|
1
|
Agoncillo ML, Gao Z, De Kraker HC, McHardy SF, Messing RO, Small L, Schmitz-Peiffer C. Effects of a protein kinase C epsilon inhibitor on insulin signalling in lipid-treated HepG2 hepatocytes and glucose tolerance in fat-fed mice. Eur J Pharmacol 2025; 997:177465. [PMID: 40054721 DOI: 10.1016/j.ejphar.2025.177465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 02/23/2025] [Accepted: 03/04/2025] [Indexed: 05/02/2025]
Abstract
AIMS Protein kinase C epsilon (PKCε) plays a causative role in the development of glucose intolerance, and is a potential target for the treatment of type 2 diabetes. Here, we examined the effects of the PKCε inhibitor CIDD-0150612 (CP612) on insulin action in palmitate-treated HepG2 hepatocytes in vitro and on glucose homeostasis in fat-fed mice in vivo. METHODS HepG2 cells were treated with palmitate and CP612 and stimulated with insulin. Insulin signalling was examined by immunoblotting and glucose incorporation into glycogen was measured using glucose tracer. Mice were fed a high-fat diet and treated with CP612 prior to glucose tolerance tests and tissue harvest. Proteomic analysis of liver was carried out by mass spectrometry. RESULTS CP612 promoted Akt phosphorylation in a highly insulin-dependent manner and reversed the inhibition of insulin-stimulated Akt phosphorylation and glucose incorporation into glycogen by palmitate. Fat-fed mice treated with CP612 had reduced fat mass, but not lean mass, compared with vehicle-treated littermates. Mice treated acutely with CP612 exhibited elevated fasting blood glucose. However, mice studied 24h after the last dose had lower fasting glucose and improved glucose tolerance with a lower insulin excursion. Proteomic analysis of liver from CP612-treated fat-fed mice indicated a reduction in gluconeogenic gene expression and decreased phosphorylation of the transcription factor Foxk1. CONCLUSIONS The PKCε inhibitor CP612 had beneficial effects on insulin action in hepatocytes and on fat mass and glucose homeostasis in mice. Because certain effects were not previously observed in genetically PKCε-deficient mice, off-target effects may be partly responsible.
Collapse
Affiliation(s)
- Miguel L Agoncillo
- Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
| | - Zhongmin Gao
- Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
| | - Harmannus C De Kraker
- Department of Chemistry, Center for Innovative Drug Discovery, University of Texas San Antonio, One UTSA Circle, San Antonio, TX, 78249, USA.
| | - Stanton F McHardy
- Department of Chemistry, Center for Innovative Drug Discovery, University of Texas San Antonio, One UTSA Circle, San Antonio, TX, 78249, USA.
| | - Robert O Messing
- Department of Neuroscience, University of Texas at Austin, E 24th Street, Austin, TX, 78712, USA.
| | - Lewin Small
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, NSW, 2006, Australia.
| | - Carsten Schmitz-Peiffer
- Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia; Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, NSW, 2006, Australia; St Vincent's Clinical School, University of New South Wales, 390 Victoria St, Darlinghurst, NSW, NSW 2010, Australia.
| |
Collapse
|
|
2
|
Morita K, Hatano A, Kokaji T, Sugimoto H, Tsuchiya T, Ozaki H, Egami R, Li D, Terakawa A, Ohno S, Inoue H, Inaba Y, Suzuki Y, Matsumoto M, Takahashi M, Izumi Y, Bamba T, Hirayama A, Soga T, Kuroda S. Structural robustness and temporal vulnerability of the starvation-responsive metabolic network in healthy and obese mouse liver. Sci Signal 2025; 18:eads2547. [PMID: 40261956 DOI: 10.1126/scisignal.ads2547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 11/13/2024] [Accepted: 04/02/2025] [Indexed: 04/24/2025]
Abstract
Adaptation to starvation is a multimolecular and temporally ordered process. We sought to elucidate how the healthy liver regulates various molecules in a temporally ordered manner during starvation and how obesity disrupts this process. We used multiomic data collected from the plasma and livers of wild-type and leptin-deficient obese (ob/ob) mice at multiple time points during starvation to construct a starvation-responsive metabolic network that included responsive molecules and their regulatory relationships. Analysis of the network structure showed that in wild-type mice, the key molecules for energy homeostasis, ATP and AMP, acted as hub molecules to regulate various metabolic reactions in the network. Although neither ATP nor AMP was responsive to starvation in ob/ob mice, the structural properties of the network were maintained. In wild-type mice, the molecules in the network were temporally ordered through metabolic processes coordinated by hub molecules, including ATP and AMP, and were positively or negatively coregulated. By contrast, both temporal order and coregulation were disrupted in ob/ob mice. These results suggest that the metabolic network that responds to starvation was structurally robust but temporally disrupted by the obesity-associated loss of responsiveness of the hub molecules. In addition, we propose how obesity alters the response to intermittent fasting.
Collapse
Affiliation(s)
- Keigo Morita
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan
- Molecular Genetics Research Laboratory, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan
| | - Atsushi Hatano
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan
- Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
- Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045 Japan
| | - Toshiya Kokaji
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan
- Data Science Center, Nara Institute of Science and Technology, Nara 630-0192, Japan
| | - Hikaru Sugimoto
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan
| | - Takaho Tsuchiya
- Bioinformatics Laboratory, Institute of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Center for Artificial Intelligence Research, University of Tsukuba, Ibaraki 305-8577, Japan
| | - Haruka Ozaki
- Bioinformatics Laboratory, Institute of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Center for Artificial Intelligence Research, University of Tsukuba, Ibaraki 305-8577, Japan
| | - Riku Egami
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Chiba 277-8562, Japan
| | - Dongzi Li
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan
| | - Akira Terakawa
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan
| | - Satoshi Ohno
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan
- Molecular Genetics Research Laboratory, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan
- Department of AI Systems Medicine, M&D Data Science Center, Institute of Integrated Research, Institute of Science Tokyo, Tokyo 113-8510, Japan
| | - Hiroshi Inoue
- Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Ishikawa 920-8641, Japan
| | - Yuka Inaba
- Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Ishikawa 920-8641, Japan
| | - Yutaka Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Chiba 277-8562, Japan
| | - Masaki Matsumoto
- Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Masatomo Takahashi
- Division of Metabolomics, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshihiro Izumi
- Division of Metabolomics, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | - Takeshi Bamba
- Division of Metabolomics, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | - Akiyoshi Hirayama
- Institute for Advanced Biosciences, Keio University, Yamagata 997-0052, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Yamagata 997-0052, Japan
- Human Biology-Microbiome-Quantum Research Center (WPI-Bio2Q), Keio University, Tokyo 108-8345, Japan
| | - Shinya Kuroda
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan
- Molecular Genetics Research Laboratory, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Chiba 277-8562, Japan
| |
Collapse
|
|
3
|
Gattu AK, Tanzer M, Yaron-Barir TM, Johnson JL, Jayavelu AK, Pan H, Dreyfuss JM, Cantley LC, Mann M, Kahn CR. Cell-intrinsic insulin signaling defects in human iPS cell-derived hepatocytes in type 2 diabetes. J Clin Invest 2025; 135:e183513. [PMID: 40231468 PMCID: PMC11996863 DOI: 10.1172/jci183513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 02/07/2025] [Indexed: 04/16/2025] Open
Abstract
Hepatic insulin resistance is central to type 2 diabetes (T2D) and metabolic syndrome, but defining the molecular basis of this defect in humans is challenging because of limited tissue access. Utilizing inducible pluripotent stem cells differentiated into hepatocytes from control individuals and patients with T2D and liquid chromatography with tandem mass spectrometry-based (LC-MS/MS-based) phosphoproteomics analysis, we identified a large network of cell-intrinsic alterations in signaling in T2D. Over 300 phosphosites showed impaired or reduced insulin signaling, including losses in the classical insulin-stimulated PI3K/AKT cascade and their downstream targets. In addition, we identified over 500 phosphosites of emergent, i.e., new or enhanced, signaling. These occurred on proteins involved in the Rho-GTPase pathway, RNA metabolism, vesicle trafficking, and chromatin modification. Kinome analysis indicated that the impaired phosphorylation sites represented reduced actions of AKT2/3, PKCθ, CHK2, PHKG2, and/or STK32C kinases. By contrast, the emergent phosphorylation sites were predicted to be mediated by increased action of the Rho-associated kinases 1 and 2 (ROCK1/2), mammalian STE20-like protein kinase 4 (MST4), and/or branched-chain α-ketoacid dehydrogenase kinase (BCKDK). Inhibiting ROCK1/2 activity in T2D induced pluripotent stem cell-derived hepatocytes restored some of the alterations in insulin action. Thus, insulin resistance in the liver in T2D did not simply involve a loss of canonical insulin signaling but the also appearance of new phosphorylations representing a change in the balance of multiple kinases. Together, these led to altered insulin action in the liver and identified important targets for the therapy of hepatic insulin resistance.
Collapse
Affiliation(s)
- Arijeet K. Gattu
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, and
- Metabolism Unit and Division of Endocrinology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Maria Tanzer
- Department of Proteomics and Signal Transduction, Max Plank Institute of Biochemistry, Martinsried, Germany
- Advanced Technology and Biology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
| | - Tomer M. Yaron-Barir
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
| | | | - Ashok Kumar Jayavelu
- Department of Proteomics and Signal Transduction, Max Plank Institute of Biochemistry, Martinsried, Germany
| | - Hui Pan
- Bioinformatics and Biostatistics Core, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Jonathan M. Dreyfuss
- Bioinformatics and Biostatistics Core, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Matthias Mann
- Department of Proteomics and Signal Transduction, Max Plank Institute of Biochemistry, Martinsried, Germany
| | - C. Ronald Kahn
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, and
| |
Collapse
|
|
4
|
Cron KR, Sivan A, Aquino-Michaels K, Ziblat A, Higgs EF, Sweis RF, Tonea R, Lee S, Gajewski TF. PKCδ Germline Variants and Genetic Deletion in Mice Augment Antitumor Immunity through Regulation of Myeloid Cells. Cancer Immunol Res 2025; 13:547-559. [PMID: 39808445 DOI: 10.1158/2326-6066.cir-23-0999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 07/04/2024] [Accepted: 01/10/2025] [Indexed: 01/16/2025]
Abstract
Based on the notion that hypomorphic germline genetic variants are linked to autoimmune diseases, we reasoned that novel targets for cancer immunotherapy might be identified through germline variants associated with greater T-cell infiltration into tumors. Here, we report that while investigating germline polymorphisms associated with a tumor immune gene signature, we identified protein kinase C delta (PKCδ) as a candidate. Genetic deletion of Prkcd in mice resulted in improved endogenous antitumor immunity and increased efficacy of anti-PD-L1. Single-cell RNA sequencing revealed myeloid cell expression of Prkcd, and PKCδ deletion caused a shift in macrophage gene expression from an M2-like to an M1-like phenotype. Conditional deletion of Prkcd in myeloid cells recapitulated improved tumor control that was augmented further with anti-PD-L1. Analysis of clinical samples confirmed an association between PRKCD variants and M1/M2 phenotype, as well as between a PKCδ knockout-like gene signature and clinical benefit from anti-PD-1. Our results identify PKCδ as a candidate therapeutic target that modulates myeloid cell states.
Collapse
Affiliation(s)
- Kyle R Cron
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Ayelet Sivan
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Keston Aquino-Michaels
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Andrea Ziblat
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Emily F Higgs
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Randy F Sweis
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Ruxandra Tonea
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Seoho Lee
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Thomas F Gajewski
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| |
Collapse
|
|
5
|
Lam SM, Wang Z, Song JW, Shi Y, Liu WY, Wan LY, Duan K, Chua GH, Zhou Y, Wang G, Huang X, Wang Y, Wang FS, Zheng MH, Shui G. Non-invasive lipid panel of MASLD fibrosis transition underscores the role of lipoprotein sulfatides in hepatic immunomodulation. Cell Metab 2025; 37:69-86.e7. [PMID: 39500328 DOI: 10.1016/j.cmet.2024.09.009] [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: 04/09/2024] [Revised: 07/18/2024] [Accepted: 09/13/2024] [Indexed: 01/11/2025]
Abstract
There exists a pressing need for a non-invasive panel that differentiates mild fibrosis from non-fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD). In this work, we applied quantitative lipidomics and sterolomics on sera from the PERSONS cohort with biopsy-based histological assessment of liver pathology. We trained a lasso regression model using quantitative omics data and clinical variables, deriving a combinatorial panel of lipids and clinical indices that differentiates mild fibrosis (>F1, n = 324) from non-fibrosis (F0, n = 195), with an area under receiver operating characteristic curve (AUROC) at 0.775 (95% confidence interval [CI]: 0.735-0.816). Circulating sulfatides (SLs) emerged as central lipids distinctly associated with fibrosis pathogenesis in MASLD. Lipidomics analysis of lipoprotein fractions revealed a redistribution of circulating SLs from high-density lipoproteins (HDLs) onto low-density lipoproteins (LDLs) in MASLD fibrosis. We further verified that patient LDLs with reduced SL content triggered a smaller activation of type II natural killer T lymphocytes, compared with control LDLs. Our results suggest that hepatic crosstalk with systemic immunity mediated by lipoprotein metabolism underlies fibrosis progression at early-stage MASLD.
