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Shudt C, Smith S, Bortsov A, Parr K, Gaynor S, Slade G, Zolnoun D, Nackley A. Vestibulodynia Presentation is Differentiated by the Presence of Additional Chronic Primary Pain Conditions. THE JOURNAL OF PAIN 2025:105450. [PMID: 40412493 DOI: 10.1016/j.jpain.2025.105450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 04/28/2025] [Accepted: 05/19/2025] [Indexed: 05/27/2025]
Abstract
Vestibulodynia (VBD) is a common chronic primary pain condition (CPPC) defined by the presence of recurrent vulvovaginal pain with no obvious root cause. As many as 3 in 4 women with VBD may have co-occurring CPPCs, such as episodic migraine, fibromyalgia, irritable bowel syndrome, and temporomandibular disorder. The purpose of the present study was to compare pain and pain-related factors in women with VBD alone and those with VBD and co-occurring CPPCs (VBD+). We enrolled 45 women with VBD, 106 with VBD+, and 198 pain-free controls, who underwent a highly specific gynecological examination, quantitative sensory testing at remote body sites, and completed an extensive array of questionnaires assessing various physical and psychological experiences. Blood samples were also collected for genome-wide association study (GWAS). Results demonstrated that women with VBD+ had distinct patterns of heightened local vulvovaginal pain intensity and increased pain sensitivity at remote body site compared to those with VBD. Further women with VBD+ reported taking more medications indicated for pain and greater adverse mood states, somatic and psychological symptoms, and pain catastrophizing. Finally, case-control GWAS analysis identified distinct genetic variants associated with VBD and VBD+ subtypes. Variants associated with VBD were located in genes that regulate reproductive and nervous system development, while those associated with VBD+ were located in genes implicated in synaptic transmission and related CPPC pathophysiology. Together, these findings emphasize the critical need for accounting for CPPC status in VBD diagnostic, mechanistic, and therapeutic methodologies. Perspective This study identifies co-occurring chronic primary pain conditions as a differentiating factor in vestibulodynia presentation, highlighting the need for precise diagnostic criteria and personalized treatment approaches to address heightened symptom burden and complexity.
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Affiliation(s)
- Chloe Shudt
- Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Shad Smith
- Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Andrey Bortsov
- Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Kayla Parr
- Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Sheila Gaynor
- Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Gary Slade
- Center for Pain Research and Innovation, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Denniz Zolnoun
- Department of Obstetrics and Gynecology, Pelvic Pain Research Unit, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Andrea Nackley
- Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
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Huang Z, Li Q, Yang C, Zhang C, Huang L, Lin Y, Wang Y, Xiang H, Zhu J. CIDEB promotes lipid deposition in goat intramuscular adipocytes. Anim Biosci 2025; 38:884-897. [PMID: 40045630 PMCID: PMC12062806 DOI: 10.5713/ab.24.0584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/28/2024] [Accepted: 11/12/2024] [Indexed: 05/09/2025] Open
Abstract
OBJECTIVE Cell death-inducing DNA fragmentation factor alpha-like effector B (CIDEB), a family member of Cell death-inducing DFF45-like effectors (CIDEs), is well known as a crucial regulator for lipid metabolic signaling pathways in various metabolic tissues and secretory glands. However, its role in regulating intramuscular fat (IMF) deposition in goat remains unclear. METHODS The expression vector pcDNA3.1-CIDEB was constructed and transfected into goat intramuscular preadipocytes; the overexpression and interference efficiency and expression of genes related to lipid metabolism were measured by Real-time polymerase chain reaction; the effect of overexpression of CIDEB and interfering with CIDEB on lipid droplet formation was observed by Oil Red O staining and glycerol phosphate oxidase-Trinder enzymatic reaction. Then RNA-Seq was used to investigate the metabolic pathway of CIDEB affecting adipocyte deposition in goat intramuscular preadipocytes. RESULTS Overexpression of CIDEB significantly promoted the lipid droplets accumulation and the triglyceride deposition, and significantly upregulated the expression of genes related to lipid metabolism. After overexpression of CIDEB in goat intramuscular preadipocytes, 171 differentially expressed genes (DEGs) were found, including 122 up-regulated and 49 down-regulated DEGs, and the top three significantly changed pathways filtered by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were Cocaine addiction, Amphetamine addiction and Malaria pathways. Conversely, the silencing of CIDEB significantly reduced lipid accumulation in goat intramuscular preadipocytes, meanwhile changing the expression of lipid metabolism genes. For CIDEB silencing, a total of 2140 DEGs were found, including 1252 up-regulated and 888 down-regulated DEGs, and the top three significantly changed pathways filtered by KEGG analysis were Ribosome, Thyroid hormone signaling pathway and Alzheimer disease. CONCLUSION The expression of CIDEB can significantly promote lipid deposition of intramuscular adipocytes in goats, and these results provide important data to support further clarifying the mechanism of CIDEB gene on the regulation of intramuscular adipogenesis, and the IMF formation in goats.
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Affiliation(s)
- Zhuohan Huang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Southwest Minzu University, Ministry of Education, Chengdu,
China
| | - Qi Li
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu,
China
| | - Changheng Yang
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu,
China
| | - Changhui Zhang
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu,
China
| | - Lian Huang
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu,
China
| | - Yaqiu Lin
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Southwest Minzu University, Ministry of Education, Chengdu,
China
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu,
China
| | - Yong Wang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Southwest Minzu University, Ministry of Education, Chengdu,
China
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu,
China
| | - Hua Xiang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Southwest Minzu University, Ministry of Education, Chengdu,
China
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu,
China
| | - Jiangjiang Zhu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Southwest Minzu University, Ministry of Education, Chengdu,
China
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu,
China
- Institute of Qinghai-Tibetan Plateau, Southwest Minzu University, Chengdu,
China
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Lu X, Chen Y, Xie Q, Tong N. Comparative effect of high intensity interval training and moderate intensity continuous training on metabolic improvements and regulation of Cidea and Cidec in obese C57BL/6 mice. PLoS One 2025; 20:e0322634. [PMID: 40305497 PMCID: PMC12043136 DOI: 10.1371/journal.pone.0322634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Accepted: 03/25/2025] [Indexed: 05/02/2025] Open
Abstract
Obesity is a chronic disease associated with increased risk of cardiovascular disease, diabetes, metabolic dysfunction associated steatotic liver disease and certain cancers. High intensity interval training (HIIT) and moderate intensity continuous training (MICT) are effective in preventing and managing obesity. However, the comparative effects of these modalities on metabolic disorders need to be better mechanistically explored. This study aimed to comprehensively assess the effects of MICT and HIIT on key metabolic organs and underlying mechanisms. C57BL/6 mice were randomized to receive either a chow diet or high fat diet for 12 weeks, followed by random assignment of high-fat-fed mice to no exercise, MICT or HIIT groups for additional 5 weeks. At the end, both HIIT and MICT significantly alleviated high-fat-induced weight gain and lipids disorder and impaired liver function. HIIT was more effective in enhancing insulin sensitivity, ameliorating hepatic steatosis, reducing adipocyte hypertrophy. Additionally, HIIT restored the high-fat-induced downregulation of Cidea, Cidec and Atgl in inguinal white adipose tissue and liver. Furthermore, HIIT resulted in upregulation of interleukin 6 (Il-6) in skeletal muscle. The exogenous addition of Il-6 to primary white adipocytes significantly downregulated Cidec, and up-regulated Atgl expression. In conclusion, HIIT is superior to MICT in improving metabolic dysfunction, likely mediated through Il-6-induced downregulation of Cidea and Cidec, thereby promoting lipolysis.
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Affiliation(s)
- Xi Lu
- Department of Endocrinology and Metabolism, Laboratory of Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, China
| | - Yonglian Chen
- Department of Endocrinology and Metabolism, Laboratory of Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, China
| | - Qingxing Xie
- Department of Endocrinology and Metabolism, Laboratory of Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, China
| | - Nanwei Tong
- Department of Endocrinology and Metabolism, Laboratory of Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, China
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Zhang J, Liu X, Jin X, Mao X, Xu X, Zhang X, Shang K, Xu Y, Zhang Y, Meng G, Yue M, Cai G, Yang S, Huang J, Fang J, Pan L, Jiang L, Shi S, Shou J. Liver-specific inactivation of Cideb improves metabolic profiles and ameliorates steatohepatitis and fibrosis in animal models for MASH. Pharmacol Res 2025; 214:107664. [PMID: 39984006 DOI: 10.1016/j.phrs.2025.107664] [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: 12/25/2024] [Revised: 02/13/2025] [Accepted: 02/14/2025] [Indexed: 02/23/2025]
Abstract
Germline mutations of CIDEB, a lipid droplets (LDs)-associated protein, confer protection against various liver diseases in humans. It remains to be determined whether liver-specific inhibition of CIDEB will bring clinical benefits. We aim to establish pharmacological proof of concept by testing GalNAc-conjugated Cideb surrogate siRNAs in respective animal models of obesity and MASH and to develop siRNA drug candidates for clinical investigations. Surrogate siRNAs targeting mouse Cideb were designed and evaluated via a panel of assays. Concurrently, humanized CIDEB knock-in mice were generated as a research tool to facilitate human therapeutic siRNA discovery. In vivo administration of the surrogate siRNAs was conducted in the diet-induced obesity (DIO) model and CDAA-HFD model of MASH. In the DIO model, Cideb knockdown led to significant reductions of serum total cholesterol (TC) and triglyceride (TG) levels, a significant decrease in hepatic macro-steatosis and notable weight loss. In the CDAA-HFD model, Cideb siRNA treatment significantly reduced liver TC and TG levels. Furthermore, remarkable reductions of hepatic steatosis and the composite NAS score were observed with a concomitant amelioration of liver fibrosis. Transcriptome analyses revealed that integrin pathways may contribute to the major pharmacological activities upon Cideb inactivation beyond lipid metabolism. CIDEB exhibits significant potential as a therapeutic target for the treatment of MASH. Liver-targeting siRNA candidates are under development for therapeutic hypothesis testing in humans.
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Affiliation(s)
- Jianhua Zhang
- EnnovaBio Pharmaceuticals, Shanghai 201206, China; Ennovabio (ZheJiang) Pharmaceuticals, Shaoxing, Zhejiang 312366, China
| | - Xujie Liu
- Shanghai Rona Therapeutics, Shanghai 201315, China
| | - Xian Jin
- EnnovaBio Pharmaceuticals, Shanghai 201206, China; Ennovabio (ZheJiang) Pharmaceuticals, Shaoxing, Zhejiang 312366, China
| | - Xudong Mao
- EnnovaBio Pharmaceuticals, Shanghai 201206, China
| | - Xueli Xu
- EnnovaBio Pharmaceuticals, Shanghai 201206, China
| | - Xing Zhang
- EnnovaBio Pharmaceuticals, Shanghai 201206, China
| | - Ke Shang
- EnnovaBio Pharmaceuticals, Shanghai 201206, China; Ennovabio (ZheJiang) Pharmaceuticals, Shaoxing, Zhejiang 312366, China
| | - Yuan Xu
- EnnovaBio Pharmaceuticals, Shanghai 201206, China; Ennovabio (ZheJiang) Pharmaceuticals, Shaoxing, Zhejiang 312366, China
| | | | - Guofeng Meng
- Shanghai Rona Therapeutics, Shanghai 201315, China
| | - Ming Yue
- Shanghai Rona Therapeutics, Shanghai 201315, China
| | - Guoqing Cai
- Shanghai Rona Therapeutics, Shanghai 201315, China
| | - Song Yang
- Shanghai Rona Therapeutics, Shanghai 201315, China
| | - Jinyu Huang
- Shanghai Rona Therapeutics, Shanghai 201315, China
| | - Jianwu Fang
- Shanghai Rona Therapeutics, Shanghai 201315, China
| | - Ling Pan
- Shanghai Rona Therapeutics, Shanghai 201315, China
| | - Lei Jiang
- EnnovaBio Pharmaceuticals, Shanghai 201206, China; Ennovabio (ZheJiang) Pharmaceuticals, Shaoxing, Zhejiang 312366, China
| | - Stella Shi
- Shanghai Rona Therapeutics, Shanghai 201315, China
| | - Jianyong Shou
- EnnovaBio Pharmaceuticals, Shanghai 201206, China; Ennovabio (ZheJiang) Pharmaceuticals, Shaoxing, Zhejiang 312366, China.
