diseases Lab, Lewis Katz School of Medicine, Fels Institute for Cancer Research, Temple University, 3307 North Broad Street, Philadelphia, PA, 19140, USA.
| | - Sterling P Arjona
- Molecular Studies of Neurodegenerative Diseases Lab, Lewis Katz School of Medicine, Fels Institute for Cancer Research, Temple University, 3307 North Broad Street, Philadelphia, PA, 19140, USA
| | - Charles Ns Allen
- Molecular Studies of Neurodegenerative Diseases Lab, Lewis Katz School of Medicine, Fels Institute for Cancer Research, Temple University, 3307 North Broad Street, Philadelphia, PA, 19140, USA
| | - Natalia Shcherbik
- Department for Cell Biology and Neuroscience, School of Osteopathic Medicine, Rowan University, 2 Medical Center Drive, Stratford, NJ, 08084, USA
| | - Bassel E Sawaya
- Molecular Studies of Neurodegenerative Diseases Lab, Lewis Katz School of Medicine, Fels Institute for Cancer Research, Temple University, 3307 North Broad Street, Philadelphia, PA, 19140, USA. .,Department of Neurology, Lewis Katz School of Medicine - Temple University Philadelphia, Philadelphia, PA, 19140, USA.
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50
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Fukase A, Fukui T, Sasamori H, Hiromura M, Terasaki M, Mori Y, Hayashi T, Yamamoto T, Ohara M, Goto S, Nagaike H, Hirano T, Yamagishi S. Pancreatic fat accumulation evaluated by multidetector computed tomography in patients with type 2 diabetes. J Diabetes Investig 2020; 11:1188-1196. [PMID: 32129002 PMCID: PMC7477536 DOI: 10.1111/jdi.13243] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 01/07/2020] [Accepted: 02/25/2020] [Indexed: 12/19/2022] Open
Abstract
AIMS To clarify the clinical impact of pancreatic fat volume on beta cell function in type 2 diabetes patients. MATERIALS AND METHODS One hundred thirty two consecutive type 2 diabetic patients (mean age, 63.7 years) were enrolled in this cross-sectional study. Total pancreatic volume (TPV), pancreatic fat volume (PFV), and pancreatic parenchymal volume (PPV), and visceral fat volume were examined quantitatively with multidetector computed tomography using SYNAPSE VINCENT image analysis system (Fujifilm Inc., Tokyo, Japan). Pancreatic fat was identified using Hounsfield Units of less than zero. The capacity of insulin secretion was assessed by C-peptide immunoreactivity (CPR) index (100 × fasting CPR/fasting plasma glucose). Insulin sensitivity was evaluated using CPR-insulin resistance (20/fasting CPR × fasting plasma glucose). RESULTS TPV, PFV, PPV, and visceral fat volume were significantly correlated with body weight (BW). PPV/BW, but not PFV/BW, significantly decreased with increasing duration of diabetes and aging. PFV/BW was positively associated with body mass index and visceral fat volume/BW. PFV/BW was significantly correlated with CPR index, while inversely associated with insulin sensitivity. CPR index, but not CPRinsulin resistance was progressively decreased in patients with a longer duration of diabetes. When patients were divided into two groups according to a median PFV/BW value, CPR index in high PFV/BW group with diabetes duration >5 years was significantly lower than those ≤5 years. However, duration-dependent decrease in CPR index was not observed in low PFV/BW group. CONCLUSIONS Our present study suggests that PFV might predict the progression of beta cell dysfunction in patients with type 2 diabetes.
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Affiliation(s)
- Ayako Fukase
- Division of Diabetes, Metabolism and EndocrinologyDepartment of MedicineShowa University School of MedicineTokyoJapan
| | - Tomoyasu Fukui
- Division of Diabetes, Metabolism and EndocrinologyDepartment of MedicineShowa University School of MedicineTokyoJapan
| | - Hiroto Sasamori
- Division of Diabetes, Metabolism and EndocrinologyDepartment of MedicineShowa University School of MedicineTokyoJapan
- Alzclinic Pet LabTokyoJapan
| | - Munenori Hiromura
- Division of Diabetes, Metabolism and EndocrinologyDepartment of MedicineShowa University School of MedicineTokyoJapan
| | - Michishige Terasaki
- Division of Diabetes, Metabolism and EndocrinologyDepartment of MedicineShowa University School of MedicineTokyoJapan
| | - Yusaku Mori
- Division of Diabetes, Metabolism and EndocrinologyDepartment of MedicineShowa University School of MedicineTokyoJapan
| | - Toshiyuki Hayashi
- Division of Diabetes, Metabolism and EndocrinologyDepartment of MedicineShowa University School of MedicineTokyoJapan
| | - Takeshi Yamamoto
- Division of Diabetes, Metabolism and EndocrinologyDepartment of MedicineShowa University School of MedicineTokyoJapan
| | - Makoto Ohara
- Division of Diabetes, Metabolism and EndocrinologyDepartment of MedicineShowa University School of MedicineTokyoJapan
| | - Satoshi Goto
- Division of Diabetes, Metabolism and EndocrinologyDepartment of MedicineShowa University School of MedicineTokyoJapan
| | - Hiroe Nagaike
- Division of Diabetes, Metabolism and EndocrinologyDepartment of MedicineShowa University School of MedicineTokyoJapan
| | - Tsutomu Hirano
- Division of Diabetes, Metabolism and EndocrinologyDepartment of MedicineShowa University School of MedicineTokyoJapan
- Ebina Memorial HospitalEbinaJapan
| | - Sho‐ichi Yamagishi
- Division of Diabetes, Metabolism and EndocrinologyDepartment of MedicineShowa University School of MedicineTokyoJapan
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