Collapse
Affiliation(s)
- Sin Man Lam
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; LipidALL Technologies Company Limited, Changzhou 213022, Jiangsu, China
| | - Zehua Wang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jin-Wen Song
- Department of Infectious Diseases, the Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China
| | - Yue Shi
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Beijing, China
| | - Wen-Yue Liu
- Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lin-Yu Wan
- Department of Infectious Diseases, the Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China
| | - Kaibo Duan
- Centre for Biomedical Informatics, Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore
| | - Gek Huey Chua
- LipidALL Technologies Company Limited, Changzhou 213022, Jiangsu, China
| | - Yingjuan Zhou
- LipidALL Technologies Company Limited, Changzhou 213022, Jiangsu, China
| | - Guibin Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
| | - Xiahe Huang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yingchun Wang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Beijing, China
| | - Fu-Sheng Wang
- Department of Infectious Diseases, the Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China.
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China; Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Guanghou Shui
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Beijing, China.
| |
Collapse
|
|
6
|
Wang P, Li F, Sun Y, Li Y, Xie X, Du X, Liu L, Wu Y, Song D, Xiong H, Chen J, Li X. Novel insights into the circadian modulation of lipid metabolism in chicken livers revealed by RNA sequencing and weighted gene co-expression network analysis. Poult Sci 2024; 103:104321. [PMID: 39361997 PMCID: PMC11474196 DOI: 10.1016/j.psj.2024.104321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 09/06/2024] [Accepted: 09/07/2024] [Indexed: 10/05/2024] Open
Abstract
The circadian clock is crucial for maintaining lipid metabolism homeostasis in mammals. Despite the economic importance of fat content in poultry, research on the regulatory effects and molecular mechanisms of the circadian clock on avian hepatic lipid metabolism has been limited. In this study, we observed significant diurnal variations (P<0.05) in triglyceride (TG), free fatty acids (FFA), fatty acid synthase (FAS), and total cholesterol (TC) levels in the chicken embryonic liver under 12-h light/12-h dark incubation conditions, with TG, FFA, and TC concentrations showing significant cosine rhythmic oscillations (P<0.05). However, such rhythmic variations were not observed under complete darkness incubation conditions. Using transcriptome sequencing technology, we identified 157 genes significantly upregulated at night and 313 genes significantly upregulated during the 12-h light/12-h dark cycle. These circadian differential genes are involved in processes and pathways such as lipid catabolic process regulation, meiotic cell cycle, circadian rhythm regulation, positive regulation of the MAPK cascade, and glycerolipid metabolism. Weighted gene co-expression network analysis (WGCNA) revealed 3 modules-green, blue, and red-that significantly correlate with FFA, FAS, and TG, respectively. Genes within these modules were enriched in processes and pathways including the cell cycle, light stimulus response, circadian rhythm regulation, phosphorylation, positive regulation of the MAPK cascade, and lipid biosynthesis. Notably, we identified ten hub genes, including protein kinase C delta (PRKCD), polo like kinase 4 (PLK4), clock circadian regulator (CLOCK), steroid 5 alpha-reductase 3 (SRD5A3), BUB1 mitotic checkpoint serine/threonine kinase (BUB1B), shugoshin 1 (SGO1), NDC80 kinetochore complex component (NDC80), NIMA related kinase 2 (NEK2), minichromosome maintenance complex component 4 (MCM4), polo like kinase 1 (PLK1), potentially link circadian regulation with lipid metabolic homeostasis. These findings demonstrate the regulatory role of the circadian clock in chicken liver lipid metabolism homeostasis and provide a theoretical basis and molecular targets for optimizing the circadian clock to reduce excessive fat deposition in chickens, which is significant for the healthy development of the poultry industry.
Collapse
Affiliation(s)
- Panlin Wang
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Fang Li
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Yanyan Sun
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Yunlei Li
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Xiuyu Xie
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Xue Du
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Lu Liu
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Yongshu Wu
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Dan Song
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Hui Xiong
- Beijing Seeme Medical Technology Co Ltd, Beijing, 100093, China
| | - Jilan Chen
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
| | - Xiangchen Li
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China.
| |
Collapse
|
|
7
|
Rada P, Carceller-López E, Hitos AB, Gómez-Santos B, Fernández-Hernández C, Rey E, Pose-Utrilla J, García-Monzón C, González-Rodríguez Á, Sabio G, García A, Aspichueta P, Iglesias T, Valverde ÁM. Protein kinase D2 modulates hepatic insulin sensitivity in male mice. Mol Metab 2024; 90:102045. [PMID: 39401614 PMCID: PMC11535753 DOI: 10.1016/j.molmet.2024.102045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/30/2024] [Accepted: 10/07/2024] [Indexed: 10/21/2024] Open
Abstract
OBJECTIVES Protein kinase D (PKD) family is emerging as relevant regulator of metabolic homeostasis. However, the precise role of PKD2 in modulating hepatic insulin signaling has not been fully elucidated and it is the aim of this study. METHODS PKD inhibition was analyzed for insulin signaling in mouse and human hepatocytes. PKD2 was overexpressed in Huh7 hepatocytes and mouse liver, and insulin responses were evaluated. Mice with hepatocyte-specific PKD2 depletion (PKD2ΔHep) and PKD2fl/fl mice were fed a chow (CHD) or high fat diet (HFD) and glucose homeostasis and lipid metabolism were investigated. RESULTS PKD2 silencing enhanced insulin signaling in hepatocytes, an effect also found in primary hepatocytes from PKD2ΔHep mice. Conversely, a constitutively active PKD2 mutant reduced insulin-stimulated AKT phosphorylation. A more in-depth analysis revealed reduced IRS1 serine phosphorylation under basal conditions and increased IRS1 tyrosine phosphorylation in PKD2ΔHep primary hepatocytes upon insulin stimulation and, importantly PKD co-immunoprecipitates with IRS1. In vivo constitutively active PKD2 overexpression resulted in a moderate impairment of glucose homeostasis and reduced insulin signaling in the liver. On the contrary, HFD-fed PKD2ΔHep male mice displayed improved glucose and pyruvate tolerance, as well as higher peripheral insulin tolerance and enhanced hepatic insulin signaling compared to control PKD2fl/fl mice. Despite of a remodeling of hepatic lipid metabolism in HFD-fed PKD2ΔHep mice, similar steatosis grade was found in both genotypes. CONCLUSIONS Results herein have unveiled an unknown role of PKD2 in the control of insulin signaling in the liver at the level of IRS1 and point PKD2 as a therapeutic target for hepatic insulin resistance.
Collapse
Affiliation(s)
- Patricia Rada
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
| | - Elena Carceller-López
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Ana B Hitos
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Beatriz Gómez-Santos
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain; BioBizkaia Health Research Institute, Barakaldo, Spain
| | - Constanza Fernández-Hernández
- Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, Spain
| | - Esther Rey
- Liver Research Unit, Santa Cristina University Hospital, Instituto de Investigación Sanitaria Princesa, Madrid, Spain
| | - Julia Pose-Utrilla
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Carmelo García-Monzón
- Liver Research Unit, Santa Cristina University Hospital, Instituto de Investigación Sanitaria Princesa, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Águeda González-Rodríguez
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain; Liver Research Unit, Santa Cristina University Hospital, Instituto de Investigación Sanitaria Princesa, Madrid, Spain
| | - Guadalupe Sabio
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Antonia García
- Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, Spain
| | - Patricia Aspichueta
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain; BioBizkaia Health Research Institute, Barakaldo, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Teresa Iglesias
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Ángela M Valverde
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
| |
Collapse
|
|
8
|
Collins J, Piscopio RA, Reyland ME, Johansen CG, Benninger RKP, Farnsworth NL. Cleavage of protein kinase c δ by caspase-3 mediates proinflammatory cytokine-induced apoptosis in pancreatic islets. J Biol Chem 2024; 300:107611. [PMID: 39074637 PMCID: PMC11381875 DOI: 10.1016/j.jbc.2024.107611] [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: 01/14/2024] [Revised: 07/04/2024] [Accepted: 07/17/2024] [Indexed: 07/31/2024] Open
Abstract
In type 1 diabetes (T1D), autoreactive immune cells infiltrate the pancreas and secrete proinflammatory cytokines that initiate cell death in insulin producing islet β-cells. Protein kinase C δ (PKCδ) plays a role in mediating cytokine-induced β-cell death; however, the exact mechanisms are not well understood. To address this, we used an inducible β-cell specific PKCδ KO mouse as well as a small peptide inhibitor of PKCδ. We identified a role for PKCδ in mediating cytokine-induced β-cell death and have shown that inhibiting PKCδ protects pancreatic β-cells from cytokine-induced apoptosis in both mouse and human islets. We determined that cytokines induced nuclear translocation and activity of PKCδ and that caspase-3 cleavage of PKCδ may be required for cytokine-mediated islet apoptosis. Further, cytokine activated PKCδ increases activity both of proapoptotic Bax with acute treatment and C-Jun N-terminal kinase with prolonged treatment. Overall, our results suggest that PKCδ mediates cytokine-induced apoptosis via nuclear translocation, cleavage by caspase-3, and upregulation of proapoptotic signaling in pancreatic β-cells. Combined with the protective effects of PKCδ inhibition with δV1-1, the results of this study will aid in the development of novel therapies to prevent or delay β-cell death and preserve β-cell function in T1D.
Collapse
Affiliation(s)
- Jillian Collins
- Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, Colorado, USA
| | - Robert A Piscopio
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Mary E Reyland
- Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Chelsea G Johansen
- Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, Colorado, USA
| | - Richard K P Benninger
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
| | - Nikki L Farnsworth
- Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, Colorado, USA; Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
| |
Collapse
|
|
9
|
Qin X, Liu J. Nanoformulations for the diagnosis and treatment of metabolic dysfunction-associated steatohepatitis. Acta Biomater 2024; 184:37-53. [PMID: 38879104 DOI: 10.1016/j.actbio.2024.06.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 05/25/2024] [Accepted: 06/10/2024] [Indexed: 06/29/2024]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive phase of metabolic dysfunction-associated steatotic liver disease (MASLD) that develops into irreversible liver cirrhosis and hepatocellular carcinoma, ultimately necessitating liver transplantation as the sole life-saving option. However, given the drawbacks of liver transplantation, including invasiveness, chronic immunosuppression, and a lack of donor livers, prompt diagnosis and effective treatment are indispensable. Due to the limitations of liver biopsy and conventional imaging modalities in diagnosing MASH, as well as the potential hazards associated with liver-protecting medicines, numerous nanoformulations have been created for MASH theranostics. Particularly, there has been significant study interest in artificial nanoparticles, natural biomaterials, and bionic nanoparticles that exhibit exceptional biocompatibility and bioavailability. In this review, we summarized extracellular vesicles (EVs)-based omics analysis and Fe3O4-based functional magnetic nanoparticles as magnetic resonance imaging (MRI) contrast agents for MASH diagnosis. Additionally, artificial nanoparticles such as organic and inorganic nanoparticles, as well as natural biomaterials such as cells and cell-derived EVs and bionic nanoparticles including cell membrane-coated nanoparticles, have also been reported for MASH treatment owing to their specific targeting and superior therapeutic effect. This review has the potential to stimulate advancements in nanoformulation fabrication techniques. By exploring their compatibility with cell biology, it could lead to the creation of innovative material systems for efficient theragnostic uses for MASH. STATEMENT OF SIGNIFICANCE: People with metabolic dysfunction-associated steatohepatitis (MASH) will progress to fibrosis, cirrhosis, or even liver cancer. It is imperative to establish effective theragnostic techniques to stop MASH from progressing into a lethal condition. In our review, we summarize the advancement of artificial, natural, and bionic nanoparticles applied in MASH theragnosis. Furthermore, the issues that need to be resolved for these cutting-edge techniques are summarized to realize a more significant clinical impact. We forecast the key fields that will advance further as nanotechnology and MASH research progress. Generally, our discovery has significant implications for the advancement of nanoformulation fabrication techniques, and their potential to be compatible with cell biology could lead to the creation of innovative materials systems for effective MASH theragnostic.