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5
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Al Harake SN, Abedin Y, Hatoum F, Nassar NZ, Ali A, Nassar A, Kanaan A, Bazzi S, Azar S, Harb F, Ghadieh HE. Involvement of a battery of investigated genes in lipid droplet pathophysiology and associated comorbidities. Adipocyte 2024; 13:2403380. [PMID: 39329369 PMCID: PMC11445895 DOI: 10.1080/21623945.2024.2403380] [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: 12/07/2023] [Revised: 08/29/2024] [Accepted: 09/05/2024] [Indexed: 09/28/2024] Open
Abstract
Lipid droplets (LDs) are highly specialized energy storage organelles involved in the maintenance of lipid homoeostasis by regulating lipid flux within white adipose tissue (WAT). The physiological function of adipocytes and LDs can be compromised by mutations in several genes, leading to NEFA-induced lipotoxicity, which ultimately manifests as metabolic complications, predominantly in the form of dyslipidemia, ectopic fat accumulation, and insulin resistance. In this review, we delineate the effects of mutations and deficiencies in genes - CIDEC, PPARG, BSCL2, AGPAT2, PLIN1, LIPE, LMNA, CAV1, CEACAM1, and INSR - involved in lipid droplet metabolism and their associated pathophysiological impairments, highlighting their roles in the development of lipodystrophies and metabolic dysfunction.
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Affiliation(s)
- Sami N. Al Harake
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Yasamin Abedin
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Fatema Hatoum
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Nour Zahraa Nassar
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Ali Ali
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Aline Nassar
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Amjad Kanaan
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Samer Bazzi
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Sami Azar
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Frederic Harb
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Hilda E. Ghadieh
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
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6
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Ford BE, Chachra SS, Alshawi A, Oakley F, Fairclough RJ, Smith DM, Tiniakos D, Agius L. Compromised chronic efficacy of a glucokinase activator AZD1656 in mouse models for common human GCKR variants. Biochem Pharmacol 2024; 229:116499. [PMID: 39173844 DOI: 10.1016/j.bcp.2024.116499] [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: 05/15/2024] [Revised: 07/23/2024] [Accepted: 08/19/2024] [Indexed: 08/24/2024]
Abstract
Glucokinase activators (GKAs) have been developed as blood glucose lowering drugs for type 2 diabetes. Despite good short-term efficacy, several GKAs showed a decline in efficacy chronically during clinical trials. The underlying mechanisms remain incompletely understood. We tested the hypothesis that deficiency in the liver glucokinase regulatory protein (GKRP) as occurs with common human GCKR variants affects chronic GKA efficacy. We used a Gckr-P446L mouse model for the GCKR exonic rs1260326 (P446L) variant and the Gckr-del/wt mouse to model transcriptional deficiency to test for chronic efficacy of the GKA, AZD1656 in GKRP-deficient states. In the Gckr-P446L mouse, the blood glucose lowering efficacy of AZD1656 (3 mg/kg body wt) after 2 weeks was independent of genotype. However after 19 weeks, efficacy was maintained in wild-type but declined in the LL genotype, in conjunction with raised hepatic glucokinase activity and without raised liver lipids. Sustained blood glucose lowering efficacy in wild-type mice was associated with qualitatively similar but more modest changes in the liver transcriptome compared with the P446L genotype, consistent with GKA therapy representing a more modest glucokinase excess than the P446L genotype. Chronic treatment with AZD1656 in the Gckr-del/wt mouse was associated with raised liver triglyceride and hepatocyte microvesicular steatosis. The results show that in mouse models of liver GKRP deficiency in conjunction with functional liver glucokinase excess as occurs in association with common human GCKR variants, GKRP-deficiency predisposes to declining efficacy of the GKA in lowering blood glucose and to GKA induced elevation in liver lipids.
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Affiliation(s)
- Brian E Ford
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Shruti S Chachra
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Ahmed Alshawi
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Medical Laboratory Technique Department, Kufa Institute, Al-Furat Al-Awsat Technical University, Kufa, Iraq
| | - Fiona Oakley
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Rebecca J Fairclough
- Emerging Innovations Unit, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - David M Smith
- Emerging Innovations Unit, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Dina Tiniakos
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Dept of Pathology, Aretaieion Hospital Medical School, National and Kapodistrian University of Athens, Greece
| | - Loranne Agius
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
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Koike N, Umemura Y, Inokawa H, Tokuda I, Tsuchiya Y, Sasawaki Y, Umemura A, Masuzawa N, Yabumoto K, Seya T, Sugimoto A, Yoo SH, Chen Z, Yagita K. Inter-individual variations in circadian misalignment-induced NAFLD pathophysiology in mice. iScience 2024; 27:108934. [PMID: 38533453 PMCID: PMC10964262 DOI: 10.1016/j.isci.2024.108934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/19/2023] [Accepted: 01/12/2024] [Indexed: 03/28/2024] Open
Abstract
Pathological consequences of circadian misalignment, such as shift work, show considerable individual differences, but the lack of mechanistic understanding hinders precision prevention to prevent and mitigate disease symptoms. Here, we employed an integrative approach involving physiological, transcriptional, and histological phenotypes to examine inter-individual differences in pre-symptomatic pathological progression, preceding irreversible disease onset, in wild-type mice exposed to chronic jet-lag (CJL). We observed that CJL markedly increased the prevalence of hepatic steatosis with pronounced inter-individual differences. Stratification of individual mice based on CJL-induced hepatic transcriptomic signature, validated by histopathological analysis, pinpoints dysregulation of lipid metabolism. Moreover, the period and power of intrinsic behavioral rhythms were found to significantly correlate with CJL-induced gene signatures. Together, our results suggest circadian rhythm robustness of the animals contributes to inter-individual variations in pathogenesis of circadian misalignment-induced diseases and raise the possibility that these physiological indicators may be available for predictive hallmarks of circadian rhythm disorders.
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Affiliation(s)
- Nobuya Koike
- Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Yasuhiro Umemura
- Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hitoshi Inokawa
- Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
- Department of Human Nutrition, Chugoku Gakuen University, Okayama 701-0197, Japan
| | - Isao Tokuda
- Department of Mechanical Engineering, Ritsumeikan University, Kusatsu 525-8577, Japan
| | - Yoshiki Tsuchiya
- Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Yuh Sasawaki
- Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Atsushi Umemura
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Naoko Masuzawa
- Department of Clinical Pathology, Otsu City Hospital, Otsu 520-0804, Japan
| | - Kazuya Yabumoto
- Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Takashi Seya
- Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Akira Sugimoto
- Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Seung-Hee Yoo
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Zheng Chen
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Kazuhiro Yagita
- Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
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Tong X, Liu C, Liang M, Ye X, Deng Z, Zhang X. Screening and validation of differentially expressed genes in adipose tissue of patients with obesity and type 2 diabetes mellitus. BIOMOLECULES & BIOMEDICINE 2024; 24:40-50. [PMID: 37597213 PMCID: PMC10787618 DOI: 10.17305/bb.2023.9498] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/01/2023] [Accepted: 08/01/2023] [Indexed: 08/21/2023]
Abstract
White adipose tissue (WAT) plays a pivotal role in the onset of type 2 diabetes mellitus (T2DM) and obesity. Despite its significance the underlying pathogenesis and key genes associated with it remain elusive. In our study, we screened the differentially expressed genes (DEGs) in intra-abdominal WAT of T2DM patients with obesity, as well as those with simple obesity, aiming to lay a foundational theory for an in-depth investigation of T2DM pathogenesis and the identification of novel therapeutic targets. Gene expression datasets (GSE16415 and GSE71416) were retrieved from the Gene Expression Omnibus (GEO) database. We employed R for screening DEGs and conducted a functional enrichment analysis using the Metascape database. Combined Lasso regression and Boruta feature selection algorithms were used to identify key DEGs. Subsequently, these were cross-verified using the GSE29231 dataset. Samples and medical records were collected from clinical study participants. The mRNA and protein expressions of the key DEGs were verified using qRT-PCR and western blotting, respectively. We discerned a total of 130 DEGs, with 40 being upregulated and 90 downregulated. Functional and pathway enrichment analyses illuminated that these genes are instrumental in mediating metabolite and energy production, neutrophil-mediated immunity, and other associated biological processes. This includes their involvement in the tricarboxylic acid cycle, glycolysis/gluconeogenesis, peroxisome proliferator-activated receptors, and other signalling pathways. Two genes, CIDEA and FSCN1 emerged as key DEGs. The low expression of CIDEA and high expression of FSCN1 in the T2DM and obesity group were verified in clinical samples (P < 0.05). We established that CIDEA and FSCN1 manifest significant differential expression in T2DM patients who are obese. This suggests their potential as risk assessment markers and therapeutic targets for T2DM.
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Affiliation(s)
- Xuewei Tong
- Department of Clinical Laboratory, Hospital of Xinjiang Production and Construction Corps/Second Affiliated Hospital, Medical School of Shihezi University, Urumqi, Xinjiang, China
- Clinical Laboratory Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Chunyan Liu
- Department of Clinical Laboratory, Hospital of Xinjiang Production and Construction Corps/Second Affiliated Hospital, Medical School of Shihezi University, Urumqi, Xinjiang, China
| | - Mengjie Liang
- Department of Clinical Laboratory, Hospital of Xinjiang Production and Construction Corps/Second Affiliated Hospital, Medical School of Shihezi University, Urumqi, Xinjiang, China
| | - Xueyan Ye
- Department of Clinical Laboratory, Hospital of Xinjiang Production and Construction Corps/Second Affiliated Hospital, Medical School of Shihezi University, Urumqi, Xinjiang, China
- Prenatal Diagnosis Center, Urumqi Maternal and Child Health Hospital, Urumqi, Xinjiang, China
| | - Zhaohui Deng
- Department of Clinical Laboratory, Hospital of Xinjiang Production and Construction Corps/Second Affiliated Hospital, Medical School of Shihezi University, Urumqi, Xinjiang, China
| | - Xin Zhang
- Department of Clinical Laboratory, Hospital of Xinjiang Production and Construction Corps/Second Affiliated Hospital, Medical School of Shihezi University, Urumqi, Xinjiang, China
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9
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Ishiyama S, Kimura M, Nakagawa T, Kishigami S, Mochizuki K. Induction of the Lipid Droplet Formation Genes in Steatohepatitis Mice by Embryo/Postnatal Nutrient Environment Is Associated with Histone Acetylation around the Genes. J Nutr Sci Vitaminol (Tokyo) 2024; 70:318-327. [PMID: 39218693 DOI: 10.3177/jnsv.70.318] [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] [Indexed: 09/04/2024]
Abstract
Recently, we have demonstrated that mice, cultured embryos in α-minimum essential medium (αMEM) and subsequent fed a high-fat, high-sugar diet, developed steatohepatitis. In this study, we investigated using these samples whether the expression of lipid droplet formation genes in the liver is higher in MEM mice, whether these expressions are regulated by histone acetylation, writers/readers of histone acetylation, and the transcriptional factors of endoplasmic reticulum stress. Mice were produced by two-cell embryos in αMEM or standard potassium simplex-optimized medium (control) in vitro for 48 h, and implanted into an oviduct for spontaneous delivery. MEM and control-mice were fed a high-fat, high-sugar diet for 18 wk, and then liver samples were collected and analyzed by histology, qRT-PCR, and chromatin immunoprecipitation assay. Gene expression of Cidea, Cidec, and Plin4 were higher in MEM mice and histone H3K9 acetylation, BRD4, and CBP were higher in MEM mice than in control mice around those genes. However, the binding of endoplasmic reticulum stress-related transcription factors (ATF4, CHOP and C/EBPα) around those genes in the liver, was not clearly differed between MEM mice and control mice. The increased expression of Cidea, Cidec and Plin4 in the liver, accompanied by the development of steatohepatitis in mice induced is positively associated with increased histone H3K9 acetylation and CBP and BRD4 binding around these genes.