Collapse
Affiliation(s)
- Xueying Qin
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China; The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225001, PR China
| | - Jingjing Liu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China; The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225001, PR China.
| |
Collapse
|
|
10
|
Ghoshal K, Luther JM, Pakala SB, Chetyrkin S, Falck JR, Zent R, Wasserman DH, Pozzi A. Epoxygenase Cyp2c44 Regulates Hepatic Lipid Metabolism and Insulin Signaling by Controlling FATP2 Localization and Activation of the DAG/PKCδ Axis. Diabetes 2024; 73:1229-1243. [PMID: 38743615 PMCID: PMC11262046 DOI: 10.2337/db23-0493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 05/05/2024] [Indexed: 05/16/2024]
Abstract
Cytochrome P450 epoxygenase Cyp2c44, a murine epoxyeicosatrienoic acid (EET)-producing enzyme, promotes insulin sensitivity, and Cyp2c44-/- mice show hepatic insulin resistance. Because insulin resistance leads to hepatic lipid accumulation and hyperlipidemia, we hypothesized that Cyp2c44 regulates hepatic lipid metabolism. Standard chow diet (SCD)-fed male Cyp2c44-/- mice had significantly decreased EET levels and increased hepatic and plasma lipid levels compared with wild-type mice. We showed increased hepatic plasma membrane localization of the FA transporter 2 (FATP2) and total unsaturated fatty acids and diacylglycerol (DAG) levels. Cyp2c44-/- mice had impaired glucose tolerance and increased hepatic plasma membrane-associated PKCδ and phosphorylated IRS-1, two negative regulators of insulin signaling. Surprisingly, SCD and high-fat diet (HFD)-fed Cyp2c44-/- mice had similar glucose tolerance and hepatic plasma membrane PKCδ levels, suggesting that SCD-fed Cyp2c44-/- mice have reached their maximal glucose intolerance. Inhibition of PKCδ resulted in decreased IRS-1 serine phosphorylation and improved insulin-mediated signaling in Cyp2c44-/- hepatocytes. Finally, Cyp2c44-/- HFD-fed mice treated with the analog EET-A showed decreased hepatic plasma membrane FATP2 and PCKδ levels with improved glucose tolerance and insulin signaling. In conclusion, loss of Cyp2c44 with concomitant decreased EET levels leads to increased hepatic FATP2 plasma membrane localization, DAG accumulation, and PKCδ-mediated attenuation of insulin signaling. Thus, Cyp2c44 acts as a regulator of lipid metabolism by linking it to insulin signaling. ARTICLE HIGHLIGHTS
Collapse
Affiliation(s)
- Kakali Ghoshal
- Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN
| | - James M Luther
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN
| | - Suman B Pakala
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN
| | - Sergei Chetyrkin
- Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN
| | | | - Roy Zent
- Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN
- Department of Veterans Affairs, Nashville, Nashville, TN
| | - David H Wasserman
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
| | - Ambra Pozzi
- Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN
- Department of Veterans Affairs, Nashville, Nashville, TN
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
| |
Collapse
|
|
11
|
Elkanawati RY, Sumiwi SA, Levita J. Impact of Lipids on Insulin Resistance: Insights from Human and Animal Studies. Drug Des Devel Ther 2024; 18:3337-3360. [PMID: 39100221 PMCID: PMC11298177 DOI: 10.2147/dddt.s468147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 07/24/2024] [Indexed: 08/06/2024] Open
Abstract
Insulin resistance (IR) is a complex pathological condition central to metabolic diseases such as type 2 diabetes mellitus (T2DM), cardiovascular disease, non-alcoholic fatty liver disease, and polycystic ovary syndrome (PCOS). This review evaluates the impact of lipids on insulin resistance (IR) by analyzing findings from human and animal studies. The articles were searched on the PubMed database using two keywords: (1) "Role of Lipids AND Insulin Resistance AND Humans" and (2) "Role of Lipids AND Insulin Resistance AND Animal Models". Studies in humans revealed that elevated levels of free fatty acids (FFAs) and triglycerides (TGs) are closely associated with reduced insulin sensitivity, and interventions like metformin and omega-3 fatty acids show potential benefits. In animal models, high-fat diets disrupt insulin signaling and increase inflammation, with lipid mediators such as diacylglycerol (DAG) and ceramides playing significant roles. DAG activates protein kinase C, which eventually impairs insulin signaling, while ceramides inhibit Akt/PKB, further contributing to IR. Understanding these mechanisms is crucial for developing effective prevention and treatment strategies for IR-related diseases.
Collapse
Affiliation(s)
- Rani Yulifah Elkanawati
- Master Program in Pharmacy, Faculty of Pharmacy, Padjadjaran University, Jawa Barat, West Java, 45363, Indonesia
| | - Sri Adi Sumiwi
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Padjadjaran University, Sumedang, West Java, 45363, Indonesia
| | - Jutti Levita
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Padjadjaran University, Sumedang, West Java, 45363, Indonesia
| |
Collapse
|
|
12
|
Qin P, He C, Ye P, Li Q, Cai C, Li Y. PKCδ regulates the vascular biology in diabetic atherosclerosis. Cell Commun Signal 2023; 21:330. [PMID: 37974282 PMCID: PMC10652453 DOI: 10.1186/s12964-023-01361-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 10/20/2023] [Indexed: 11/19/2023] Open
Abstract
Diabetes mellitus, known for its complications, especially vascular complications, is becoming a globally serious social problem. Atherosclerosis has been recognized as a common vascular complication mechanism in diabetes. The diacylglycerol (DAG)-protein kinase C (PKC) pathway plays an important role in atherosclerosis. PKCs can be divided into three subgroups: conventional PKCs (cPKCs), novel PKCs (nPKCs), and atypical PKCs (aPKCs). The aim of this review is to provide a comprehensive overview of the role of the PKCδ pathway, an isoform of nPKC, in regulating the function of endothelial cells, vascular smooth muscle cells, and macrophages in diabetic atherosclerosis. In addition, potential therapeutic targets regarding the PKCδ pathway are summarized. Video Abstract.
Collapse
Affiliation(s)
- Peiliang Qin
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Changhuai He
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Pin Ye
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qin Li
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chuanqi Cai
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Yiqing Li
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| |
Collapse
|
|
13
|
Kim Y, Kim HK, Kang S, Kim H, Go GW. Rottlerin suppresses lipid accumulation by inhibiting de novo lipogenesis and adipogenesis via LRP6/mTOR/SREBP1C in 3T3-L1 adipocytes. Food Sci Biotechnol 2023; 32:1445-1452. [PMID: 37457404 PMCID: PMC10349001 DOI: 10.1007/s10068-023-01339-5] [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: 02/20/2023] [Revised: 04/24/2023] [Accepted: 05/12/2023] [Indexed: 07/18/2023] Open
Abstract
Rottlerin is isolated from Mallotus japonicus, a plant rich in polyphenols. Rottlerin is a selective PKCδ-inhibitor and is also known as an uncoupler of oxidative phosphorylation and anti-neoplastic agent. However, its anti-obesity effect is yet to be established. Therefore, this study tested whether rottlerin inhibits adipogenesis and de novo lipogenesis via the LRP6/mTOR/SREBP1C pathway in 3T3-L1 adipocytes. Rottlerin dramatically decreased lipid accumulation assessed by Oil Red O as evidence to support the cellular phenotype (p < 0.001). Pivotal messenger RNA and protein expressions associated with de novo lipogenesis (SREBP1C, ACC1, FAS, and SCD1) and adipogenesis (PPARγ and C/EBPα) were subsequentially verified by rottlerin in a dose-dependent manner (p < 0.05). Further investigation revealed that rottlerin reduced the AKT/mTOR pathway via diminished total protein of LRP6 (p < 0.05). Collectively, these findings establish a causal link between rottlerin, LRP6, and the altered nutrient-sensing mTOR pathway, in which rottlerin regulates de novo lipogenesis and adipogenesis in white adipocytes.
Collapse
Affiliation(s)
- Yejin Kim
- Department of Food and Nutrition, Hanyang University, Seoul, 04763 Republic of Korea
| | - Hyun Kyung Kim
- Department of Food and Nutrition, Hanyang University, Seoul, 04763 Republic of Korea
| | - Sumin Kang
- Department of Food and Nutrition, Hanyang University, Seoul, 04763 Republic of Korea
| | - Hayoon Kim
- Department of Food and Nutrition, Hanyang University, Seoul, 04763 Republic of Korea
| | - Gwang-woong Go
- Department of Food and Nutrition, Hanyang University, Seoul, 04763 Republic of Korea
| |
Collapse
|
|
14
|
Shu Y, Gumma N, Hassan F, Branch DA, Baer LA, Ostrowski MC, Stanford KI, Baskin KK, Mehta KD. Hepatic protein kinase Cbeta deficiency mitigates late-onset obesity. J Biol Chem 2023; 299:104917. [PMID: 37315788 PMCID: PMC10393818 DOI: 10.1016/j.jbc.2023.104917] [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: 02/24/2023] [Revised: 05/27/2023] [Accepted: 05/30/2023] [Indexed: 06/16/2023] Open
Abstract
Although aging is associated with progressive adiposity and a decline in liver function, the underlying molecular mechanisms and metabolic interplay are incompletely understood. Here, we demonstrate that aging induces hepatic protein kinase Cbeta (PKCβ) expression, while hepatocyte PKCβ deficiency (PKCβHep-/-) in mice significantly attenuates obesity in aged mice fed a high-fat diet. Compared with control PKCβfl/fl mice, PKCβHep-/- mice showed elevated energy expenditure with augmentation of oxygen consumption and carbon dioxide production which was dependent on β3-adrenergic receptor signaling, thereby favoring negative energy balance. This effect was accompanied by induction of thermogenic genes in brown adipose tissue (BAT) and increased BAT respiratory capacity, as well as a shift to oxidative muscle fiber type with an improved mitochondrial function, thereby enhancing oxidative capacity of thermogenic tissues. Furthermore, in PKCβHep-/- mice, we determined that PKCβ overexpression in the liver mitigated elevated expression of thermogenic genes in BAT. In conclusion, our study thus establishes hepatocyte PKCβ induction as a critical component of pathophysiological energy metabolism by promoting progressive hepatic and extrahepatic metabolic derangements in energy homeostasis, contributing to late-onset obesity. These findings have potential implications for augmenting thermogenesis as a means of combating aging-induced obesity.
Collapse
Affiliation(s)
- Yaoling Shu
- Department of Biological Chemistry & Pharmacology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Nikhil Gumma
- Department of Biological Chemistry & Pharmacology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Faizule Hassan
- Department of Biological Chemistry & Pharmacology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Daniel A Branch
- Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Lisa A Baer
- Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Michael C Ostrowski
- Department of Biochemistry & Molecular Biology, Holling Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Kristin I Stanford
- Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Kedryn K Baskin
- Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Kamal D Mehta
- Department of Biological Chemistry & Pharmacology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Division of Metabolic Syndrome, Instacare Therapeutics, Dublin, Ohio, USA.
| |
Collapse
|
|
15
|
Rah SY, Joe Y, Park J, Ryter SW, Park C, Chung HT, Kim UH. CD38/ADP-ribose/TRPM2-mediated nuclear Ca 2+ signaling is essential for hepatic gluconeogenesis in fasting and diabetes. Exp Mol Med 2023; 55:1492-1505. [PMID: 37394593 PMCID: PMC10393965 DOI: 10.1038/s12276-023-01034-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 02/06/2023] [Accepted: 04/17/2023] [Indexed: 07/04/2023] Open
Abstract
Hepatic glucose production by glucagon is crucial for glucose homeostasis during fasting, yet the underlying mechanisms remain incompletely delineated. Although CD38 has been detected in the nucleus, its function in this compartment is unknown. Here, we demonstrate that nuclear CD38 (nCD38) controls glucagon-induced gluconeogenesis in primary hepatocytes and liver in a manner distinct from CD38 occurring in the cytoplasm and lysosomal compartments. We found that the localization of CD38 in the nucleus is required for glucose production by glucagon and that nCD38 activation requires NAD+ supplied by PKCδ-phosphorylated connexin 43. In fasting and diabetes, nCD38 promotes sustained Ca2+ signals via transient receptor potential melastatin 2 (TRPM2) activation by ADP-ribose, which enhances the transcription of glucose-6 phosphatase and phosphoenolpyruvate carboxykinase 1. These findings shed light on the role of nCD38 in glucagon-induced gluconeogenesis and provide insight into nuclear Ca2+ signals that mediate the transcription of key genes in gluconeogenesis under physiological conditions.
Collapse
Affiliation(s)
- So-Young Rah
- Department of Biochemistry and National Creative Research Laboratory for Ca2+ Signaling Network, Jeonbuk National University, Medical School, Keum-am dong, Jeonju, 54907, Republic of Korea
| | - Yeonsoo Joe
- School of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea
| | - Jeongmin Park
- School of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea
| | | | - Chansu Park
- Department of Biochemistry and National Creative Research Laboratory for Ca2+ Signaling Network, Jeonbuk National University, Medical School, Keum-am dong, Jeonju, 54907, Republic of Korea
| | - Hun Taeg Chung
- School of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea.
| | - Uh-Hyun Kim
- Department of Biochemistry and National Creative Research Laboratory for Ca2+ Signaling Network, Jeonbuk National University, Medical School, Keum-am dong, Jeonju, 54907, Republic of Korea.
- Department of Biochemistry, School of Medicine, Wonkwang University, Iksan, 54538, Republic of Korea.
| |
Collapse
|
|
16
|
Niranjan S, Phillips BE, Giannoukakis N. Uncoupling hepatic insulin resistance - hepatic inflammation to improve insulin sensitivity and to prevent impaired metabolism-associated fatty liver disease in type 2 diabetes. Front Endocrinol (Lausanne) 2023; 14:1193373. [PMID: 37396181 PMCID: PMC10313404 DOI: 10.3389/fendo.2023.1193373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 06/01/2023] [Indexed: 07/04/2023] Open
Abstract
Diabetes mellitus is a metabolic disease clinically-characterized as acute and chronic hyperglycemia. It is emerging as one of the common conditions associated with incident liver disease in the US. The mechanism by which diabetes drives liver disease has become an intense topic of discussion and a highly sought-after therapeutic target. Insulin resistance (IR) appears early in the progression of type 2 diabetes (T2D), particularly in obese individuals. One of the co-morbid conditions of obesity-associated diabetes that is on the rise globally is referred to as non-alcoholic fatty liver disease (NAFLD). IR is one of a number of known and suspected mechanism that underlie the progression of NAFLD which concurrently exhibits hepatic inflammation, particularly enriched in cells of the innate arm of the immune system. In this review we focus on the known mechanisms that are suspected to play a role in the cause-effect relationship between hepatic IR and hepatic inflammation and its role in the progression of T2D-associated NAFLD. Uncoupling hepatic IR/hepatic inflammation may break an intra-hepatic vicious cycle, facilitating the attenuation or prevention of NAFLD with a concurrent restoration of physiologic glycemic control. As part of this review, we therefore also assess the potential of a number of existing and emerging therapeutic interventions that can target both conditions simultaneously as treatment options to break this cycle.
Collapse
Affiliation(s)
- Sitara Niranjan
- Department of Internal Medicine, Allegheny Health Network, Pittsburgh, PA, United States
| | - Brett E. Phillips
- Department of Internal Medicine, Allegheny Health Network, Pittsburgh, PA, United States
| | - Nick Giannoukakis
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
| |
Collapse
|
|
17
|
Zhang K, Yang C, Zhou X, Liang J, Guo J, Li M, Zhang Y, Shao S, Sun P, Li K, Huang J, Chen F, Liang X, Su D. TRIM21 ameliorates hepatic glucose and lipid metabolic disorders in type 2 diabetes mellitus by ubiquitination of PEPCK1 and FASN. Cell Mol Life Sci 2023; 80:168. [PMID: 37249651 DOI: 10.1007/s00018-023-04820-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 05/18/2023] [Accepted: 05/20/2023] [Indexed: 05/31/2023]
Abstract
Hepatic glucose and lipid metabolism disorders promote the development and progression of type 2 diabetes mellitus (T2DM), yet the underlying mechanisms are not fully understood. Here, we identify tripartite motif-containing protein 21 (TRIM21), a class IV TRIM family member, as a pivotal regulator of hepatic metabolism in T2DM for the first time. Bioinformatic analysis suggests that TRIM21 expression is significantly reduced in T2DM patients. Intriguingly, in a mouse model of obese diabetes, TRIM21 expression is predominantly reduced in the liver rather than in other metabolic organs. It is further demonstrated that hepatic overexpression of TRIM21 significantly ameliorates glucose intolerance, insulin resistance, hepatic steatosis, and dyslipidemia in obese diabetic mice. In contrast, the knockdown of TRIM21 promotes glucose intolerance, insulin resistance, and triglyceride accumulation. Mechanistically, both phosphoenolpyruvate carboxykinase 1 (PEPCK1) and fatty acid synthase (FASN) are the hepatic targets of TRIM21. We revealed that TRIM21 promotes the degradation of PEPCK1 and FASN through a direct protein-protein interaction mediated K48-linked ubiquitination. Notably, overexpression of PEPCK1 and FASN essentially abolished the beneficial effects achieved by TRIM21 overexpression in obese diabetic mice. Overall, our data demonstrate that TRIM21 is a novel regulator of hepatic metabolic disorder, and suggest TRIM21 as a promising therapeutic target for T2DM.
Collapse
Affiliation(s)
- Kaini Zhang
- Department of Pathophysiology, Nanjing Medical University, Nanjing, 211166, China
| | - Chen Yang
- Department of Pathology, Nanjing Medical University, Nanjing, 211166, China
| | - Xin Zhou
- Department of Pathophysiology, Nanjing Medical University, Nanjing, 211166, China
| | - Jin Liang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, China
| | - Jianjin Guo
- Department of General Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
- Department of General Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Min Li
- Department of Pathology, Nanjing Medical University, Nanjing, 211166, China
| | - Yi Zhang
- Department of Pathology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, 211800, China
| | - Shulin Shao
- Department of Laboratory, Nanjing Pukou Hospital of Traditional Chinese Medicine, Nanjing, 211800, China
| | - Peng Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, China
| | - Kai Li
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, China
| | - Jingjing Huang
- Department of Geriatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 211166, China
| | - Fang Chen
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, China.
| | - Xiubin Liang
- Department of Pathophysiology, Nanjing Medical University, Nanjing, 211166, China.
| | - Dongming Su
- Department of Pathology, Nanjing Medical University, Nanjing, 211166, China.
| |
Collapse
|
|
18
|
Hammerling U, Kim YK, Quadro L. Quantum chemistry rules retinoid biology. Commun Biol 2023; 6:227. [PMID: 36854887 PMCID: PMC9974979 DOI: 10.1038/s42003-023-04602-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 02/16/2023] [Indexed: 03/02/2023] Open
Abstract
This Perspective discusses how retinol catalyzes resonance energy transfer (RET) reactions pivotally important for mitochondrial energy homeostasis by protein kinase C δ (PKCδ). PKCδ signals to the pyruvate dehydrogenase complex, controlling oxidative phosphorylation. The PKCδ-retinol complex reversibly responds to the redox potential of cytochrome c, that changes with the electron transfer chain workload. In contrast, the natural retinoid anhydroretinol irreversibly activates PKCδ. Its elongated conjugated-double-bond system limits the energy quantum absorbed by RET. Consequently, while capable of triggering the exergonic activating pathway, anhydroretinol fails to activate the endergonic silencing path, trapping PKCδ in the ON position and causing harmful levels of reactive oxygen species. However, physiological retinol levels displace anhydroretinol, buffer cyotoxicity and potentially render anhydroretinol useful for rapid energy generation. Intriguingly, apocarotenoids, the primary products of the mitochondrial β-carotene,9'-10'-oxygenase, have all the anhydroretinol-like features, including modulation of energy homeostasis. We predict significant conceptual advances to stem from further understanding of the retinoid-catalyzed RET.
Collapse
Affiliation(s)
- Ulrich Hammerling
- Department of Food Science, Rutgers Center for Lipid Research and Institute of Food Nutrition and Health, Rutgers University, New Brunswick, NJ, USA.
| | - Youn-Kyung Kim
- Department of Food Science, Rutgers Center for Lipid Research and Institute of Food Nutrition and Health, Rutgers University, New Brunswick, NJ, USA
| | - Loredana Quadro
- Department of Food Science, Rutgers Center for Lipid Research and Institute of Food Nutrition and Health, Rutgers University, New Brunswick, NJ, USA.
| |
Collapse
|
|
19
|
Demaria TM, Crepaldi LD, Costa-Bartuli E, Branco JR, Zancan P, Sola-Penna M. Once a week consumption of Western diet over twelve weeks promotes sustained insulin resistance and non-alcoholic fat liver disease in C57BL/6 J mice. Sci Rep 2023; 13:3058. [PMID: 36810903 PMCID: PMC9942638 DOI: 10.1038/s41598-023-30254-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/20/2023] [Indexed: 02/24/2023] Open
Abstract
The Western diet (high in fat and sucrose) consumption is a highly prevalent feature in the whole world, mainly due to the increasing consumption of ultra-processed foods (UPF), which are cheaper and easier-to-eat, as compared to fresh and highly nutritive meals. Epidemiological studies have associated UPF consumption with development of obesity, non-alcoholic fat liver disease (NAFLD) and insulin resistance. For molecular studies, mice fed with Western diets have been used to characterize signaling pathways involved in these diet-induced pathologies. However, these studies fed mice continuously with the diets, which is not compatible with what occurs in real life, when consumption is occasional. Here, we fed mice once-a-week with a high fat, high sucrose (HFHS) diet and compared these animals with those fed continuously with HFHS diet or with a standard diet. Our results show that after a single day of consuming HFHS, animals presented impaired oral glucose tolerance test (oGTT) as compared to control group. Although this impairment was reversed after 24 h consuming regular diet, repetition of HFHS consumption once-a-week aggravated the picture such as after 12-weeks, oGTT impairment was not reversed after 6 days under control diet. Liver steatosis, inflammation, impaired insulin signaling pathway and endoplasmic reticulum stress are similar comparing animals that consumed HFHS once-a-week with those that continuously consumed HFHS, though weekly-fed animals did not gain as much weight. Therefore, we conclude that regimen of one day HFHS plus 6 days normal diet over 12 weeks is sufficient to induce insulin resistance and NAFLD in mice.
Collapse
Affiliation(s)
- Thainá Magalhães Demaria
- grid.8536.80000 0001 2294 473XThe Metabolizsm’ Group, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ 21941-902 Brazil
| | - Leticia Diniz Crepaldi
- grid.8536.80000 0001 2294 473XThe Metabolizsm’ Group, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ 21941-902 Brazil
| | - Emylle Costa-Bartuli
- grid.8536.80000 0001 2294 473XThe Metabolizsm’ Group, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ 21941-902 Brazil
| | - Jessica Ristow Branco
- grid.8536.80000 0001 2294 473XThe Metabolizsm’ Group, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ 21941-902 Brazil
| | - Patricia Zancan
- grid.8536.80000 0001 2294 473XThe Metabolizsm’ Group, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ 21941-902 Brazil
| | - Mauro Sola-Penna
- The Metabolizsm' Group, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.
| |
Collapse
|
|
20
|
Migliozzi S, Oh YT, Hasanain M, Garofano L, D'Angelo F, Najac RD, Picca A, Bielle F, Di Stefano AL, Lerond J, Sarkaria JN, Ceccarelli M, Sanson M, Lasorella A, Iavarone A. Integrative multi-omics networks identify PKCδ and DNA-PK as master kinases of glioblastoma subtypes and guide targeted cancer therapy. NATURE CANCER 2023; 4:181-202. [PMID: 36732634 PMCID: PMC9970878 DOI: 10.1038/s43018-022-00510-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 12/21/2022] [Indexed: 02/04/2023]
Abstract
Despite producing a panoply of potential cancer-specific targets, the proteogenomic characterization of human tumors has yet to demonstrate value for precision cancer medicine. Integrative multi-omics using a machine-learning network identified master kinases responsible for effecting phenotypic hallmarks of functional glioblastoma subtypes. In subtype-matched patient-derived models, we validated PKCδ and DNA-PK as master kinases of glycolytic/plurimetabolic and proliferative/progenitor subtypes, respectively, and qualified the kinases as potent and actionable glioblastoma subtype-specific therapeutic targets. Glioblastoma subtypes were associated with clinical and radiomics features, orthogonally validated by proteomics, phospho-proteomics, metabolomics, lipidomics and acetylomics analyses, and recapitulated in pediatric glioma, breast and lung squamous cell carcinoma, including subtype specificity of PKCδ and DNA-PK activity. We developed a probabilistic classification tool that performs optimally with RNA from frozen and paraffin-embedded tissues, which can be used to evaluate the association of therapeutic response with glioblastoma subtypes and to inform patient selection in prospective clinical trials.