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Affiliation(s)
- Shiori Ishiyama
- Faculty of Life and Environmental Sciences, University of Yamanashi
- Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi
| | - Mayu Kimura
- Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi
| | | | - Satoshi Kishigami
- Faculty of Life and Environmental Sciences, University of Yamanashi
- Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi
- Advanced Biotechnology Center, University of Yamanashi
- Center for Advanced Assisted Reproductive Technologies, University of Yamanashi
| | - Kazuki Mochizuki
- Faculty of Life and Environmental Sciences, University of Yamanashi
- Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi
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10
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Perrone G, Rigacci L, Urru S, Kovalchuk S, Brugia M, Fabbri A, Iovino L, Puccini B, Cencini E, Orciuolo E, Birtolo S, Melosi A, Santini S, Landini I, Roviello G, Santi R, Macciotta A, Ricceri F, Bosi A, Bocchia M, Petrini M, Mini E, Nobili S. Exploratory Genome-Wide Association Analysis to Identify Pharmacogenetic Determinants of Response to R-CHOP in Diffuse Large B-Cell Lymphoma. Cancers (Basel) 2023; 15:2753. [PMID: 37345090 PMCID: PMC10216814 DOI: 10.3390/cancers15102753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/05/2023] [Accepted: 05/07/2023] [Indexed: 06/23/2023] Open
Abstract
R-CHOP standard chemotherapy is successful in about 60% of diffuse large B-cell lymphoma (DLBCL) patients. Unresponsive patients have a poor prognosis, and predictive biomarkers of response to R-CHOP are lacking. We conducted the first prospective GWAS study aimed at exploring constitutional biomarkers predictive of R-CHOP efficacy and toxicity. Overall, 216 any-stage chemonaïve DLBCL patients candidate to R-CHOP were enrolled. The median age of the 185 eligible patients was 59.2 years, 49.7% were women and 45.4% were stage I-II patients. According to the Revised International Prognostic Index (R-IPI), 14.1%, 56.8% and 29.2% were in the very good, good and poor prognosis groups, respectively. Of the patients, 85.9% produced a complete response. Highly significant associations (i.e., p < 5 × 10-8) were found between progression-free survival (PFS) and six SNPs (i.e., rs116665727, rs1607795, rs75614943, rs77241831, rs117500207, rs78466241). Additionally, five SNPs (i.e., rs74832512, rs117500207, rs35789195, rs11721010, rs12356569) were highly associated with overall survival (OS). Wild-type patients showed a prolonged PFS or OS compared with patients carrying deleterious alleles (p < 0.001). No association with the adequate significant threshold was observed between SNPs and the objective response or toxicity. In the future, these SNPs, alone or in combination, after a proper validation in an independent cohort, could contribute to improving the prediction of R-CHOP response.
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Affiliation(s)
- Gabriele Perrone
- Department of Health Sciences, University of Florence, 50139 Florence, Italy; (G.P.); (I.L.); (G.R.); (R.S.)
- DENOTHE Excellence Center, University of Florence, 50139 Florence, Italy
| | - Luigi Rigacci
- Research Unit of Hematology, Department of Medicine and Surgery, Campus Biomedico University, 00128 Roma, Italy;
| | - Sara Urru
- Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy;
| | - Sofya Kovalchuk
- Unit of Hematology, Careggi University-Hospital, 50134 Florence, Italy; (S.K.); (B.P.); (A.B.)
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Marco Brugia
- Unit of Medical Oncology, Careggi University-Hospital, 50134 Florence, Italy;
| | - Alberto Fabbri
- Unit of Hematology, Azienda Ospedaliera Universitaria Senese, University of Siena, 53100 Siena, Italy; (A.F.); (E.C.); (M.B.)
| | - Lorenzo Iovino
- Unit of Hematology, Santa Chiara University Hospital, University of Pisa, 56100 Pisa, Italy; (L.I.); (E.O.); (M.P.)
| | - Benedetta Puccini
- Unit of Hematology, Careggi University-Hospital, 50134 Florence, Italy; (S.K.); (B.P.); (A.B.)
| | - Emanuele Cencini
- Unit of Hematology, Azienda Ospedaliera Universitaria Senese, University of Siena, 53100 Siena, Italy; (A.F.); (E.C.); (M.B.)
| | - Enrico Orciuolo
- Unit of Hematology, Santa Chiara University Hospital, University of Pisa, 56100 Pisa, Italy; (L.I.); (E.O.); (M.P.)
| | - Silvia Birtolo
- Unit of Hematology, Ospedale SS. Cosma e Damiano, 51017 Pescia, Italy;
| | | | - Simone Santini
- ASL Toscana Centro, Department of Oncology, Oncohematology Unit, Santo Stefano Hospital, 59100 Prato, Italy;
| | - Ida Landini
- Department of Health Sciences, University of Florence, 50139 Florence, Italy; (G.P.); (I.L.); (G.R.); (R.S.)
- DENOTHE Excellence Center, University of Florence, 50139 Florence, Italy
| | - Giandomenico Roviello
- Department of Health Sciences, University of Florence, 50139 Florence, Italy; (G.P.); (I.L.); (G.R.); (R.S.)
- DENOTHE Excellence Center, University of Florence, 50139 Florence, Italy
| | - Raffaella Santi
- Department of Health Sciences, University of Florence, 50139 Florence, Italy; (G.P.); (I.L.); (G.R.); (R.S.)
| | - Alessandra Macciotta
- Department of Clinical and Biological Sciences, University of Turin, 10043 Turin, Italy; (A.M.); (F.R.)
| | - Fulvio Ricceri
- Department of Clinical and Biological Sciences, University of Turin, 10043 Turin, Italy; (A.M.); (F.R.)
| | - Alberto Bosi
- Unit of Hematology, Careggi University-Hospital, 50134 Florence, Italy; (S.K.); (B.P.); (A.B.)
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Monica Bocchia
- Unit of Hematology, Azienda Ospedaliera Universitaria Senese, University of Siena, 53100 Siena, Italy; (A.F.); (E.C.); (M.B.)
| | - Mario Petrini
- Unit of Hematology, Santa Chiara University Hospital, University of Pisa, 56100 Pisa, Italy; (L.I.); (E.O.); (M.P.)
| | - Enrico Mini
- Department of Health Sciences, University of Florence, 50139 Florence, Italy; (G.P.); (I.L.); (G.R.); (R.S.)
- DENOTHE Excellence Center, University of Florence, 50139 Florence, Italy
| | - Stefania Nobili
- DENOTHE Excellence Center, University of Florence, 50139 Florence, Italy
- Department of Neuroscience, Psychology, Drug Research and Child Health—NEUROFARBA, University of Florence, 50139 Florence, Italy
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11
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Liu X, Zhang L, Tang W, Zhang T, Xiang P, Shen Q, Ye T, Xiao Y. Transcriptomic profiling and differential analysis reveal the renal toxicity mechanisms of mice under cantharidin exposure. Toxicol Appl Pharmacol 2023; 465:116450. [PMID: 36907384 DOI: 10.1016/j.taap.2023.116450] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/14/2023]
Abstract
Cantharidin (CTD), extracted from the traditional Chinese medicine mylabris, has shown significant curative effects against a variety of tumors, but its clinical application is limited by its high toxicity. Studies have revealed that CTD can cause toxicity in the kidneys; however, the underlying molecular mechanisms remain unclear. In this study, we investigated the toxic effects in mouse kidneys following CTD treatment by pathological and ultrastructure observations, biochemical index detection, and transcriptomics, and explored the underlying molecular mechanisms by RNA sequencing (RNA-seq). The results showed that after CTD exposure, the kidneys had different degrees of pathological damage, altered uric acid and creatinine levels in serum, and the antioxidant indexes in tissues were significantly increased. These changes were more pronounced at medium and high doses of CTD. RNA-seq analysis revealed 674 differentially expressed genes compared with the control group, of which 131 were upregulated and 543 were downregulated. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that many differentially expressed genes were closely related to the stress response, the CIDE protein family, and the transporter superfamily, as well as the MAPK, AMPK, and HIF-1 pathways. The reliability of the RNA-seq results was verified by qRT-PCR of the six target genes. These findings offer insight into the molecular mechanisms of renal toxicity caused by CTD and provide an important theoretical basis for the clinical treatment of CTD-induced nephrotoxicity.
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Affiliation(s)
- Xin Liu
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Linghan Zhang
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Wenchao Tang
- Guizhou University of Traditional Chinese Medicine, Guiyang, China; Key Laboratory of Forensic Toxicology of Herbal Medicines, Guizhou Education Department, Guiyang, China.
| | - Tingting Zhang
- Chongqing university three gorges hospital, Chongqing, China
| | - Ping Xiang
- Institute of Environmental Remediation and Human Health, School of Ecology and Environment, Southwest Forestry University, Kunming 650224, China
| | - Qin Shen
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Taotao Ye
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Yuanyuan Xiao
- Guizhou University of Traditional Chinese Medicine, Guiyang, China.
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12
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Park CY, Kim D, Seo MK, Kim J, Choe H, Kim JH, Hong JP, Lee YJ, Heo Y, Kim HJ, Park HS, Jang YJ. Dysregulation of Lipid Droplet Protein Expression in Adipose Tissues and Association with Metabolic Risk Factors in Adult Females with Obesity and Type 2 Diabetes. J Nutr 2023; 153:691-702. [PMID: 36931749 DOI: 10.1016/j.tjnut.2023.01.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 01/05/2023] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Adipocyte dysregulation of lipid droplet (LD) metabolism caused by altered expression of LD proteins contributes to obesity-related metabolic diseases. OBJECTIVES We aimed to investigate whether expression levels of PLIN1, CIDEA, and CIDEC were altered in adipose tissues of women with obesity and type 2 diabetes and whether their alterations were associated with metabolic risk factors. METHODS Normal-weight (NW; 18.5 kg/m2 < BMI ≤ 25 kg/m2; n = 43), nondiabetic obese (OB; BMI > 30 kg/m2; n = 38), and diabetic obese (OB/DM; BMI > 30 kg/m2, fasting glucose ≥ 126 mg/dL, HbA1c ≥ 6.5%; n = 22) women were recruited. Metabolic parameters were measured, and expressions of PLIN1, CIDEA, CIDEC, and obesity-related genes were quantified in abdominal subcutaneous (SAT) and visceral adipose tissues (VAT). Effects of proinflammatory cytokines, endoplasmic reticulum (ER) stress inducers, and metabolic improvement agents on LD protein gene expressions were investigated in human adipocytes. RESULTS PLIN1, CIDEA, and CIDEC expressions were lower in SAT and higher in VAT in OB subjects relative to NW subjects; however, they were suppressed in both fat depots in OB/DM subjects relative to OB (P < 0.05). Across the entire cohort, whereas VAT PLIN1 (r = 0.349) and CIDEC expressions (r = 0.282) were positively associated with BMI (P < 0.05), SAT PLIN1 (r = -0.390) and CIDEA expressions (r = -0.565) were inversely associated. After adjustment for BMI, some or all of the adipose LD protein gene expressions were negatively associated with fasting glucose (r = -0.259 or higher) and triglyceride levels (r = -0.284 or higher) and positively associated with UCP1 expression (r = 0.353 or higher) (P < 0.05). In adipocytes, LD protein gene expressions were 55-70% downregulated by increased proinflammatory cytokines and ER stress but 2-4-fold upregulated by the metabolic improvement agents exendin-4 and dapagliflozin (P < 0.05). CONCLUSIONS The findings suggest that reduction of adipose LD protein expression is involved in the pathogenesis of metabolic disorders in women with obesity and type 2 diabetes and that increasing LD protein expression in adipocytes could control development of metabolic disorders.