Collapse
Affiliation(s)
- Simona Migliozzi
- Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Young Taek Oh
- Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Mohammad Hasanain
- Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Luciano Garofano
- Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Fulvio D'Angelo
- Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Ryan D Najac
- Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA
| | - Alberto Picca
- AP-HP, Hôpital de la Pitié-Salpêtrière, Service de Neurologie 2, Paris, France.,Sorbonne Université, INSERM Unité 1127, CNRS UMR 7225, Paris Brain Institute, Equipe labellissée LNCC, Paris, France
| | - Franck Bielle
- Sorbonne Université, INSERM Unité 1127, CNRS UMR 7225, Paris Brain Institute, Equipe labellissée LNCC, Paris, France.,Department of Neuropathology, Pitié-Salpêtrière-Charles Foix, AP-HP, Paris, France
| | - Anna Luisa Di Stefano
- Sorbonne Université, INSERM Unité 1127, CNRS UMR 7225, Paris Brain Institute, Equipe labellissée LNCC, Paris, France.,Department of Neurology, Foch Hospital, Suresnes, Paris, France.,Neurosurgery Unit, Spedali Riuniti, Livorno, Italy
| | - Julie Lerond
- Sorbonne Université, INSERM Unité 1127, CNRS UMR 7225, Paris Brain Institute, Equipe labellissée LNCC, Paris, France
| | - Jann N Sarkaria
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
| | - Michele Ceccarelli
- Department of Electrical Engineering and Information Technology (DIETI), University of Naples Federico II, Napoli, Italy.,BIOGEM Institute of Molecular Biology and Genetics, Via Camporeale, Ariano Irpino, Italy
| | - Marc Sanson
- AP-HP, Hôpital de la Pitié-Salpêtrière, Service de Neurologie 2, Paris, France.,Sorbonne Université, INSERM Unité 1127, CNRS UMR 7225, Paris Brain Institute, Equipe labellissée LNCC, Paris, France.,Onconeurotek Tumor Bank, Paris Brain Institute ICM, Paris, France
| | - Anna Lasorella
- Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA. .,Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA. .,Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA. .,Department of Pediatrics, Columbia University Medical Center, New York, NY, USA. .,Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA.
| | - Antonio Iavarone
- Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA. .,Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA. .,Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA. .,Department of Neurology, Columbia University Medical Center, New York, NY, USA. .,Department of Neurological Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA.
| |
Collapse
|
|
21
|
Nag A, Dhindsa RS, Mitchell J, Vasavda C, Harper AR, Vitsios D, Ahnmark A, Bilican B, Madeyski-Bengtson K, Zarrouki B, Zoghbi AW, Wang Q, Smith KR, Alegre-Díaz J, Kuri-Morales P, Berumen J, Tapia-Conyer R, Emberson J, Torres JM, Collins R, Smith DM, Challis B, Paul DS, Bohlooly-Y M, Snowden M, Baker D, Fritsche-Danielson R, Pangalos MN, Petrovski S. Human genetics uncovers MAP3K15 as an obesity-independent therapeutic target for diabetes. SCIENCE ADVANCES 2022; 8:eadd5430. [PMID: 36383675 PMCID: PMC9668288 DOI: 10.1126/sciadv.add5430] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 09/27/2022] [Indexed: 05/30/2023]
Abstract
We performed collapsing analyses on 454,796 UK Biobank (UKB) exomes to detect gene-level associations with diabetes. Recessive carriers of nonsynonymous variants in MAP3K15 were 30% less likely to develop diabetes (P = 5.7 × 10-10) and had lower glycosylated hemoglobin (β = -0.14 SD units, P = 1.1 × 10-24). These associations were independent of body mass index, suggesting protection against insulin resistance even in the setting of obesity. We replicated these findings in 96,811 Admixed Americans in the Mexico City Prospective Study (P < 0.05)Moreover, the protective effect of MAP3K15 variants was stronger in individuals who did not carry the Latino-enriched SLC16A11 risk haplotype (P = 6.0 × 10-4). Separately, we identified a Finnish-enriched MAP3K15 protein-truncating variant associated with decreased odds of both type 1 and type 2 diabetes (P < 0.05) in FinnGen. No adverse phenotypes were associated with protein-truncating MAP3K15 variants in the UKB, supporting this gene as a therapeutic target for diabetes.
Collapse
Affiliation(s)
- Abhishek Nag
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Ryan S. Dhindsa
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA, USA
| | - Jonathan Mitchell
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Chirag Vasavda
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA, USA
| | - Andrew R. Harper
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Dimitrios Vitsios
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Andrea Ahnmark
- Bioscience Metabolism, Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Bilada Bilican
- Discovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Katja Madeyski-Bengtson
- Discovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Bader Zarrouki
- Bioscience Metabolism, Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Anthony W. Zoghbi
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA, USA
| | - Quanli Wang
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA, USA
| | - Katherine R. Smith
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Jesus Alegre-Díaz
- Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Coyoacán, 4360 Ciudad de México, Mexico
| | - Pablo Kuri-Morales
- Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Coyoacán, 4360 Ciudad de México, Mexico
| | - Jaime Berumen
- Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Coyoacán, 4360 Ciudad de México, Mexico
| | - Roberto Tapia-Conyer
- Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Coyoacán, 4360 Ciudad de México, Mexico
| | - Jonathan Emberson
- Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, England, UK
| | - Jason M. Torres
- Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, England, UK
| | - Rory Collins
- Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, England, UK
| | - David M. Smith
- Emerging Innovations, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Benjamin Challis
- Translational Science and Experimental Medicine, Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Dirk S. Paul
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Mohammad Bohlooly-Y
- Discovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Mike Snowden
- Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - David Baker
- Bioscience Metabolism, Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | | | | | - Slavé Petrovski
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
- Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia
| |
Collapse
|
|
22
|
Haslem L, Hays JM, Hays FA. p66Shc in Cardiovascular Pathology. Cells 2022; 11:cells11111855. [PMID: 35681549 PMCID: PMC9180016 DOI: 10.3390/cells11111855] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/30/2022] [Accepted: 06/01/2022] [Indexed: 02/06/2023] Open
Abstract
p66Shc is a widely expressed protein that governs a variety of cardiovascular pathologies by generating, and exacerbating, pro-apoptotic ROS signals. Here, we review p66Shc’s connections to reactive oxygen species, expression, localization, and discuss p66Shc signaling and mitochondrial functions. Emphasis is placed on recent p66Shc mitochondrial function discoveries including structure/function relationships, ROS identity and regulation, mechanistic insights, and how p66Shc-cyt c interactions can influence p66Shc mitochondrial function. Based on recent findings, a new p66Shc mitochondrial function model is also put forth wherein p66Shc acts as a rheostat that can promote or antagonize apoptosis. A discussion of how the revised p66Shc model fits previous findings in p66Shc-mediated cardiovascular pathology follows.
Collapse
Affiliation(s)
- Landon Haslem
- Biochemistry and Molecular Biology Department, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.H.); (J.M.H.)
| | - Jennifer M. Hays
- Biochemistry and Molecular Biology Department, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.H.); (J.M.H.)
| | - Franklin A. Hays
- Biochemistry and Molecular Biology Department, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.H.); (J.M.H.)
- Stephenson Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Correspondence:
| |
Collapse
|
|
23
|
Proteomics and Phosphoproteomics of Circulating Extracellular Vesicles Provide New Insights into Diabetes Pathobiology. Int J Mol Sci 2022; 23:ijms23105779. [PMID: 35628588 PMCID: PMC9147902 DOI: 10.3390/ijms23105779] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 05/14/2022] [Accepted: 05/18/2022] [Indexed: 02/04/2023] Open
Abstract
The purpose of this study was to define the proteomic and phosphoproteomic landscape of circulating extracellular vesicles (EVs) in people with normal glucose tolerance (NGT), prediabetes (PDM), and diabetes (T2DM). Archived serum samples from 30 human subjects (n = 10 per group, ORIGINS study, NCT02226640) were used. EVs were isolated using EVtrap®. Mass spectrometry-based methods were used to detect the global EV proteome and phosphoproteome. Differentially expressed features, correlation, enriched pathways, and enriched tissue-specific protein sets were identified using custom R scripts. Phosphosite-centric analyses were conducted using directPA and PhosR software packages. A total of 2372 unique EV proteins and 716 unique EV phosphoproteins were identified among all samples. Unsupervised clustering of the differentially expressed (fold change ≥ 2, p < 0.05, FDR < 0.05) proteins and, particularly, phosphoproteins showed excellent discrimination among the three groups. CDK1 and PKCδ appear to drive key upstream phosphorylation events that define the phosphoproteomic signatures of PDM and T2DM. Circulating EVs from people with diabetes carry increased levels of specific phosphorylated kinases (i.e., AKT1, GSK3B, LYN, MAP2K2, MYLK, and PRKCD) and could potentially distribute activated kinases systemically. Among characteristic changes in the PDM and T2DM EVs, “integrin switching” appeared to be a central feature. Proteins involved in oxidative phosphorylation (OXPHOS), known to be reduced in various tissues in diabetes, were significantly increased in EVs from PDM and T2DM, which suggests that an abnormally elevated EV-mediated secretion of OXPHOS components may underlie the development of diabetes. A highly enriched signature of liver-specific markers among the downregulated EV proteins and phosphoproteins in both PDM and T2DM groups was also detected. This suggests that an alteration in liver EV composition and/or secretion may occur early in prediabetes. This study identified EV proteomic and phosphoproteomic signatures in people with prediabetes and T2DM and provides novel insight into the pathobiology of diabetes.
Collapse
|
|
24
|
Recombinant humanized IgG1 maintain liver triglyceride homeostasis through Arylacetamide deacetylase in ApoE -/- mice. Int Immunopharmacol 2022; 108:108741. [PMID: 35397394 DOI: 10.1016/j.intimp.2022.108741] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 03/11/2022] [Accepted: 03/28/2022] [Indexed: 11/21/2022]
Abstract
BACKGROUND & AIMS Hyperlipidemia is a lipid metabolism disorder associated with elevated serum triglyceride (TG) and/or cholesterol. Over the years, studies have shown that hyperlipidemia is associated with combordities, incluing diabetes and obesity, gradually becoming a public health concern. Current treatment approaches remain limited due to the lack of effective drugs. Here we investigated the function of recombinant humanized IgG1 in maintaining liver TG homeostasis and the underlying mechanisms. METHODS ApoE-/- mice were fed a high-fat diet (HFD) for 20 weeks to induce hyperlipidemia. RNA sequencing (RNA-Seq) was performed to identify differences in gene expression in different groups of ApoE-/- mice liver. In vitro lipid accumulation in primary mouse hepatocytes was induced using a free fatty acid (FFA) mixture. Gene and protein expression were assessed in primary mouse hepatocytes by qPCR and Western blot. Gene reporter assays and ChIP-PCR were used to determine arylacetamide deacetylase (Aadac) promoter activity. RESULTS Recombinant humanized IgG1 could significantly decrease the serum level of TG and low-density lipoproteins (LDL-C). Moreover, hepatic TG and lipid droplets were also reduced compared to the HFD group. Mouse liver RNA-Seq revealed that administration of recombinant humanized IgG1 significantly elevated the expression of Aadac. In vitro, knock-down of Aadac could nullify the effect of recombinant humanized IgG1 on decreasing the lipid droplets induced by FFA in primary mouse hepatocytes. Gene Reporter assays and ChIP-PCR demonstrated that the foxa1 response element in the Aadac promoter played a key role in Aadac expression induced by recombinant humanized IgG1. Moreover, recombinant humanized IgG1 repressed phosphorylation of PKCδ and resulted in foxa1 elevation. Finally, neonatal Fc receptor (FcRn) knock-down reversed the effect of recombinant humanized IgG1 on the expression of PKCδ phosphorylation, foxa1 and Aadac. CONCLUSIONS Our findings suggest that recombinant humanized IgG1 plays an important role in maintaining liver TG homeostasis via the FcRn/PKCδ/foxa1/Aadac pathway.
Collapse
|
|
25
|
Mahmoudi A, Butler AE, Majeed M, Banach M, Sahebkar A. Investigation of the Effect of Curcumin on Protein Targets in NAFLD Using Bioinformatic Analysis. Nutrients 2022; 14:1331. [PMID: 35405942 PMCID: PMC9002953 DOI: 10.3390/nu14071331] [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: 02/04/2022] [Revised: 03/15/2022] [Accepted: 03/21/2022] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder. Defects in function/expression of genes/proteins are critical in initiation/progression of NAFLD. Natural products may modulate these genes/proteins. Curcumin improves steatosis, inflammation, and fibrosis progression. Here, bioinformatic tools, gene−drug and gene-disease databases were utilized to explore targets, interactions, and pathways through which curcumin could impact NAFLD. METHODS: Significant curcumin−protein interaction was identified (high-confidence:0.7) in the STITCH database. Identified proteins were investigated to determine association with NAFLD. gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were analyzed for significantly involved targets (p < 0.01). Specificity of obtained targets with NAFLD was estimated and investigated in Tissue/Cells−gene associations (PanglaoDB Augmented 2021, Mouse Gene Atlas) and Disease−gene association-based EnrichR algorithms (Jensen DISEASES, DisGeNET). RESULTS: Two collections were constructed: 227 protein−curcumin interactions and 95 NAFLD-associated genes. By Venn diagram, 14 significant targets were identified, and their biological pathways evaluated. Based on gene ontology, most targets involved stress and lipid metabolism. KEGG revealed chemical carcinogenesis, the AGE-RAGE signaling pathway in diabetic complications and NAFLD as the most common significant pathways. Specificity to diseases database (EnrichR algorithm) revealed specificity for steatosis/steatohepatitis. CONCLUSION: Curcumin may improve, or inhibit, progression of NAFLD through activation/inhibition of NAFLD-related genes.