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Affiliation(s)
- Chan Yoon Park
- Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Food & Nutrition, College of Health Science, The University of Suwon, Hwaseong-si, Gyeonggi-do, Republic of Korea
| | - Donguk Kim
- Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Min Kyeong Seo
- Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jimin Kim
- Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Brexogen Research Center, Brexogen Inc., Seoul, Republic of Korea
| | - Han Choe
- Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jong-Hyeok Kim
- Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Joon Pio Hong
- Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yeon Ji Lee
- Department of Family Medicine, Inha University School of Medicine, Incheon, Republic of Korea
| | - Yoonseok Heo
- Department of General Surgery, Inha University School of Medicine, Incheon, Republic of Korea
| | - Hwa Jung Kim
- Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, Seoul, Republic of Korea
| | - Hye Soon Park
- Department of Family Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Yeon Jin Jang
- Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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13
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Wang S, Yang M, Li P, Sit J, Wong A, Rodrigues K, Lank D, Zhang D, Zhang K, Yin L, Tong X. High-Fat Diet-Induced DeSUMOylation of E4BP4 Promotes Lipid Droplet Biogenesis and Liver Steatosis in Mice. Diabetes 2023; 72:348-361. [PMID: 36508222 PMCID: PMC9935497 DOI: 10.2337/db22-0332] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022]
Abstract
Dysregulated lipid droplet accumulation has been identified as one of the main contributors to liver steatosis during nonalcoholic fatty liver disease (NAFLD). However, the underlying molecular mechanisms for excessive lipid droplet formation in the liver remain largely unknown. In the current study, hepatic E4 promoter-binding protein 4 (E4BP4) plays a critical role in promoting lipid droplet formation and liver steatosis in a high-fat diet (HFD)-induced NAFLD mouse model. Hepatic E4bp4 deficiency (E4bp4-LKO) protects mice from HFD-induced liver steatosis independently of obesity and insulin resistance. Our microarray study showed a markedly reduced expression of lipid droplet binding genes, such as Fsp27, in the liver of E4bp4-LKO mice. E4BP4 is both necessary and sufficient to activate Fsp27 expression and lipid droplet formation in primary mouse hepatocytes. Overexpression of Fsp27 increased lipid droplets and triglycerides in E4bp4-LKO primary mouse hepatocytes and restored hepatic steatosis in HFD-fed E4bp4-LKO mice. Mechanistically, E4BP4 enhances the transactivation of Fsp27 by CREBH in hepatocytes. Furthermore, E4BP4 is modified by SUMOylation, and HFD feeding induces deSUMOylation of hepatic E4BP4. SUMOylation of five lysine residues of E4BP4 is critical for the downregulation of Fsp27 and lipid droplets by cAMP signaling in hepatocytes. Taken together, this study revealed that E4BP4 drives liver steatosis in HFD-fed mice through its regulation of lipid droplet binding proteins. Our study also highlights the critical role of deSUMOylation of hepatic E4BP4 in promoting NAFLD.
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Affiliation(s)
- Sujuan Wang
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China
| | - Meichan Yang
- Department of Radiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, People’s Republic of China
| | - Pei Li
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ
| | - Julian Sit
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI
| | - Audrey Wong
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI
| | - Kyle Rodrigues
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI
| | - Daniel Lank
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI
- Department of Pharmacology, University of Virginia, Charlottesville, VA
| | - Deqiang Zhang
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI
| | - Kezhong Zhang
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI
| | - Lei Yin
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI
| | - Xin Tong
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI
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14
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Balakrishnan B, Gupta A, Basri R, Sharma VM, Slayton M, Gentner K, Becker CC, Karki S, Muturi H, Najjar SM, Loria AS, Gokce N, Puri V. Endothelial-Specific Expression of CIDEC Improves High-Fat Diet-Induced Vascular and Metabolic Dysfunction. Diabetes 2023; 72:19-32. [PMID: 36256836 PMCID: PMC9797323 DOI: 10.2337/db22-0294] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 10/10/2022] [Indexed: 01/19/2023]
Abstract
Cell death-inducing DNA fragmentation factor-α-like effector C (CIDEC), originally identified to be a lipid droplet-associated protein in adipocytes, positively associates with insulin sensitivity. Recently, we discovered that it is expressed abundantly in human endothelial cells and regulates vascular function. The current study was designed to characterize the physiological effects and molecular actions of endothelial CIDEC in the control of vascular phenotype and whole-body glucose homeostasis. To achieve this, we generated a humanized mouse model expressing endothelial-specific human CIDEC (E-CIDECtg). E-CIDECtg mice exhibited protection against high-fat diet-induced glucose intolerance, insulin resistance, and dyslipidemia. Moreover, these mice displayed improved insulin signaling and endothelial nitric oxide synthase activation, enhanced endothelium-dependent vascular relaxation, and improved vascularization of adipose tissue, skeletal muscle, and heart. Mechanistically, we identified a novel interplay of CIDEC-vascular endothelial growth factor A (VEGFA)-vascular endothelial growth factor receptor 2 (VEGFR2) that reduced VEGFA and VEGFR2 degradation, thereby increasing VEGFR2 activation. Overall, our results demonstrate a protective role of endothelial CIDEC against obesity-induced metabolic and vascular dysfunction, in part, by modulation of VEGF signaling. These data suggest that CIDEC may be investigated as a potential future therapeutic target for mitigating obesity-related cardiometabolic disease.
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Affiliation(s)
- Bijinu Balakrishnan
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH
| | - Abhishek Gupta
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH
| | - Rabia Basri
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH
| | - Vishva M. Sharma
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH
| | - Mark Slayton
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH
| | - Kailey Gentner
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH
| | - Chloe C. Becker
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH
| | - Shakun Karki
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA
| | - Harrison Muturi
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH
| | - Sonia M. Najjar
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH
| | - Analia S. Loria
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY
| | - Noyan Gokce
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA
| | - Vishwajeet Puri
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH
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15
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Gupta A, Balakrishnan B, Karki S, Slayton M, Jash S, Banerjee S, Grahn THM, Jambunathan S, Disney S, Hussein H, Kong D, Lowell BB, Natarajan P, Reddy UK, Gokce N, Sharma VM, Puri V. Human CIDEC transgene improves lipid metabolism and protects against high-fat diet-induced glucose intolerance in mice. J Biol Chem 2022; 298:102347. [PMID: 35963433 PMCID: PMC9472082 DOI: 10.1016/j.jbc.2022.102347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 07/08/2022] [Accepted: 07/20/2022] [Indexed: 11/12/2022] Open
Abstract
Cell death–inducing DNA fragmentation factor-like effector C (CIDEC) expression in adipose tissue positively correlates with insulin sensitivity in obese humans. Further, E186X, a single-nucleotide CIDEC variant is associated with lipodystrophy, hypertriglyceridemia, and insulin resistance. To establish the unknown mechanistic link between CIDEC and maintenance of systemic glucose homeostasis, we generated transgenic mouse models expressing CIDEC (Ad-CIDECtg) and CIDEC E186X variant (Ad-CIDECmut) transgene specifically in the adipose tissue. We found that Ad-CIDECtg but not Ad-CIDECmut mice were protected against high-fat diet-induced glucose intolerance. Furthermore, we revealed the role of CIDEC in lipid metabolism using transcriptomics and lipidomics. Serum triglycerides, cholesterol, and low-density lipoproteins were lower in high-fat diet-fed Ad-CIDECtg mice compared to their littermate controls. Mechanistically, we demonstrated that CIDEC regulates the enzymatic activity of adipose triglyceride lipase via interacting with its activator, CGI-58, to reduce free fatty acid release and lipotoxicity. In addition, we confirmed that CIDEC is indeed a vital regulator of lipolysis in adipose tissue of obese humans, and treatment with recombinant CIDEC decreased triglyceride breakdown in visceral human adipose tissue. Our study unravels a central pathway whereby adipocyte-specific CIDEC plays a pivotal role in regulating adipose lipid metabolism and whole-body glucose homeostasis. In summary, our findings identify human CIDEC as a potential ‘drug’ or a ‘druggable’ target to reverse obesity-induced lipotoxicity and glucose intolerance.
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Affiliation(s)
- Abhishek Gupta
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Bijinu Balakrishnan
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Shakun Karki
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
| | - Mark Slayton
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Sukanta Jash
- Alpert Medical school of Brown University, Brown University, RI, USA
| | - Sayani Banerjee
- Alpert Medical school of Brown University, Brown University, RI, USA
| | - Tan Hooi Min Grahn
- Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University Hospital, Lund, Sweden
| | | | - Sarah Disney
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Hebaallaha Hussein
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Dong Kong
- Division of Endocrinology, Department of Pediatrics, F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | - Bradford B Lowell
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; Program in Neuroscience, Harvard Medical School, Boston, MA, USA
| | | | - Umesh K Reddy
- Department of Biology, West Virginia State University, Institute, WV, USA
| | - Noyan Gokce
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
| | - Vishva M Sharma
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA.
| | - Vishwajeet Puri
- Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA.
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16
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Ping Z, Guo Z, Lu M, Chen Y, Liu L. Association of CIDEB gene promoter methylation with overweight or obesity in adults. Aging (Albany NY) 2022; 14:3607-3616. [PMID: 35475772 PMCID: PMC9085220 DOI: 10.18632/aging.204032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 03/25/2022] [Indexed: 12/02/2022]
Abstract
Objective: To explore the association of the methylation level of cell death-inducing DFF45-like effector B (CIDEB) gene promoter with overweight or obesity in the abdominal subcutaneous adipose tissue (SAT) and omental adipose tissue (OAT) of adults. Methods: A total of 61 patients undergoing abdominal surgery in the hospital were selected with an average age of 51.87 years. According to the diagnostic criteria of Chinese adult obesity, the subjects were divided into normal-weight group (n = 28) and overweight/obesity group (n = 33). CIDEB promoter methylation level in abdominal SAT and OAT was detected by the MethylTarget technology, then its relationship with overweight or obesity was analyzed. Results: (1) There were no statistical differences between the normal-weight group and overweight/obesity group in Methylation levels of 16 CpG sites in the CIDEB gene promoter sequence. (2) The methylation level of OAT was higher than that of SAT, and there were significant differences in 16 CpG sites. (3) There were 3 statistically significant haplotypes between the normal-weight group and overweight/obesity group (2 in SAT and 1 in OAT). Conclusions: The methylation level of CIDEB gene promoter in abdominal SAT and OAT may be related to overweight or obesity in adults, and the specific regulatory mechanism needs to be further studied.
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Affiliation(s)
- Zhiguang Ping
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Zhaoyan Guo
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Ming Lu
- Nursing Department of Jiaozuo People's Hospital, Jiaozuo, Henan, China
| | - Yanzi Chen
- Henan Huapu Pharmaceutical Technology Co., Ltd., Zhengzhou, Henan, China
| | - Li Liu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
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17
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Kozlov AP. Mammalian tumor-like organs. 2. Mammalian adipose has many tumor features and obesity is a tumor-like process. Infect Agent Cancer 2022; 17:15. [PMID: 35395810 PMCID: PMC8994355 DOI: 10.1186/s13027-022-00423-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 03/03/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND In previous publications, the author developed the theory of carcino-evo-devo, which predicts that evolutionarily novel organs should recapitulate some features of tumors in their development. MAIN TEXT Mammalian adipose is currently recognized as a multi-depot metabolic and endocrine organ consisting of several adipose tissues. Although lipid-storing cells and proteins are ancient, the adipose organ as a whole is evolutionarily novel to mammals. The adipose expansion has remarkable similarities with the growth of solid tumors. These similarities are the following: (1) The capability to unlimited expansion; (2) Reversible plasticity; (3) Induction of angiogenesis; (4) Chronic inflammation; (5) Remodeling and disfunction; (6) Systemic influence on the organism; (7) Hormone production; (8) Production of miRNAs that influence other tissues; (9) Immunosuppression; (10) DNA damage and resistance to apoptosis; (11) Destructive infiltration in other organs and tissues. These similarities include the majority of "hallmarks of cancer". In addition, lipomas are the most frequent soft tissue tumors, and similar drugs may be used for the treatment of obesity and cancer by preventing infiltration. This raises the possibility that obesity, at least in part, may represent an oncological problem. The existing similarities between adipose and tumors suggest the possible evolutionary origin of mammalian adipose from some ancestral benign mesenchymal hereditary tumors. Indeed, using a transgenic inducible zebrafish tumor model, we described many genes, which originated in fish and were expressed in fish tumors. Their human orthologs LEP, NOTCH1, SPRY1, PPARG, ID2, and CIDEA acquired functions connected with the adipose organ. They are also involved in tumor development in humans. CONCLUSION If the hypothesis of the evolutionary origin of the adipose organ from the ancestral hereditary tumor is correct, it may open new opportunities to resolve the oncological problem and the problem of the obesity epidemic. New interventions targeting LEP, NOTCH1, SPRY1, PPARG, ID2, and CIDEA gene network, in addition to what already is going on, can be designed for treatment and prevention of both obesity and tumors.
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Affiliation(s)
- A P Kozlov
- Vavilov Institute of General Genetics, Russian Academy of Sciences, 3, Gubkina Street, Moscow, Russia, 117971.
- Peter the Great St. Petersburg Polytechnic University, 29, Polytekhnicheskaya Street, St. Petersburg, Russia, 195251.
- The Biomedical Center, 8, Viborgskaya Street, St. Petersburg, Russia, 194044.
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18
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Liou JW, Mani H, Yen JH. Viral Hepatitis, Cholesterol Metabolism, and Cholesterol-Lowering Natural Compounds. Int J Mol Sci 2022; 23:ijms23073897. [PMID: 35409259 PMCID: PMC8999150 DOI: 10.3390/ijms23073897] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/27/2022] [Accepted: 03/30/2022] [Indexed: 11/24/2022] Open
Abstract
Hepatitis is defined as inflammation of the liver; it can be acute or chronic. In chronic cases, the prolonged inflammation gradually damages the liver, resulting in liver fibrosis, cirrhosis, and sometimes liver failure or cancer. Hepatitis is often caused by viral infections. The most common causes of viral hepatitis are the five hepatitis viruses—hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). While HAV and HEV rarely (or do not) cause chronic hepatitis, a considerable proportion of acute hepatitis cases caused by HBV (sometimes co-infected with HDV) and HCV infections become chronic. Thus, many medical researchers have focused on the treatment of HBV and HCV. It has been documented that host lipid metabolism, particularly cholesterol metabolism, is required for the hepatitis viral infection and life cycle. Thus, manipulating host cholesterol metabolism-related genes and proteins is a strategy used in fighting the viral infections. Efforts have been made to evaluate the efficacy of cholesterol-lowering drugs, particularly 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, in the treatment of hepatitis viral infections; promising results have been obtained. This review provides information on the relationships between hepatitis viruses and host cholesterol metabolism/homeostasis, as well as the discovery/development of cholesterol-lowering natural phytochemicals that could potentially be applied in the treatment of viral hepatitis.
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Affiliation(s)
- Je-Wen Liou
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan;
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan;
| | - Hemalatha Mani
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan;
| | - Jui-Hung Yen
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan;
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan
- Correspondence: or ; Tel.: +886-3-856-5301 (ext. 2683)
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19
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Yamindago A, Lee N, Lee N, Jo Y, Woo S, Yum S. Fluoxetine in the environment may interfere with the neurotransmission or endocrine systems of aquatic animals. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 227:112931. [PMID: 34715500 DOI: 10.1016/j.ecoenv.2021.112931] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/28/2021] [Accepted: 10/19/2021] [Indexed: 06/13/2023]
Abstract
Antidepressants are extensively used to treat the symptoms of depression in humans, and the environmentally discharged drugs potentially threaten aquatic organisms. In this study, the acute toxic effects of fluoxetine (FLX) were investigated in two aquatic organisms, the freshwater polyp (Hydra magnipapillata) and Javanese medaka (Oryzias javanicus). The median lethal concentration (LC50) of FLX in H. magnipapillata was 3.678, 3.082, and 2.901 mg/L after 24, 48, and 72 h, respectively. Morphological observations of the FLX-exposed H. magnipapillata showed that 1.5 mg/L FLX induced the contraction of the tentacles and body column. The LC50 of FLX in O. javanicus was 2.046, 1.936, 1.532, and 1.237 mg/L after 24, 48, 72, and 96 h, respectively. Observation of the behavior of the FLX-exposed fish showed that FLX reduced their swimming performance at a minimum concentration of 10 µg/L. The half-maximal effective concentration (EC50) of FLX for swimming behavior in O. javanicus was 0.135, 0.108, and 0.011 mg/L after 12, 24, and 96 h, respectively. Transcriptomic analyses indicated that FLX affects various physiological and metabolic processes in both species. FLX exposure induced oxidative stress, reproductive deficiency, abnormal pattern formation, DNA damage, and neurotransmission disturbance in H. magnipapillata, whereas it adversely affected O. javanicus by inducing oxidative stress, DNA damage, endoplasmic reticulum stress, and mRNA instability. Neurotransmission-based behavioral changes and endocrine disruption were strongly suspected in the FLX-exposed fish. These results suggest that FLX affects the behavior and metabolic regulation of aquatic organisms.
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Affiliation(s)
- Ade Yamindago
- CORECT Research Group, Faculty of Fisheries and Marine Science, Universitas Brawijaya, Malang 65145, Indonesia; Study Program of Marine Science, Faculty of Fisheries and Marine Science, Universitas Brawijaya, Malang 65145, Indonesia.
| | - Nayun Lee
- Ecological Risk Research Division, Korea Institute of Ocean Science and Technology, Geoje 53201, Republic of Korea
| | - Nayoung Lee
- Ecological Risk Research Division, Korea Institute of Ocean Science and Technology, Geoje 53201, Republic of Korea
| | - Yejin Jo
- Ecological Risk Research Division, Korea Institute of Ocean Science and Technology, Geoje 53201, Republic of Korea
| | - Seonock Woo
- Marine Biotechnology Research Center, Korea Institute of Ocean Science and Technology, Busan 49111, Republic of Korea
| | - Seungshic Yum
- Ecological Risk Research Division, Korea Institute of Ocean Science and Technology, Geoje 53201, Republic of Korea; KIOST School, University of Science and Technology, Geoje 53201, Republic of Korea.
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20
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Ilias N, Hamzah H, Ismail IS, Mohidin TBM, Idris MF, Ajat M. An insight on the future therapeutic application potential of Stevia rebaudiana Bertoni for atherosclerosis and cardiovascular diseases. Biomed Pharmacother 2021; 143:112207. [PMID: 34563950 DOI: 10.1016/j.biopha.2021.112207] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/07/2021] [Accepted: 09/13/2021] [Indexed: 12/22/2022] Open
Abstract
Stevia rebaudiana Bertoni is a native plant to Paraguay. The extracts have been used as a famous sweetening agent, and the bioactive components derived from stevia possess a broad spectrum of therapeutical potential for various illnesses. Among its medicinal benefits are anti-hypertensive, anti-tumorigenic, anti-diabetic, and anti-hyperlipidemia. Statins (3-hydro-3-methylglutaryl-coenzyme A reductase inhibitor) are a class of drugs used to treat atherosclerosis. Statins are explicitly targeting the HMG-CoA reductase, an enzyme in the rate-limiting step of cholesterol biosynthesis. Despite being widely used in regulating plasma cholesterol levels, the adverse effects of the drug are a significant concern among clinicians and patients. Hence, steviol glycosides derived from stevia have been proposed as an alternative in replacing statins. Diterpene glycosides from stevia, such as stevioside and rebaudioside A have been evaluated for their efficacy in alleviating cholesterol levels. These glycosides are a potential candidate in treating and preventing atherosclerosis provoked by circulating lipid retention in the sub-endothelial lining of the artery. The present review is an effort to integrate the pathogenesis of atherosclerosis, involvement of lipid droplets biogenesis and its associated proteins in atherogenesis, current approaches to treat atherosclerosis, and pharmacological potential of stevia in treating the disease.
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Affiliation(s)
- Nazhan Ilias
- Department of Veterinary Preclinical Sciences, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 UPM, Malaysia.
| | - Hazilawati Hamzah
- Department of Veterinary Pathology and Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 UPM, Malaysia.
| | - Intan Safinar Ismail
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM, Malaysia; Natural Medicines and Products Research Laboratory (NaturMeds), Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM, Malaysia.
| | - Taznim Begam Mohd Mohidin
- Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Mohd Faiz Idris
- Pusat Bahasa dan Pengajian Umum, Universiti Pendidikan Sultan Idris, 35900 Tanjong Malim, Malaysia
| | - Mokrish Ajat
- Department of Veterinary Preclinical Sciences, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 UPM, Malaysia; Natural Medicines and Products Research Laboratory (NaturMeds), Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM, Malaysia.
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21
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Royo-García A, Courtois S, Parejo-Alonso B, Espiau-Romera P, Sancho P. Lipid droplets as metabolic determinants for stemness and chemoresistance in cancer. World J Stem Cells 2021; 13:1307-1317. [PMID: 34630864 PMCID: PMC8474722 DOI: 10.4252/wjsc.v13.i9.1307] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 05/13/2021] [Accepted: 08/18/2021] [Indexed: 02/06/2023] Open
Abstract
Previously regarded as simple fat storage particles, new evidence suggests that lipid droplets (LDs) are dynamic and functional organelles involved in key cellular processes such as membrane biosynthesis, lipid metabolism, cell signalling and inflammation. Indeed, an increased LD content is one of the most apparent features resulting from lipid metabolism reprogramming necessary to support the basic functions of cancer cells. LDs have been associated to different cellular processes involved in cancer progression and aggressiveness, such as tumorigenicity, invasion and metastasis, as well as chemoresistance. Interestingly, all of these processes are controlled by a subpopulation of highly aggressive tumoral cells named cancer stem cells (CSCs), suggesting that LDs may be fundamental elements for stemness in cancer. Considering the key role of CSCs on chemoresistance and disease relapse, main factors of therapy failure, the design of novel therapeutic approaches targeting these cells may be the only chance for long-term survival in cancer patients. In this sense, their biology and functional properties render LDs excellent candidates for target discovery and design of combined therapeutic strategies. In this review, we summarise the current knowledge identifying LDs and CSCs as main contributors to cancer aggressiveness, metastasis and chemoresistance.
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Affiliation(s)
- Alba Royo-García
- Hospital Universitario Miguel Servet, IIS Aragón, Zaragoza 50009, Spain
| | - Sarah Courtois
- Hospital Universitario Miguel Servet, IIS Aragón, Zaragoza 50009, Spain
| | | | | | - Patricia Sancho
- Hospital Universitario Miguel Servet, IIS Aragón, Zaragoza 50009, Spain
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22
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Sánchez-Ceinos J, Guzmán-Ruiz R, Rangel-Zúñiga OA, López-Alcalá J, Moreno-Caño E, Del Río-Moreno M, Romero-Cabrera JL, Pérez-Martínez P, Maymo-Masip E, Vendrell J, Fernández-Veledo S, Fernández-Real JM, Laurencikiene J, Rydén M, Membrives A, Luque RM, López-Miranda J, Malagón MM. Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease. eLife 2021; 10:65996. [PMID: 34545810 PMCID: PMC8545398 DOI: 10.7554/elife.65996] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 09/20/2021] [Indexed: 12/17/2022] Open
Abstract
Preadipocytes are crucial for healthy adipose tissue expansion. Preadipocyte differentiation is altered in obese individuals, which has been proposed to contribute to obesity-associated metabolic disturbances. Here, we aimed at identifying the pathogenic processes underlying impaired adipocyte differentiation in obese individuals with insulin resistance (IR)/type 2 diabetes (T2D). We report that down-regulation of a key member of the major spliceosome, PRFP8/PRP8, as observed in IR/T2D preadipocytes from subcutaneous (SC) fat, prevented adipogenesis by altering both the expression and splicing patterns of adipogenic transcription factors and lipid droplet-related proteins, while adipocyte differentiation was restored upon recovery of PRFP8/PRP8 normal levels. Adipocyte differentiation was also compromised under conditions of endoplasmic reticulum (ER)-associated protein degradation (ERAD) hyperactivation, as occurs in SC and omental (OM) preadipocytes in IR/T2D obesity. Thus, targeting mRNA splicing and ER proteostasis in preadipocytes could improve adipose tissue function and thus contribute to metabolic health in obese individuals.