Collapse
Affiliation(s)
- Ali Mahmoudi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 9177899191, Iran;
| | - Alexandra E. Butler
- Research Department, Royal College of Surgeons in Ireland Bahrain, Adliya 15503, Bahrain;
| | | | - Maciej Banach
- Nephrology and Hypertension, Department of Preventive Cardiology and Lipidology, Medical University of Lodz, 93-338 Lodz, Poland
- Cardiovascular Research Centre, University of Zielona Gora, 65-417 Zielona Gora, Poland
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 9177899191, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad 9177899191, Iran
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 9177899191, Iran
| |
Collapse
|
|
26
|
Adipogenesis of ear mesenchymal stem cells (EMSCs): adipose biomarker-based assessment of genetic variation, adipocyte function, and brown/brite differentiation. Mol Cell Biochem 2022; 477:1053-1063. [PMID: 34997885 DOI: 10.1007/s11010-021-04350-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 12/23/2021] [Indexed: 10/19/2022]
Abstract
Ear mesenchymal stem cells (EMSCs) have been investigated to differentiate into adipocytes, chondrocytes, and muscle cells in vitro. However, the factors controlling adipogenesis of this stem cell population in vitro, function, and type of adipocytes raised from them are still unclear. Here we found that genetics have a modest effect on adipogenic capacity of EMSCs. Adipocytes differentiated from EMSCs have a potential function in lipid metabolism as indicated by expression of lipogenic genes and this function of EMSC adipocytes is regulated by genetics. EMSCs failed to be differentiated into brite/brown adipocytes due to their lack of a thermogenic program, but adipocytes raised from EMSCs showed a fate of white adipocytes. Overall, our data suggest that EMSCs differentiate into functional white adipocytes in vitro and this is genetic-dependent.
Collapse
|
|
27
|
Mastrototaro L, Roden M. Insulin resistance and insulin sensitizing agents. Metabolism 2021; 125:154892. [PMID: 34563556 DOI: 10.1016/j.metabol.2021.154892] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 09/08/2021] [Accepted: 09/20/2021] [Indexed: 02/06/2023]
Abstract
Insulin resistance is a common feature of obesity and type 2 diabetes, but novel approaches of diabetes subtyping (clustering) revealed variable degrees of insulin resistance in people with diabetes. Specifically, the severe insulin resistant diabetes (SIRD) subtype not only exhibits metabolic abnormalities, but also bears a higher risk for cardiovascular, renal and hepatic comorbidities. In humans, insulin resistance comprises dysfunctional adipose tissue, lipotoxic insulin signaling followed by glucotoxicity, oxidative stress and low-grade inflammation. Recent studies show that aside from metabolites (free fatty acids, amino acids) and signaling proteins (myokines, adipokines, hepatokines) also exosomes with their cargo (proteins, mRNA and microRNA) contribute to altered crosstalk between skeletal muscle, liver and adipose tissue during the development of insulin resistance. Reduction of fat mass mainly, but not exclusively, explains the success of lifestyle modification and bariatric surgery to improve insulin sensitivity. Moreover, some older antihyperglycemic drugs (metformin, thiazolidinediones), but also novel therapeutic concepts (new peroxisome proliferator-activated receptor agonists, incretin mimetics, sodium glucose cotransporter inhibitors, modulators of energy metabolism) can directly or indirectly reduce insulin resistance. This review summarizes molecular mechanisms underlying insulin resistance including the roles of exosomes and microRNAs, as well as strategies for the management of insulin resistance in humans.
Collapse
Affiliation(s)
- Lucia Mastrototaro
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
| |
Collapse
|
|
28
|
Shu Y, Hassan F, Ostrowski MC, Mehta KD. Role of hepatic PKCβ in nutritional regulation of hepatic glycogen synthesis. JCI Insight 2021; 6:149023. [PMID: 34622807 PMCID: PMC8525638 DOI: 10.1172/jci.insight.149023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 08/12/2021] [Indexed: 01/12/2023] Open
Abstract
The signaling mechanisms by which dietary fat and cholesterol signals regulate central pathways of glucose homeostasis are not completely understood. By using a hepatocyte-specific PKCβ-deficient (PKCβHep-/-) mouse model, we demonstrated the role of hepatic PKCβ in slowing disposal of glucose overload by suppressing glycogenesis and increasing hepatic glucose output. PKCβHep-/- mice exhibited lower plasma glucose under the fed condition, modestly improved systemic glucose tolerance and mildly suppressed gluconeogenesis, increased hepatic glycogen accumulation and synthesis due to elevated glucokinase expression and activated glycogen synthase (GS), and suppressed glucose-6-phosphatase expression compared with controls. These events were independent of hepatic AKT/GSK-3α/β signaling and were accompanied by increased HNF-4α transactivation, reduced FoxO1 protein abundance, and elevated expression of GS targeting protein phosphatase 1 regulatory subunit 3C in the PKCβHep-/- liver compared with controls. The above data strongly imply that hepatic PKCβ deficiency causes hypoglycemia postprandially by promoting glucose phosphorylation via upregulating glucokinase and subsequently redirecting more glucose-6-phosphate to glycogen via activating GS. In summary, hepatic PKCβ has a unique and essential ability to induce a coordinated response that negatively affects glycogenesis at multiple levels under physiological postprandial conditions, thereby integrating nutritional fat intake with dysregulation of glucose homeostasis.
Collapse
Affiliation(s)
- Yaoling Shu
- Department of Biological Chemistry & Pharmacology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Faizule Hassan
- Department of Biological Chemistry & Pharmacology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Michael C Ostrowski
- Department of Biochemistry & Molecular Biology, Holling Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Kamal D Mehta
- Department of Biological Chemistry & Pharmacology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.,Instacare Therapeutics, Dublin, Ohio, USA
| |
Collapse
|
|
29
|
Nawrot M, Peschard S, Lestavel S, Staels B. Intestine-liver crosstalk in Type 2 Diabetes and non-alcoholic fatty liver disease. Metabolism 2021; 123:154844. [PMID: 34343577 DOI: 10.1016/j.metabol.2021.154844] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 02/08/2023]
Abstract
Type 2 diabetes (T2D) and Non-Alcoholic Fatty Liver Disease (NAFLD) are pathologies whose prevalence continues to increase worldwide. Both diseases are precipitated by an excessive caloric intake, which promotes insulin resistance and fatty liver. The role of the intestine and its crosstalk with the liver in the development of these metabolic diseases is receiving increasing attention. Alterations in diet-intestinal microbiota interactions lead to the dysregulation of intestinal functions, resulting in altered metabolite and energy substrate production and increased intestinal permeability. Connected through the portal circulation, these changes in intestinal functions impact the liver and other metabolic organs, such as visceral adipose tissue, hence participating in the development of insulin resistance, and worsening T2D and NAFLD. Thus, targeting the intestine may be an efficient therapeutic approach to cure T2D and NAFLD. In this review, we will first introduce the signaling pathways linking T2D and NAFLD. Next, we will address the role of the gut-liver crosstalk in the development of T2D and NAFLD, with a particular focus on the gut microbiota and the molecular pathways behind the increased intestinal permeability and inflammation. Finally, we will summarize the therapeutic strategies which target the gut and its functions and are currently used or under development to treat T2D and NAFLD.
Collapse
Affiliation(s)
- Margaux Nawrot
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France
| | - Simon Peschard
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France
| | - Sophie Lestavel
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France
| | - Bart Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France.
| |
Collapse
|
|
30
|
Lien CF, Chen SJ, Tsai MC, Lin CS. Potential Role of Protein Kinase C in the Pathophysiology of Diabetes-Associated Atherosclerosis. Front Pharmacol 2021; 12:716332. [PMID: 34276388 PMCID: PMC8283198 DOI: 10.3389/fphar.2021.716332] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 06/22/2021] [Indexed: 12/13/2022] Open
Abstract
Diabetes mellitus is a metabolic syndrome that affects millions of people worldwide. Recent studies have demonstrated that protein kinase C (PKC) activation plays an important role in hyperglycemia-induced atherosclerosis. PKC activation is involved in several cellular responses such as the expression of various growth factors, activation of signaling pathways, and enhancement of oxidative stress in hyperglycemia. However, the role of PKC activation in pro-atherogenic and anti-atherogenic mechanisms remains controversial, especially under hyperglycemic condition. In this review, we discuss the role of different PKC isoforms in lipid regulation, oxidative stress, inflammatory response, and apoptosis. These intracellular events are linked to the pathogenesis of atherosclerosis in diabetes. PKC deletion or treatment with PKC inhibitors has been studied in the regulation of atherosclerotic plaque formation and evolution. Furthermore, some preclinical and clinical studies have indicated that PKCβ and PKCδ are potential targets for the treatment of diabetic vascular complications. The current review summarizes these multiple signaling pathways and cellular responses regulated by PKC activation and the potential therapeutic targets of PKC in diabetic complications.
Collapse
Affiliation(s)
- Chih-Feng Lien
- Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Sy-Jou Chen
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Min-Chien Tsai
- Department of Physiology and Biophysics, Graduate Institute of Physiology, National Defense Medical Center, Taipei, Taiwan
| | - Chin-Sheng Lin
- Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| |
Collapse
|
|
31
|
Feng L, Wang S, Chen F, Zhang C, Wang Q, Zhao Y, Zhang Z. Hepatic Knockdown of Endothelin Type A Receptor (ETAR) Ameliorates Hepatic Insulin Resistance and Hyperglycemia Through Suppressing p66Shc-Mediated Mitochondrial Fragmentation in High-Fat Diet-Fed Mice. Diabetes Metab Syndr Obes 2021; 14:963-981. [PMID: 33688230 PMCID: PMC7936928 DOI: 10.2147/dmso.s299570] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 02/23/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Emerging evidence from animal studies and clinical trials indicates that systemic inhibition of endothelin1 (ET1) signaling by endothelin receptor antagonists improves pathological features of diabetes and its complications. It is indicated that endothelin type A receptor (ETAR) plays a major role in ET1-mediated pathophysiological actions including diabetic pathology. However, the effects as well as the mechanistic targets of hepatic ET1/ETAR signaling inhibition on the pathology of metabolic diseases remain unclear. This study aimed to investigate the beneficial effects as well as the underlying mechanisms of hepatic ETAR knockdown on metabolism abnormalities in high-fat diet (HFD)-fed mice. METHODS Mice were fed a HFD to induce insulin resistance and metabolism abnormalities. L02 cells were treated with ET1 to assess the action of ET1/ETAR signaling in vitro. Liver-selective knockdown of ETAR was achieved by tail vein injection of adeno-associated virus 8 (AAV8). Systemic and peripheral metabolism abnormalities were determined in vivo and in vitro. Mitochondrial fragmentation was observed by transmission electron microscope (TEM) and mitoTracker red staining. RESULTS Here we provided in vivo and in vitro evidence to demonstrate that liver-selective knockdown of ETAR effectively ameliorated hepatic insulin resistance and hyperglycemia in HFD-fed mice. Mechanistically, hepatic ETAR knockdown alleviated mitochondrial fragmentation and dysfunction via inactivating 66-kDa Src homology 2 domain-containing protein (p66Shc) to recover mitochondrial dynamics, which was mediated by inhibiting protein kinase Cδ (PKCδ), in the livers of HFD-fed mice. Ultimately, hepatic ETAR knockdown attenuated mitochondria-derived oxidative stress and related liver injuries in HFD-fed mice. These ETAR knockdown-mediated actions were confirmed in ET1-treated L02 cells. CONCLUSION This study defined an ameliorative role of hepatic ETAR knockdown in HFD-induced metabolism abnormalities by alleviating p66Shc-mediated mitochondrial fragmentation and consequent oxidative stress-related disorders and indicated that hepatic ETAR knockdown may be a promising therapeutic strategy for metabolic diseases.