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Affiliation(s)
- Julia Sánchez-Ceinos
- Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain.,CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - Rocío Guzmán-Ruiz
- Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain.,CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - Oriol Alberto Rangel-Zúñiga
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.,Lipids and Atherosclerosis Unit, Department of Internal Medicine, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - Jaime López-Alcalá
- Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain.,CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - Elena Moreno-Caño
- Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - Mercedes Del Río-Moreno
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.,OncObesity and Metabolism Group. Department of Cell Biology, Physiology and Immunology, IMIBIC/University of Córdoba/Reina Sofía University Hospital, Córdoba, Spain
| | - Juan Luis Romero-Cabrera
- Lipids and Atherosclerosis Unit, Department of Internal Medicine, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - Pablo Pérez-Martínez
- Lipids and Atherosclerosis Unit, Department of Internal Medicine, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - Elsa Maymo-Masip
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain.,Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili Universitat Rovira i Virgil, Tarragona, Spain
| | - Joan Vendrell
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain.,Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili Universitat Rovira i Virgil, Tarragona, Spain
| | - Sonia Fernández-Veledo
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain.,Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili Universitat Rovira i Virgil, Tarragona, Spain
| | - José Manuel Fernández-Real
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.,Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, and Eumetabolism and Health Group, Girona Biomedical Research Institute (IdibGi), Girona, Spain
| | - Jurga Laurencikiene
- Lipid Laboratory. Department of Medicine Huddinge/Karolinska Institute (KI)/Karolinska University Hospital, Stockholm, Sweden
| | - Mikael Rydén
- Lipid Laboratory. Department of Medicine Huddinge/Karolinska Institute (KI)/Karolinska University Hospital, Stockholm, Sweden
| | - Antonio Membrives
- Unidad de Gestión Clínica de Cirugía General y Digestivo, Sección de Obesidad, Reina Sofia University Hospital, Córdoba, Spain
| | - Raul M Luque
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.,OncObesity and Metabolism Group. Department of Cell Biology, Physiology and Immunology, IMIBIC/University of Córdoba/Reina Sofía University Hospital, Córdoba, Spain
| | - José López-Miranda
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.,Lipids and Atherosclerosis Unit, Department of Internal Medicine, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - María M Malagón
- Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain.,CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
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23
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Hammoudeh SM, Hammoudeh AM, Bhamidimarri PM, Mahboub B, Halwani R, Hamid Q, Rahmani M, Hamoudi R. Insight into molecular mechanisms underlying hepatic dysfunction in severe COVID-19 patients using systems biology. World J Gastroenterol 2021; 27:2850-2870. [PMID: 34135558 PMCID: PMC8173390 DOI: 10.3748/wjg.v27.i21.2850] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/30/2021] [Accepted: 05/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The coronavirus disease 2019 (COVID-19), a pandemic contributing to more than 105 million cases and more than 2.3 million deaths worldwide, was described to be frequently accompanied by extrapulmonary manifestations, including liver dysfunction. Liver dysfunction and elevated liver enzymes were observed in about 53% of COVID-19 patients. AIM To gain insight into transcriptional abnormalities in liver tissue of severe COVID-19 patients that may result in liver dysfunction. METHODS The transcriptome of liver autopsy samples from severe COVID-19 patients against those of non-COVID donors was analyzed. Differentially expressed genes were identified from normalized RNA-seq data and analyzed for the enrichment of functional clusters and pathways. The differentially expressed genes were then compared against the genetic signatures of liver diseases including cirrhosis, fibrosis, non-alcoholic fatty liver disease (NAFLD), and hepatitis A/B/C. Gene expression of some differentially expressed genes was assessed in the blood samples of severe COVID-19 patients with liver dysfunction using qRT-PCR. RESULTS Analysis of the differential transcriptome of the liver tissue of severe COVID-19 patients revealed a significant upregulation of transcripts implicated in tissue remodeling including G-coupled protein receptors family genes, DNAJB1, IGF2, EGFR, and HDGF. Concordantly, the differential transcriptome of severe COVID-19 liver tissues substantially overlapped with the disease signature of liver diseases characterized with pathological tissue remodeling (liver cirrhosis, Fibrosis, NAFLD, and hepatitis A/B/C). Moreover, we observed a significant suppression of transcripts implicated in metabolic pathways as well as mitochondrial function, including cytochrome P450 family members, ACAD11, CIDEB, GNMT, and GPAM. Consequently, drug and xenobiotics metabolism pathways are significantly suppressed suggesting a decrease in liver detoxification capacity. In correspondence with the RNA-seq data analysis, we observed a significant upregulation of DNAJB1 and HSP90AB1 as well as significant downregulation of CYP39A1 in the blood plasma of severe COVID-19 patients with liver dysfunction. CONCLUSION Severe COVID-19 patients appear to experience significant transcriptional shift that may ensue tissue remodeling, mitochondrial dysfunction and lower hepatic detoxification resulting in the clinically observed liver dysfunction.
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Affiliation(s)
- Sarah Musa Hammoudeh
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Arabella Musa Hammoudeh
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- General Surgery Department, Tawam Hospital, SEHA, Al-Ain 15258, United Arab Emirates
| | - Poorna Manasa Bhamidimarri
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Bassam Mahboub
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Rashid Hospital, 315 Umm Hurair Second, Dubai Health Authority, Dubai 4545, United Arab Emirates
| | - Rabih Halwani
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Qutayba Hamid
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Meakins-Christie Laboratories, McGill University, Quebec H4A 3J1, Montreal, Canada
| | - Mohamed Rahmani
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Rifat Hamoudi
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Division of Surgery and Interventional Science, University College London, London W1W 7TY, United Kingdom
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24
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Bai R, Rebelo A, Kleeff J, Sunami Y. Identification of prognostic lipid droplet-associated genes in pancreatic cancer patients via bioinformatics analysis. Lipids Health Dis 2021; 20:58. [PMID: 34078402 PMCID: PMC8171034 DOI: 10.1186/s12944-021-01476-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 04/27/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Pancreatic cancer is the fourth leading cause of cancer deaths in the United States both in females and in males, and is projected to become the second deadliest cancer by 2030. The overall 5-year survival rate remains at around 10%. Cancer metabolism and specifically lipid metabolism plays an important role in pancreatic cancer progression and metastasis. Lipid droplets can not only store and transfer lipids, but also act as molecular messengers, and signaling factors. As lipid droplets are implicated in reprogramming tumor cell metabolism and in invasion and migration of pancreatic cancer cells, we aimed to identify lipid droplet-associated genes as prognostic markers in pancreatic cancer. METHODS We performed a literature search on review articles related to lipid droplet-associated proteins. To select relevant lipid droplet-associated factors, bioinformatics analysis on the GEPIA platform (data are publicly available) was carried out for selected genes to identify differential expression in pancreatic cancer versus healthy pancreatic tissues. Differentially expressed genes were further analyzed regarding overall survival of pancreatic cancer patients. RESULTS 65 factors were identified as lipid droplet-associated factors. Bioinformatics analysis of 179 pancreatic cancer samples and 171 normal pancreatic tissue samples on the GEPIA platform identified 39 deferentially expressed genes in pancreatic cancer with 36 up-regulated genes (ACSL3, ACSL4, AGPAT2, BSCL2, CAV1, CAV2, CAVIN1, CES1, CIDEC, DGAT1, DGAT2, FAF2, G0S2, HILPDA, HSD17B11, ICE2, LDAH, LIPE, LPCAT1, LPCAT2, LPIN1, MGLL, NAPA, NCEH1, PCYT1A, PLIN2, PLIN3, RAB5A, RAB7A, RAB8A, RAB18, SNAP23, SQLE, VAPA, VCP, VMP1) and 3 down-regulated genes (FITM1, PLIN4, PLIN5). Among 39 differentially expressed factors, seven up-regulated genes (CAV2, CIDEC, HILPDA, HSD17B11, NCEH1, RAB5A, and SQLE) and two down-regulation genes (BSCL2 and FITM1) were significantly associated with overall survival of pancreatic cancer patients. Multivariate Cox regression analysis identified CAV2 as the only independent prognostic factor. CONCLUSIONS Through bioinformatics analysis, we identified nine prognostic relevant differentially expressed genes highlighting the role of lipid droplet-associated factors in pancreatic cancer.
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Affiliation(s)
- Rubing Bai
- Department of Visceral, Vascular and Endocrine Surgery, University Medical Center, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06120, Halle (Saale), Germany
| | - Artur Rebelo
- Department of Visceral, Vascular and Endocrine Surgery, University Medical Center, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06120, Halle (Saale), Germany
| | - Jörg Kleeff
- Department of Visceral, Vascular and Endocrine Surgery, University Medical Center, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06120, Halle (Saale), Germany
| | - Yoshiaki Sunami
- Department of Visceral, Vascular and Endocrine Surgery, University Medical Center, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06120, Halle (Saale), Germany.
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Morishita Y, Kellogg AP, Larkin D, Chen W, Vadrevu S, Satin L, Liu M, Arvan P. Cell death-associated lipid droplet protein CIDE-A is a noncanonical marker of endoplasmic reticulum stress. JCI Insight 2021; 6:143980. [PMID: 33661766 PMCID: PMC8119190 DOI: 10.1172/jci.insight.143980] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 03/02/2021] [Indexed: 01/05/2023] Open
Abstract
Secretory protein misfolding has been linked to ER stress and cell death. We expressed a TGrdw transgene encoding TG-G(2298)R, a misfolded mutant thyroglobulin reported to be linked to thyroid cell death. When the TGrdw transgene was expressed at low level in thyrocytes of TGcog/cog mice that experienced severe ER stress, we observed increased thyrocyte cell death and increased expression of CIDE-A (cell death-inducing DFFA-like effector-A, a protein of lipid droplets) in whole thyroid gland. Here we demonstrate that acute ER stress in cultured PCCL3 thyrocytes increases Cidea mRNA levels, maintained at least in part by increased mRNA stability, while being negatively regulated by activating transcription factor 6 - with similar observations that ER stress increases Cidea mRNA levels in other cell types. CIDE-A protein is sensitive to proteasomal degradation yet is stabilized by ER stress, and elevated expression levels accompany increased cell death. Unlike acute ER stress, PCCL3 cells adapted and surviving chronic ER stress maintained a disproportionately lower relative mRNA level of Cidea compared with that of other, classical ER stress markers, as well as a blunted Cidea mRNA response to a new, unrelated acute ER stress challenge. We suggest that CIDE-A is a novel marker linked to a noncanonical ER stress response program, with implications for cell death and survival.
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Affiliation(s)
- Yoshiaki Morishita
- Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University, Aichi, Japan
| | - Aaron P. Kellogg
- Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Dennis Larkin
- Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Wei Chen
- Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Suryakiran Vadrevu
- Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, Michigan, USA
| | - Leslie Satin
- Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, Michigan, USA
| | - Ming Liu
- Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Department of Endocrinology & Diabetes, Tianjin Medical University, Tianjin, China
| | - Peter Arvan
- Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
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Zhang W, Xu M, Wang J, Wang S, Wang X, Yang J, Gao L, Gan S. Comparative Transcriptome Analysis of Key Genes and Pathways Activated in Response to Fat Deposition in Two Sheep Breeds With Distinct Tail Phenotype. Front Genet 2021; 12:639030. [PMID: 33897762 PMCID: PMC8060577 DOI: 10.3389/fgene.2021.639030] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 03/08/2021] [Indexed: 01/21/2023] Open
Abstract
Fat tail in sheep presents a valuable energy reserve that has historically facilitated adaptation to harsh environments. However, in modern intensive and semi-intensive sheep industry systems, breeds with leaner tails are more desirable. In the present study, RNA sequencing (RNA-Seq) was applied to determine the transcriptome profiles of tail fat tissues in two Chinese sheep breeds, fat-rumped Altay sheep and thin-tailed Xinjiang fine wool (XFW) sheep, with extreme fat tail phenotype difference. Then the differentially expressed genes (DEGs) and their sequence variations were further analyzed. In total, 21,527 genes were detected, among which 3,965 displayed significant expression variations in tail fat tissues of the two sheep breeds (P < 0.05), including 707 upregulated and 3,258 downregulated genes. Gene Ontology (GO) analysis disclosed that 198 DEGs were related to fat metabolism. In Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, the majority of DEGs were significantly enriched in "adipocytokine signaling," "PPAR signaling," and "metabolic pathways" (P < 0.05); moreover, some genes were involved in multiple pathways. Among the 198 DEGs, 22 genes were markedly up- or downregulated in tail fat tissue of Altay sheep, indicating that these genes might be closely related to the fat tail trait of this breed. A total of 41,724 and 42,193 SNPs were detected in the transcriptomic data of tail fat tissues obtained from Altay and XFW sheep, respectively. The distribution of seven SNPs in the coding regions of the 22 candidate genes was further investigated in populations of three sheep breeds with distinct tail phenotypes. In particular, the g.18167532T/C (Oar_v3.1) mutation of the ATP-binding cassette transporter A1 (ABCA1) gene and g.57036072G/T (Oar_v3.1) mutation of the solute carrier family 27 member 2 (SLC27A2) gene showed significantly different distributions and were closely associated with tail phenotype (P < 0.05). The present study provides transcriptomic evidence explaining the differences in fat- and thin-tailed sheep breeds and reveals numerous DEGs and SNPs associated with tail phenotype. Our data provide a valuable theoretical basis for selection of lean-tailed sheep breeds.
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Affiliation(s)
- Wei Zhang
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural and Reclamation Sciences, Shihezi, China
- Xinjiang Agricultural Vocational Technical College, Changji, China
| | - Mengsi Xu
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural and Reclamation Sciences, Shihezi, China
| | - Juanjuan Wang
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural and Reclamation Sciences, Shihezi, China
| | - Shiyin Wang
- Xinjiang Agricultural Vocational Technical College, Changji, China
| | - Xinhua Wang
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural and Reclamation Sciences, Shihezi, China
| | - Jingquan Yang
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural and Reclamation Sciences, Shihezi, China
| | - Lei Gao
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural and Reclamation Sciences, Shihezi, China
| | - Shangquan Gan
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural and Reclamation Sciences, Shihezi, China
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Zhang M, Nie X, Yuan Y, Wang Y, Ma X, Yin J, Bao Y. Osteocalcin Alleviates Nonalcoholic Fatty Liver Disease in Mice through GPRC6A. Int J Endocrinol 2021; 2021:9178616. [PMID: 33531899 PMCID: PMC7834799 DOI: 10.1155/2021/9178616] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 01/02/2021] [Accepted: 01/06/2021] [Indexed: 12/15/2022] Open
Abstract
Osteocalcin is a bone-derived hormone that plays an important role in the crosstalk between bone and energy metabolism. Previous studies have found that treatment with uncarboxylated osteocalcin can protect mice from high-fat diet-induced nonalcoholic fatty liver disease (NAFLD). However, the potential mechanisms remain unclear. Although the G protein-coupled receptor family C group 6 subtype A (GPRC6A) is the putative receptor of osteocalcin, there is no direct evidence showing that GPRC6A mediates the effects of uncarboxylated osteocalcin in alleviating NAFLD in mice. We aimed to figure out this using liver-specific GPRC6A knockout (GPRC6ALKO) mice. Consistent with previous studies, uncarboxylated osteocalcin significantly protected high-fat diet-fed wild-type mice from obesity and NAFLD, while it did not protect high-fat diet-fed GPRC6ALKO mice from NAFLD. Differential mRNA expression of lipogenesis and lipolysis between GPRC6ALKO mice and control mice revealed that GPRC6A mediated the effects of osteocalcin in alleviating NAFLD through inhibiting lipid synthesis and promoting lipolysis. In conclusion, this study found that uncarboxylated osteocalcin alleviates NAFLD in mice through the GPRC6A signaling pathway. Our study suggests that liver GPRC6A may be a potential target for treating NAFLD.
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Affiliation(s)
- Mingliang Zhang
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai 200233, China
| | - Xiaomin Nie
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai 200233, China
| | - Yeqing Yuan
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai 200233, China
| | - Yansu Wang
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai 200233, China
| | - Xiaojing Ma
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai 200233, China
| | - Jun Yin
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai 200233, China
| | - Yuqian Bao
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai 200233, China
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28
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Sayers NS, Anujan P, Yu HN, Palmer SS, Nautiyal J, Franks S, Hanyaloglu AC. Follicle-Stimulating Hormone Induces Lipid Droplets via Gαi/o and β-Arrestin in an Endometrial Cancer Cell Line. Front Endocrinol (Lausanne) 2021; 12:798866. [PMID: 35185785 PMCID: PMC8850301 DOI: 10.3389/fendo.2021.798866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 12/20/2021] [Indexed: 12/04/2022] Open
Abstract
Follicle-stimulating hormone (FSH) and its G protein-coupled receptor, FSHR, represents a paradigm for receptor signaling systems that activate multiple and complex pathways. Classically, FSHR activates Gαs to increase intracellular levels of cAMP, but its ability to activate other G proteins, and β-arrestin-mediated signaling is well documented in many different cell systems. The pleiotropic signal capacity of FSHR offers a mechanism for how FSH drives multiple and dynamic downstream functions in both gonadal and non-gonadal cell types, including distinct diseases, and how signal bias may be achieved at a pharmacological and cell system-specific manner. In this study, we identify an additional mechanism of FSH-mediated signaling and downstream function in the endometrial adenocarcinoma Ishikawa cell line. While FSH did not induce increases in cAMP levels, this hormone potently activated pertussis toxin sensitive Gαi/o signaling. A selective allosteric FSHR ligand, B3, also activated Gαi/o signaling in these cells, supporting a role for receptor-mediated activation despite the low levels of FSHR mRNA. The low expression levels may attribute to the lack of Gαs/cAMP signaling as increasing FSHR expression resulted in FSH-mediated activation of the Gαs pathway. Unlike prior reports for FSH-mediated Gαs/cAMP signaling, FSH-mediated Gαi/o signaling was not affected by inhibition of dynamin-dependent receptor internalization. While chronic FSH did not alter cell viability, FSH was able to increase lipid droplet size. The β-arrestins are key adaptor proteins known to regulate FSHR signaling. Indeed, a rapid, FSH-dependent increase in interactions between β-arrestin1 and Gαi1 was observed via NanoBiT complementation in Ishikawa cells. Furthermore, both inhibition of Gαi/o signaling and siRNA knockdown of β-arrestin 1/2 significantly reduced FSH-induced lipid droplet accumulation, implying a role for a Gαi/o/β-arrestin complex in FSH functions in this cell type. As FSH/FSHR has been implicated in distinct hormone-dependent cancers, including endometrial cancer, analysis of the cancer genome database from 575 human endometrial adenocarcinoma tumors revealed that a subpopulation of samples expressed FSHR. Overall, this study highlights a novel mechanism for FSHR signal pleiotropy that may be exploited for future personalized therapeutic approaches.
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Affiliation(s)
- Niamh S. Sayers
- Department of Metabolism, Digestion and Reproduction, Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
| | - Priyanka Anujan
- Department of Metabolism, Digestion and Reproduction, Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
| | - Henry N. Yu
- CanWell Pharma Inc., Wellesley, MA, United States
| | - Stephen S. Palmer
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, United States
| | - Jaya Nautiyal
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Stephen Franks
- Department of Metabolism, Digestion and Reproduction, Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
| | - Aylin C. Hanyaloglu
- Department of Metabolism, Digestion and Reproduction, Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
- *Correspondence: Aylin C. Hanyaloglu,
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29
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Sharma R, Kopchick JJ, Puri V, Sharma VM. Effect of growth hormone on insulin signaling. Mol Cell Endocrinol 2020; 518:111038. [PMID: 32966863 PMCID: PMC7606590 DOI: 10.1016/j.mce.2020.111038] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/31/2020] [Accepted: 09/17/2020] [Indexed: 12/21/2022]
Abstract
Growth hormone (GH) is a pleiotropic hormone that coordinates an array of physiological processes, including effects on bone, muscle, and fat, ultimately resulting in growth. Metabolically, GH promotes anabolic action in most tissues except adipose, where its catabolic action causes the breakdown of stored triglycerides into free fatty acids (FFA). GH antagonizes insulin action via various molecular pathways. Chronic GH secretion suppresses the anti-lipolytic action of insulin and increases FFA flux into the systemic circulation; thus, promoting lipotoxicity, which causes pathophysiological problems, including insulin resistance. In this review, we will provide an update on GH-stimulated adipose lipolysis and its consequences on insulin signaling in liver, skeletal muscle, and adipose tissue. Furthermore, we will discuss the mechanisms that contribute to the diabetogenic action of GH.
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Affiliation(s)
- Rita Sharma
- Department of Biomedical Sciences, Ohio University, Athens, OH, 45701, USA
| | - John J Kopchick
- Department of Biomedical Sciences, Ohio University, Athens, OH, 45701, USA; Edison Biotechnology Institute, Ohio University, Athens, OH, 45701, USA; Diabetes Institute, Ohio University, Athens, OH, 45701, USA
| | - Vishwajeet Puri
- Department of Biomedical Sciences, Ohio University, Athens, OH, 45701, USA; Diabetes Institute, Ohio University, Athens, OH, 45701, USA
| | - Vishva M Sharma
- Department of Biomedical Sciences, Ohio University, Athens, OH, 45701, USA; Diabetes Institute, Ohio University, Athens, OH, 45701, USA.
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30
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Li Z, Liu H, Luo X. Lipid droplet and its implication in cancer progression. Am J Cancer Res 2020; 10:4112-4122. [PMID: 33414989 PMCID: PMC7783747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 11/12/2020] [Indexed: 06/12/2023] Open
Abstract
Lipid droplets (LDs) are a kind of organelle that is commonly found in eukaryotic cells to store lipids, which encompass a hydrophobic core composed of a single layer of phospholipids and neutral lipids (mainly including triacylglycerol (TAG) and cholesterol ester (CE)) as well as a small amount of proteins. LD accumulation is gradually recognized as a prominent characteristic in a variety of cancers and attracts increasing attention on this field. In this article, we not only summarize the composition, synthesis and decomposition of LD, but also highlight its role in carcinogenesis and malignant development of cancers.
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Affiliation(s)
- Zhenzhen Li
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South UniversityChangsha 410078, Hunan, PR China
- Cancer Research Institute, School of Basic Medicine, Central South UniversityChangsha 410078, Hunan, PR China
- Key Laboratory of Carcinogenesis, Chinese Ministry of HealthChangsha 410078, Hunan, PR China
| | - Huiwen Liu
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South UniversityChangsha 410078, Hunan, PR China
- Cancer Research Institute, School of Basic Medicine, Central South UniversityChangsha 410078, Hunan, PR China
- Key Laboratory of Carcinogenesis, Chinese Ministry of HealthChangsha 410078, Hunan, PR China
| | - Xiangjian Luo
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South UniversityChangsha 410078, Hunan, PR China
- Cancer Research Institute, School of Basic Medicine, Central South UniversityChangsha 410078, Hunan, PR China
- Key Laboratory of Carcinogenesis, Chinese Ministry of HealthChangsha 410078, Hunan, PR China
- Molecular Imaging Research Center of Central South UniversityChangsha 410078, Hunan, PR China
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31
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Bosi E, Marselli L, De Luca C, Suleiman M, Tesi M, Ibberson M, Eizirik DL, Cnop M, Marchetti P. Integration of single-cell datasets reveals novel transcriptomic signatures of β-cells in human type 2 diabetes. NAR Genom Bioinform 2020; 2:lqaa097. [PMID: 33575641 PMCID: PMC7679065 DOI: 10.1093/nargab/lqaa097] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/26/2020] [Accepted: 10/30/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic islet β-cell failure is key to the onset and progression of type 2 diabetes (T2D). The advent of single-cell RNA sequencing (scRNA-seq) has opened the possibility to determine transcriptional signatures specifically relevant for T2D at the β-cell level. Yet, applications of this technique have been underwhelming, as three independent studies failed to show shared differentially expressed genes in T2D β-cells. We performed an integrative analysis of the available datasets from these studies to overcome confounding sources of variability and better highlight common T2D β-cell transcriptomic signatures. After removing low-quality transcriptomes, we retained 3046 single cells expressing 27 931 genes. Cells were integrated to attenuate dataset-specific biases, and clustered into cell type groups. In T2D β-cells (n = 801), we found 210 upregulated and 16 downregulated genes, identifying key pathways for T2D pathogenesis, including defective insulin secretion, SREBP signaling and oxidative stress. We also compared these results with previous data of human T2D β-cells from laser capture microdissection and diabetic rat islets, revealing shared β-cell genes. Overall, the present study encourages the pursuit of single β-cell RNA-seq analysis, preventing presently identified sources of variability, to identify transcriptomic changes associated with human T2D and underscores specific traits of dysfunctional β-cells across different models and techniques.
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Affiliation(s)
- Emanuele Bosi
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Lorella Marselli
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Carmela De Luca
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Mara Suleiman
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Marta Tesi
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Mark Ibberson
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, University of Lausanne, Quartier Sorge, CH-1015 Lausanne, Switzerland
| | - Decio L Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, B-1070, Belgium
| | - Miriam Cnop
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, B-1070, Belgium
| | - Piero Marchetti
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
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Salo VT, Hölttä-Vuori M, Ikonen E. Seipin-Mediated Contacts as Gatekeepers of Lipid Flux at the Endoplasmic Reticulum–Lipid Droplet Nexus. ACTA ACUST UNITED AC 2020. [DOI: 10.1177/2515256420945820] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Lipid droplets (LDs) are dynamic cellular hubs of lipid metabolism. While LDs contact a plethora of organelles, they have the most intimate relationship with the endoplasmic reticulum (ER). Indeed, LDs are initially assembled at specialized ER subdomains, and recent work has unraveled an increasing array of proteins regulating ER-LD contacts. Among these, seipin, a highly conserved lipodystrophy protein critical for LD growth and adipogenesis, deserves special attention. Here, we review recent insights into the role of seipin in LD biogenesis and as a regulator of ER-LD contacts. These studies have also highlighted the evolving concept of ER and LDs as a functional continuum for lipid partitioning and pinpointed a role for seipin at the ER-LD nexus in controlling lipid flux between these compartments.