Collapse
Affiliation(s)
- Li Feng
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China
| | - Songhua Wang
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China
| | - Feng Chen
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China
| | - Cheng Zhang
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China
| | - Qiao Wang
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China
| | - Yuting Zhao
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China
| | - Zifeng Zhang
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China
- Correspondence: Zifeng Zhang 101 Shanghai Road, Xuzhou, Jiangsu Province, 221116, People’s Republic of ChinaTel + 86 516 83403729 Email
| |
Collapse
|
|
32
|
Yang M, Chen Z, Xiang S, Xia F, Tang W, Yao X, Zhou B. Hugan Qingzhi medication ameliorates free fatty acid-induced L02 hepatocyte endoplasmic reticulum stress by regulating the activation of PKC-δ. BMC Complement Med Ther 2020; 20:377. [PMID: 33308192 PMCID: PMC7730760 DOI: 10.1186/s12906-020-03164-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 11/23/2020] [Indexed: 12/16/2022] Open
Abstract
Background Previous studies have found that Hugan Qingzhi tablet (HQT) has significant lipid-lowering and antioxidant effects on non-alcoholic fatty liver disease (NAFLD). Moreover, the results of proteomic analysis confirmed that various proteins in endoplasmic reticulum stress (ERS) pathway were activated and recovered by HQT. However, its mechanism remains confused. The purpose of this study was to explore the effects of HQT-medicated serum on hepatic ERS and its relevant mechanisms. Methods L02 cells were induced by Free Fatty Acid (FFA) for 24 h to establish a model of hepatic ERS and pretreated with the drug-medicated rat serum for 24 h. Accumulation of intracellular lipid was evaluated using Oil Red O staining and Triglyceride detection kit. The morphological changes of ER were observed by TEM. PKC-δ was silenced by specific siRNA. Western blot and RT-qPCR were applied to detect the expression of markers related to ERS, calcium disorder, steatosis and insulin resistance. The fluorescence of Ca2+ influx was recorded using fluorescence spectrophotometer. Results HQT-medicated serum significantly decreased the intracellular TG content. Furthermore, it caused significant reduction in the expression of ERS markers and an improvement in ER structure of L02 cells. PKC-δ was activated into phosphorylated PKC-δ in FFA-induced L02 hepatocytes while these changes can be reversed by HQT-medicated serum. Silencing PKC-δ in L02 cells can restore the expression and activity of SERCA2 in ER and down-regulate the expression of IP3R protein to maintain intracellular calcium homeostasis, so as to relieve FFA-induced ERS and its lipid accumulation and insulin resistance. Conclusions The results concluded that HQT-medicated serum exerts protective effects against hepatic ERS, steatosis and insulin resistance in FFA-induced L02 hepatocyte. And its potential mechanism might be down-regulating the activation of PKC-δ and stabilization of intracellular calcium. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-020-03164-3.
Collapse
Affiliation(s)
- Miaoting Yang
- Department of Pharmacy, People's Hospital of Longhua, Shenzhen, 518109, Guangdong, China
| | - Zhijuan Chen
- Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Shijian Xiang
- Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Fan Xia
- Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Waijiao Tang
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Xiaorui Yao
- Department of Pharmacy, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen University, Shantou, 515041, Guangdong, China
| | - Benjie Zhou
- Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.
| |
Collapse
|
|
33
|
Batista TM, Jayavelu AK, Wewer Albrechtsen NJ, Iovino S, Lebastchi J, Pan H, Dreyfuss JM, Krook A, Zierath JR, Mann M, Kahn CR. A Cell-Autonomous Signature of Dysregulated Protein Phosphorylation Underlies Muscle Insulin Resistance in Type 2 Diabetes. Cell Metab 2020; 32:844-859.e5. [PMID: 32888406 PMCID: PMC7875546 DOI: 10.1016/j.cmet.2020.08.007] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 05/26/2020] [Accepted: 08/11/2020] [Indexed: 02/06/2023]
Abstract
Skeletal muscle insulin resistance is the earliest defect in type 2 diabetes (T2D), preceding and predicting disease development. To what extent this reflects a primary defect or is secondary to tissue cross talk due to changes in hormones or circulating metabolites is unknown. To address this question, we have developed an in vitro disease-in-a-dish model using iPS cells from T2D patients differentiated into myoblasts (iMyos). We find that T2D iMyos in culture exhibit multiple defects mirroring human disease, including an altered insulin signaling, decreased insulin-stimulated glucose uptake, and reduced mitochondrial oxidation. More strikingly, global phosphoproteomic analysis reveals a multidimensional network of signaling defects in T2D iMyos going beyond the canonical insulin-signaling cascade, including proteins involved in regulation of Rho GTPases, mRNA splicing and/or processing, vesicular trafficking, gene transcription, and chromatin remodeling. These cell-autonomous defects and the dysregulated network of protein phosphorylation reveal a new dimension in the cellular mechanisms underlying the fundamental defects in T2D.
Collapse
Affiliation(s)
- Thiago M Batista
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - Ashok Kumar Jayavelu
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany
| | - Nicolai J Wewer Albrechtsen
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark; Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark
| | - Salvatore Iovino
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - Jasmin Lebastchi
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - Hui Pan
- Bioinformatics and Biostatistics Core, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - Jonathan M Dreyfuss
- Bioinformatics and Biostatistics Core, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - Anna Krook
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 171 77, Sweden
| | - Juleen R Zierath
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark; Section of Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 171 76, Sweden
| | - Matthias Mann
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - C Ronald Kahn
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
| |
Collapse
|
|
34
|
Kim YK, Hammerling U. The mitochondrial PKCδ/retinol signal complex exerts real-time control on energy homeostasis. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158614. [PMID: 31927141 PMCID: PMC7347429 DOI: 10.1016/j.bbalip.2020.158614] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 01/03/2020] [Accepted: 01/04/2020] [Indexed: 12/17/2022]
Abstract
The review focuses on the role of vitamin A (retinol) in the control of energy homeostasis, and on the manner in which certain retinoids subvert this process, leading potentially to disease. In eukaryotic cells, the pyruvate dehydrogenase complex (PDHC) is negatively regulated by four pyruvate dehydrogenase kinases (PDKs) and two antagonistically acting pyruvate dehydrogenase phosphatases (PDPs). The second isoform, PDK2, is regulated by an autonomous mitochondrial signal cascade that is anchored on protein kinase Cδ (PKCδ), where retinoids play an indispensible co-factor role. Along with its companion proteins p66Shc, cytochrome c, and vitamin A, the PKCδ/retinol complex is located in the intermembrane space of mitochondria. At this site, and in contrast to cytosolic locations, PKCδ is activated by the site-specific oxidation of its cysteine-rich activation domain (CRD) that is configured into a complex RING-finger. Oxidation involves the transfer of electrons from cysteine moieties to oxidized cytochrome c, a step catalyzed by vitamin A. The PKCδ/retinol signalosome monitors the internal cytochrome c redox state that reflects the workload of the respiratory chain. Upon sensing demands for energy PKCδ signals the PDHC to increase glucose-derived fuel flux entering the KREBS cycle. Conversely, if excessive fuel flux surpasses the capacity of the respiratory chain, threatening the release of damaging reactive oxygen species (ROS), the polarity of the cytochrome c redox system is reversed, resulting in the chemical reduction of the PKCδ CRD, restoration of the RING-finger, refolding of PKCδ into the inactive, globular form, and curtailment of PDHC output, thereby constraining the respiratory capacity within safe margins. Several retinoids, notably anhydroretinol and fenretinide, capable of displacing retinol from binding sites on PKCδ, can co-activate PKCδ signaling but, owing to their extended system of conjugated double bonds, are unable to silence PKCδ in a timely manner. Left in the ON position, PKCδ causes chronic overload of the respiratory chain leading to mitochondrial dysfunction. This review explores how defects in the PKCδ signal machinery potentially contribute to metabolic and degenerative diseases.
Collapse
Affiliation(s)
- Youn-Kyung Kim
- Food Science Department, Rutgers Center for Lipid Research and Institute of Food Nutrition and Health, Rutgers University, New Brunswick, NJ, USA
| | - Ulrich Hammerling
- Food Science Department, Rutgers Center for Lipid Research and Institute of Food Nutrition and Health, Rutgers University, New Brunswick, NJ, USA.
| |
Collapse
|
|
35
|
Kolczynska K, Loza-Valdes A, Hawro I, Sumara G. Diacylglycerol-evoked activation of PKC and PKD isoforms in regulation of glucose and lipid metabolism: a review. Lipids Health Dis 2020; 19:113. [PMID: 32466765 PMCID: PMC7257441 DOI: 10.1186/s12944-020-01286-8] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 05/14/2020] [Indexed: 12/15/2022] Open
Abstract
Protein kinase C (PKC) and Protein kinase D (PKD) isoforms can sense diacylglycerol (DAG) generated in the different cellular compartments in various physiological processes. DAG accumulates in multiple organs of the obese subjects, which leads to the disruption of metabolic homeostasis and the development of diabetes as well as associated diseases. Multiple studies proved that aberrant activation of PKCs and PKDs contributes to the development of metabolic diseases. DAG-sensing PKC and PKD isoforms play a crucial role in the regulation of metabolic homeostasis and therefore might serve as targets for the treatment of metabolic disorders such as obesity and diabetes.
Collapse
Affiliation(s)
- Katarzyna Kolczynska
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093, Warszawa, Poland
| | - Angel Loza-Valdes
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093, Warszawa, Poland
| | - Izabela Hawro
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093, Warszawa, Poland
| | - Grzegorz Sumara
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093, Warszawa, Poland.
| |
Collapse
|
|
36
|
Schmitz-Peiffer C. Deconstructing the Role of PKC Epsilon in Glucose Homeostasis. Trends Endocrinol Metab 2020; 31:344-356. [PMID: 32305097 DOI: 10.1016/j.tem.2020.01.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 01/22/2020] [Accepted: 01/24/2020] [Indexed: 02/06/2023]
Abstract
The failure of insulin to suppress glucose production by the liver is a key aspect of the insulin resistance seen in type 2 diabetes. Lipid-activated protein kinase C epsilon has long been identified as an important mediator of diet-induced glucose intolerance and hepatic insulin resistance and the current view emphasizes a mechanism involving phosphorylation of the insulin receptor by the kinase to inhibit downstream insulin action. However, the significance of this direct effect in the liver has now been challenged by tissue-specific deletion of PKCε, which demonstrated a more prominent role for the kinase in adipose tissue to promote glucose intolerance. New insights regarding the role of PKCε therefore contribute to the understanding of indirect effects on hepatic glucose metabolism.
Collapse
Affiliation(s)
- Carsten Schmitz-Peiffer
- Garvan Institute of Medical Research, Darlinghurst Sydney, NSW 2010, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW 2010, Australia.
| |
Collapse
|
|
37
|
Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes. Cells 2020; 9:cells9030706. [PMID: 32183037 PMCID: PMC7140703 DOI: 10.3390/cells9030706] [Citation(s) in RCA: 145] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/16/2020] [Accepted: 03/11/2020] [Indexed: 12/13/2022] Open
Abstract
Obesity has been described as a global epidemic and is a low-grade chronic inflammatory disease that arises as a consequence of energy imbalance. Obesity increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely clarified. Elevated circulating pro-inflammatory cytokines and free fatty acids (FFA) during obesity cause insulin resistance and ß-cell dysfunction, the two main features of T2D, which are both aggravated with the progressive development of hyperglycemia. The inflammatory kinase c-jun N-terminal kinase (JNK) responds to various cellular stress signals activated by cytokines, free fatty acids and hyperglycemia, and is a key mediator in the transition between obesity and T2D. Specifically, JNK mediates both insulin resistance and ß-cell dysfunction, and is therefore a potential target for T2D therapy.
Collapse
|
|
38
|
Excess Accumulation of Lipid Impairs Insulin Sensitivity in Skeletal Muscle. Int J Mol Sci 2020; 21:ijms21061949. [PMID: 32178449 PMCID: PMC7139950 DOI: 10.3390/ijms21061949] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/09/2020] [Accepted: 03/10/2020] [Indexed: 12/12/2022] Open
Abstract
Both glucose and free fatty acids (FFAs) are used as fuel sources for energy production in a living organism. Compelling evidence supports a role for excess fatty acids synthesized in intramuscular space or dietary intermediates in the regulation of skeletal muscle function. Excess FFA and lipid droplets leads to intramuscular accumulation of lipid intermediates. The resulting downregulation of the insulin signaling cascade prevents the translocation of glucose transporter to the plasma membrane and glucose uptake into skeletal muscle, leading to metabolic disorders such as type 2 diabetes. The mechanisms underlining metabolic dysfunction in skeletal muscle include accumulation of intracellular lipid derivatives from elevated plasma FFAs. This paper provides a review of the molecular mechanisms underlying insulin-related signaling pathways after excess accumulation of lipids.