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Affiliation(s)
- Veijo T. Salo
- Department of Anatomy and Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Maarit Hölttä-Vuori
- Department of Anatomy and Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Elina Ikonen
- Department of Anatomy and Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
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Efremova A, Colleluori G, Thomsky M, Perugini J, Protasoni M, Reguzzoni M, Faragalli A, Carle F, Giordano A, Cinti S. Biomarkers of Browning in Cold Exposed Siberian Adults. Nutrients 2020; 12:2162. [PMID: 32707748 PMCID: PMC7468804 DOI: 10.3390/nu12082162] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/06/2020] [Accepted: 07/14/2020] [Indexed: 12/11/2022] Open
Abstract
Cold-exposure promotes energy expenditure by inducing brown adipose tissue (BAT) thermogenesis, which over time, is also sustained by browning, the appearance, or increase, of brown-like cells into white fat depots. Identification of circulating markers reflecting BAT activity and browning is crucial to study this phenomenon and its triggers, also holding possible implications for the therapy of obesity and metabolic diseases. Using RT-qPCR, we evaluated the peripheral blood mononuclear cells (PBMC) expression profile of regulators of BAT activity (CIDEA, PRDM16), white adipocytes browning (HOXC9 and SLC27A1), and fatty acid β-oxidation (CPT1A) in 150 Siberian healthy miners living at extremely cold temperatures compared to 29 healthy subjects living in thermoneutral conditions. Anthropometric parameters, glucose, and lipid profiles were also assessed. The cold-exposed group showed significantly lower weight, BMI, hip circumference, and PBMC expression of CIDEA, but higher expression of HOXC9 and higher circulating glucose compared to controls. Within the cold-exposed group, BMI, total cholesterol, and the atherogenic coefficient were lower in individuals exposed to low temperatures for a longer time. In conclusion, human PBMC expresses the brown adipocytes marker CIDEA and the browning marker HOXC9, which, varying according to cold-exposure, possibly reflect changes in BAT activation and white fat browning.
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Affiliation(s)
- Agrafena Efremova
- Yakut Scientific Center of Complex Medical Problems, 677010 Yakutsk, Russia; (A.E.); (M.T.)
| | - Georgia Colleluori
- Center for the Study of Obesity, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Via Tronto 10A, 60020 Ancona, Italy; (G.C.); (J.P.); (A.G.)
| | - Mikhail Thomsky
- Yakut Scientific Center of Complex Medical Problems, 677010 Yakutsk, Russia; (A.E.); (M.T.)
| | - Jessica Perugini
- Center for the Study of Obesity, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Via Tronto 10A, 60020 Ancona, Italy; (G.C.); (J.P.); (A.G.)
| | - Marina Protasoni
- Department of Medicine and Surgery, University of Insubria, Via Ravasi 2, 21100 Varese, Italy; (M.P.); (M.R.)
| | - Marcella Reguzzoni
- Department of Medicine and Surgery, University of Insubria, Via Ravasi 2, 21100 Varese, Italy; (M.P.); (M.R.)
| | - Andrea Faragalli
- Center of Epidemiology, Biostatistics and Medical Information Technology, Marche Polytechnic University, Via Tronto 10A, 60020 Ancona, Italy; (A.F.); (F.C.)
| | - Flavia Carle
- Center of Epidemiology, Biostatistics and Medical Information Technology, Marche Polytechnic University, Via Tronto 10A, 60020 Ancona, Italy; (A.F.); (F.C.)
| | - Antonio Giordano
- Center for the Study of Obesity, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Via Tronto 10A, 60020 Ancona, Italy; (G.C.); (J.P.); (A.G.)
| | - Saverio Cinti
- Center for the Study of Obesity, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Via Tronto 10A, 60020 Ancona, Italy; (G.C.); (J.P.); (A.G.)
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Arumugam MK, Talawar S, Listenberger L, Donohue TM, Osna NA, Kharbanda KK. Role of Elevated Intracellular S-Adenosylhomocysteine in the Pathogenesis of Alcohol-Related Liver Disease. Cells 2020; 9:1526. [PMID: 32585865 PMCID: PMC7349643 DOI: 10.3390/cells9061526] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/19/2020] [Accepted: 06/21/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The earliest manifestation of alcohol-related liver disease (ALD) is steatosis, characterized by the accumulation of lipid droplets (LDs) in hepatocytes. Findings from our laboratory have indicated that many pathological changes, including steatosis, correlate with the alcohol-induced hepatocellular increases in S-adenosylhomocysteine (SAH). Based on these considerations, we hypothesized that an experimental increase in intracellular SAH alone will result in similar steatotic changes to those seen after alcohol exposure. METHODS Freshly isolated rat hepatocytes grown on collagen-coated plates were exposed to serum-free medium containing 50 µmol/L oleic acid and varying concentrations of 3-deazaadenosine (DZA) to experimentally elevate intracellular SAH levels. RESULTS Overnight exposure to DZA treatment dose-dependently increased hepatocellular triglyceride accumulation, which was also evident by morphological visualization of larger-sized LDs. The rise in triglycerides and LDs accompanied increases in mRNA and protein levels of several LD-associated proteins known to regulate LD number and size. Furthermore, DZA treatment caused a decline in the levels of lipases that prevent fat accumulation as well as increased the expression of factors involved in lipogenesis and fatty acid mobilization. Collectively, our results indicate that the elevation of intracellular SAH is sufficient to promote fat accumulation in hepatocytes, which is similar to that seen after alcohol exposure.
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Affiliation(s)
- Madan Kumar Arumugam
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.T.); (T.M.D.J.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sharanappa Talawar
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.T.); (T.M.D.J.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Laura Listenberger
- Departments of Biology and Chemistry, St. Olaf College, Northfield, MN 55057, USA;
| | - Terrence M. Donohue
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.T.); (T.M.D.J.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.T.); (T.M.D.J.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.T.); (T.M.D.J.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Kopchick JJ, Berryman DE, Puri V, Lee KY, Jorgensen JOL. The effects of growth hormone on adipose tissue: old observations, new mechanisms. Nat Rev Endocrinol 2020; 16:135-146. [PMID: 31780780 PMCID: PMC7180987 DOI: 10.1038/s41574-019-0280-9] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/16/2019] [Indexed: 12/18/2022]
Abstract
The ability of growth hormone (GH) to induce adipose tissue lipolysis has been known for over five decades; however, the molecular mechanisms that mediate this effect and the ability of GH to inhibit insulin-stimulated glucose uptake have scarcely been documented. In this same time frame, our understanding of adipose tissue has evolved to reveal a complex structure with distinct types of adipocyte, depot-specific differences, a biologically significant extracellular matrix and important endocrine properties mediated by adipokines. All these aforementioned features, in turn, can influence lipolysis. In this Review, we provide a historical and current overview of the lipolytic effect of GH in humans, mice and cultured cells. More globally, we explain lipolysis in terms of GH-induced intracellular signalling and its effect on obesity, insulin resistance and lipotoxicity. In this regard, findings that define molecular mechanisms by which GH induces lipolysis are described. Finally, data are presented for the differential effect of GH on specific adipose tissue depots and on distinct classes of metabolically active adipocytes. Together, these cellular, animal and human studies reveal novel cellular phenotypes and molecular pathways regulating the metabolic effects of GH on adipose tissue.
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Affiliation(s)
- John J Kopchick
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA.
- The Diabetes Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA.
- Department of Biomedical Sciences, Ohio University College of Osteopathic Medicine, Athens, OH, USA.
| | - Darlene E Berryman
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- The Diabetes Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA
- Department of Biomedical Sciences, Ohio University College of Osteopathic Medicine, Athens, OH, USA
| | - Vishwajeet Puri
- The Diabetes Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA
- Department of Biomedical Sciences, Ohio University College of Osteopathic Medicine, Athens, OH, USA
| | - Kevin Y Lee
- The Diabetes Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA
- Department of Biomedical Sciences, Ohio University College of Osteopathic Medicine, Athens, OH, USA
| | - Jens O L Jorgensen
- Department of Endocrinology and Diabetes, Aarhus University Hospital, Aarhus, Denmark
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Chen F, Yin Y, Chua BT, Li P. CIDE family proteins control lipid homeostasis and the development of metabolic diseases. Traffic 2019; 21:94-105. [PMID: 31746121 DOI: 10.1111/tra.12717] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/03/2019] [Accepted: 11/15/2019] [Indexed: 12/11/2022]
Affiliation(s)
- Feng‐Jung Chen
- Institute of Metabolism and Integrative Biology, the Human Phenome InstituteFudan University, and Zhongshan Hospital of Fudan University Shanghai China
| | - Yesheng Yin
- Institute of Metabolism and Integrative Biology, the Human Phenome InstituteFudan University, and Zhongshan Hospital of Fudan University Shanghai China
| | - Boon Tin Chua
- Institute of Metabolism and Integrative Biology, the Human Phenome InstituteFudan University, and Zhongshan Hospital of Fudan University Shanghai China
| | - Peng Li
- State Key Laboratory of Membrane Biology and Tsinghua‐Peking Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life SciencesTsinghua University Beijing China
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Wang J, Liu H, Xie G, Cai W, Xu J. Identification of hub genes and key pathways of dietary advanced glycation end products‑induced non‑alcoholic fatty liver disease by bioinformatics analysis and animal experiments. Mol Med Rep 2019; 21:685-694. [PMID: 31974594 PMCID: PMC6947946 DOI: 10.3892/mmr.2019.10872] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 11/18/2019] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease. Advanced glycation end products (AGEs) negatively affect the liver and accelerate NAFLD progression; however, the underlying mechanisms remain unclear. The present study aimed to examine the effect and mechanism of dietary AGEs on the mouse liver using bioinformatics and in vivo experimental approaches. Gene expression datasets associated with NAFLD were obtained from the Gene Expression Omnibus and differentially expressed genes (DEGs) were identified using GEO2R. Functional enrichment analyses were performed using the Database for Annotation, Visualization and Integrated Discovery and a protein-protein interaction network for the DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes database. MCODE, a Cytoscape plugin, was subsequently used to identify the most significant module. The key genes involved were verified in a dietary AGE-induced non-alcoholic steatohepatitis (NASH) mouse model using reverse transcription-quantitative PCR (RT-qPCR). The 462 DEGs associated with NAFLD in the two datasets, of which 34 overlapping genes were found in two microarray datasets. Functional analysis demonstrated that the 34 DEGs were enriched in the ‘PPAR signaling pathway’, ‘central carbon metabolism in cancer’, and ‘cell adhesion molecules (CAMs)’. Moreover, four hub genes (cell death-inducing DFFA-like effector a, cell death-inducing DFFA-like effector c, fatty acid-binding protein 4 and perilipin 4) were identified from a protein-protein interaction network and were verified using RT-qPCR in a mouse model of NASH. The results suggested that AGEs and their receptor axis may be involved in NAFLD onset and/or progression. This integrative analysis identified candidate genes and pathways in NAFLD, as well as DEGs and hub genes related to NAFLD progression in silico and in vivo.
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Affiliation(s)
- Jiao Wang
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Honghong Liu
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Guijiao Xie
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Wei Cai
- Department of Medical Genetics and Cell Biology, Medical College of Nanchang University,
Nanchang, Jiangxi 330006, P.R. China
| | - Jixiong Xu
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Lipid Droplets in Disease. Cells 2019; 8:cells8090974. [PMID: 31454885 PMCID: PMC6770496 DOI: 10.3390/cells8090974] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 08/22/2019] [Accepted: 08/23/2019] [Indexed: 12/13/2022] Open
Abstract
Lipid droplets (LDs) are a crucial part of lipid storage; thus, they are important players in a variety of diseases that are affected by lipid imbalances such as obesity, fatty liver disease, type 2 diabetes, Alzheimer's disease, cardiovascular disease, and cancer [...].
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Mineo C. A Novel Proangiogenic Function of Fsp27 in Endothelium: You Only Live Thrice? J Am Heart Assoc 2019; 8:e013042. [PMID: 31433705 PMCID: PMC6585346 DOI: 10.1161/jaha.119.013042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
See Article Karki et al.
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Affiliation(s)
- Chieko Mineo
- Department of PediatricsCenter for Pulmonary and Vascular BiologyUniversity of Texas Southwestern Medical CenterDallasTX
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