Collapse
|
|
39
|
Ren J, Zhou T, Pilli VSS, Phan N, Wang Q, Gupta K, Liu Z, Sheibani N, Liu B. Novel Paracrine Functions of Smooth Muscle Cells in Supporting Endothelial Regeneration Following Arterial Injury. Circ Res 2020; 124:1253-1265. [PMID: 30739581 DOI: 10.1161/circresaha.118.314567] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
RATIONALE Regeneration of denuded or injured endothelium is an important component of vascular injury response. Cell-cell communication between endothelial cells and smooth muscle cells (SMCs) plays a critical role not only in vascular homeostasis but also in disease. We have previously demonstrated that PKCδ (protein kinase C-delta) regulates multiple components of vascular injury response including apoptosis of SMCs and production of chemokines, thus is an attractive candidate for a role in SMC-endothelial cells communication. OBJECTIVE To test whether PKCδ-mediated paracrine functions of SMCs influence reendothelialization in rodent models of arterial injury. METHODS AND RESULTS Femoral artery wire injury was performed in SMC-conditional Prkcd knockout mice, and carotid angioplasty was conducted in rats receiving transient Prkcd knockdown or overexpression. SMC-specific knockout of Prkcd impaired reendothelialization, reflected by a smaller Evans blue-excluding area in the knockout compared with the wild-type controls. A similar impediment to reendothelialization was observed in rats with SMC-specific knockdown of Prkcd. In contrast, SMC-specific gene transfer of Prkcd accelerated reendothelialization. In vitro, medium conditioned by AdPKCδ-infected SMCs increased endothelial wound closure without affecting their proliferation. A polymerase chain reaction-based array analysis identified Cxcl1 and Cxcl7 among others as PKCδ-mediated chemokines produced by SMCs. Mechanistically, we postulated that PKCδ regulates Cxcl7 expression through STAT3 (signal transducer and activator of transcription 3) as knockdown of STAT3 abolished Cxcl7 expression. The role of CXCL7 in SMC-endothelial cells communication was demonstrated by blocking CXCL7 or its receptor CXCR2, both significantly inhibited endothelial wound closure. Furthermore, insertion of a Cxcl7 cDNA in the lentiviral vector that carries a Prkcd shRNA overcame the adverse effects of Prkcd knockdown on reendothelialization. CONCLUSIONS SMCs promote reendothelialization in a PKCδ-dependent paracrine mechanism, likely through CXCL7-mediated recruitment of endothelial cells from uninjured endothelium.
Collapse
Affiliation(s)
- Jun Ren
- From the Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison (J.R., T.Z., V.S.S.P., N.P., Q.W., K.G., Z.L., B.L.)
| | - Ting Zhou
- From the Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison (J.R., T.Z., V.S.S.P., N.P., Q.W., K.G., Z.L., B.L.)
| | - Vijaya Satish Sekhar Pilli
- From the Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison (J.R., T.Z., V.S.S.P., N.P., Q.W., K.G., Z.L., B.L.)
| | - Noel Phan
- From the Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison (J.R., T.Z., V.S.S.P., N.P., Q.W., K.G., Z.L., B.L.)
| | - Qiwei Wang
- From the Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison (J.R., T.Z., V.S.S.P., N.P., Q.W., K.G., Z.L., B.L.)
| | - Kartik Gupta
- From the Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison (J.R., T.Z., V.S.S.P., N.P., Q.W., K.G., Z.L., B.L.)
| | - Zhenjie Liu
- From the Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison (J.R., T.Z., V.S.S.P., N.P., Q.W., K.G., Z.L., B.L.).,Department of Vascular Surgery, 2nd Affiliated Hospital School of Medicine, Zhejiang University (Z.L.)
| | - Nader Sheibani
- Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison (N.S.)
| | - Bo Liu
- From the Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison (J.R., T.Z., V.S.S.P., N.P., Q.W., K.G., Z.L., B.L.)
| |
Collapse
|
|
40
|
Accuracy of proton magnetic resonance for diagnosing non-alcoholic steatohepatitis: a meta-analysis. Sci Rep 2019; 9:15002. [PMID: 31628409 PMCID: PMC6802098 DOI: 10.1038/s41598-019-51302-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 09/28/2019] [Indexed: 12/19/2022] Open
Abstract
Liver biopsy is the reference standard test to differentiate between non-alcoholic steatohepatitis (NASH) and simple steatosis (SS) in non-alcoholic fatty liver disease (NAFLD), but noninvasive diagnostics are warranted. The diagnostic accuracy in NASH using MR imaging modality have not yet been clearly identified. This study was assessed the accuracy of magnetic resonance imaging (MRI) method for diagnosing NASH. Data were extracted from research articles obtained after a literature search from multiple electronic databases. Random-effects meta-analyses were performed to obtain overall effect size of the area under the receiver operating characteristic(ROC) curve, sensitivity, specificity, likelihood ratios(LR), diagnostic odds ratio(DOR) of MRI method in detecting histopathologically-proven SS(or non-NASH) and NASH. Seven studies were analyzed 485 patients, which included 207 SS and 278 NASH. The pooled sensitivity was 87.4% (95% CI, 76.4–95.3) and specificity was 74.3% (95% CI, 62.4–84.6). Pooled positive LR was 2.59 (95% CI, 1.96–3.42) and negative LR was 0.17 (95% CI, 0.07–0.38). DOR was 21.57 (95% CI, 7.27–63.99). The area under the curve of summary ROC was 0.89. Our meta-analysis shows that the MRI-based diagnostic methods are valuable additions in detecting NASH.
Collapse
|
|
41
|
Sparks R, Lui A, Bader D, Patel R, Murr M, Guida W, Fratti R, Patel NA. A specific small-molecule inhibitor of protein kinase CδI activity improves metabolic dysfunction in human adipocytes from obese individuals. J Biol Chem 2019; 294:14896-14910. [PMID: 31413114 DOI: 10.1074/jbc.ra119.008777] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 07/11/2019] [Indexed: 12/17/2022] Open
Abstract
The metabolic consequences and sequelae of obesity promote life-threatening morbidities. PKCδI is an important elicitor of inflammation and apoptosis in adipocytes. Here we report increased PKCδI activation via release of its catalytic domain concurrent with increased expression of proinflammatory cytokines in adipocytes from obese individuals. Using a screening strategy of dual recognition of PKCδI isozymes and a caspase-3 binding site on the PKCδI hinge domain with Schrödinger software and molecular dynamics simulations, we identified NP627, an organic small-molecule inhibitor of PKCδI. Characterization of NP627 by surface plasmon resonance (SPR) revealed that PKCδI and NP627 interact with each other with high affinity and specificity, SPR kinetics revealed that NP627 disrupts caspase-3 binding to PKCδI, and in vitro kinase assays demonstrated that NP627 specifically inhibits PKCδI activity. The SPR results also indicated that NP627 affects macromolecular interactions between protein surfaces. Of note, release of the PKCδI catalytic fragment was sufficient to induce apoptosis and inflammation in adipocytes. NP627 treatment of adipocytes from obese individuals significantly inhibited PKCδI catalytic fragment release, decreased inflammation and apoptosis, and significantly improved mitochondrial metabolism. These results indicate that PKCδI is a robust candidate for targeted interventions to manage obesity-associated chronic inflammatory diseases. We propose that NP627 may also be used in other biological systems to better understand the impact of caspase-3-mediated activation of kinase activity.
Collapse
Affiliation(s)
- Robert Sparks
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Illinois 61801
| | - Ashley Lui
- Department of Molecular Medicine, University of South Florida, Tampa, Florida 33612
| | - Deena Bader
- James A. Haley Veterans Hospital, Tampa, Florida 33612
| | - Rekha Patel
- Department of Chemistry, University of South Florida, Tampa, Florida 33612
| | - Michel Murr
- Surgery Department, University of Central Florida, Orlando, Florida 32816.,Bariatric and Metabolic Institute, AdventHealth, Tampa, Florida 33612
| | - Wayne Guida
- Department of Chemistry, University of South Florida, Tampa, Florida 33612
| | - Rutilio Fratti
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Illinois 61801
| | - Niketa A Patel
- Department of Molecular Medicine, University of South Florida, Tampa, Florida 33612 .,James A. Haley Veterans Hospital, Tampa, Florida 33612
| |
Collapse
|
|
42
|
Kim TH, Jeong CW, Jun HY, Kim YR, Kim JY, Lee YH, Yoon KH. Noninvasive Differential Diagnosis of Liver Iron Contents in Nonalcoholic Steatohepatitis and Simple Steatosis Using Multiecho Dixon Magnetic Resonance Imaging. Acad Radiol 2019; 26:766-774. [PMID: 30143402 DOI: 10.1016/j.acra.2018.06.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 06/26/2018] [Accepted: 06/26/2018] [Indexed: 12/19/2022]
Abstract
RATIONALE AND OBJECTIVES The roles of iron stores in nonalcoholic fatty liver disease have not yet been clearly identified, and it is lack of uniform criteria and a standardized study design for assessing the liver iron content (LIC) in nonalcoholic steatohepatitis (NASH). This study was to compare LICs in biopsy-proven simple steatosis (SS) and NASH based on T2⁎-relaxometry. MATERIAL AND METHODS A total of 32 subjects divided to three groups, consisting of 10 healthy controls, 12 SS and 10 NASH. All MRI examinations were performed on a 3 T MRI with a 32-channel body coil. To measure T2⁎-value, we used a gradient echo sequence with six multiechoes within a single breath-hold. Hepatic iron contents among three groups were compared using Kruskal-Wallis H test and Mann-Whitney's posthoc tests. Diagnostic accuracy was determined by calculating the area under the receiver operating characteristics curve. To identify the reliability of iron measurements in the different region of interests, coefficient of variance (CV) was calculated overall CV values for the variability of measurements. Interobserver agreement and reliability were estimated by calculating the intraclass correlation coefficient. RESULTS The variations of all LIC measurements are not exceeded 20%, as a mean CV value 18.3%. intraclass correlation coefficients were higher than 0.9. Mean T2⁎-values at localized region of interests were healthy controls 45.42 ± 7.19 ms, SS 20.96 ± 4.28 ms, and NASH 15.49 ± 2.87 ms. The mean T2⁎-value in NASH is significantly shorter than that in SS (p = 0.008). The area under the receiver operating characteristics curve to distinguish NASH from SS was 0.908 (95% confidence interval 0.775-1.000, p = 0.001) at a cut-off of iron contents greater than 17.95 ms, and its diagnostic accuracy had 0.833 sensitivity and 0.800 specificity. CONCLUSION This study demonstrates that the T2⁎ calculation can help to differentially diagnose NASH.
Collapse
Affiliation(s)
- Tae-Hoon Kim
- Medical Convergence Research Center, Wonkwang University, Iksan, Republic of Korea
| | - Chang-Won Jeong
- Medical Convergence Research Center, Wonkwang University, Iksan, Republic of Korea
| | - Hong Young Jun
- Medical Convergence Research Center, Wonkwang University, Iksan, Republic of Korea
| | - Youe Ree Kim
- Department of Radiology, Wonkwang University School of Medicine, Iksan, Republic of Korea
| | - Ju Young Kim
- Medical Convergence Research Center, Wonkwang University, Iksan, Republic of Korea
| | - Young Hwan Lee
- Medical Convergence Research Center, Wonkwang University, Iksan, Republic of Korea; Department of Radiology, Wonkwang University School of Medicine, Iksan, Republic of Korea
| | - Kwon-Ha Yoon
- Medical Convergence Research Center, Wonkwang University, Iksan, Republic of Korea; Department of Radiology, Wonkwang University School of Medicine, Iksan, Republic of Korea.
| |
Collapse
|
|
43
|
Rivers SL, Klip A, Giacca A. NOD1: An Interface Between Innate Immunity and Insulin Resistance. Endocrinology 2019; 160:1021-1030. [PMID: 30807635 PMCID: PMC6477778 DOI: 10.1210/en.2018-01061] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 02/19/2019] [Indexed: 12/17/2022]
Abstract
Insulin resistance is driven, in part, by activation of the innate immune system. We have discussed the evidence linking nucleotide-binding oligomerization domain (NOD)1, an intracellular pattern recognition receptor, to the onset and progression of obesity-induced insulin resistance. On a molecular level, crosstalk between downstream NOD1 effectors and the insulin receptor pathway inhibits insulin signaling, potentially through reduced insulin receptor substrate action. In vivo studies have demonstrated that NOD1 activation induces peripheral, hepatic, and whole-body insulin resistance. Also, NOD1-deficient models are protected from high-fat diet (HFD)-induced insulin resistance. Moreover, hematopoietic NOD1 deficiency prevented HFD-induced changes in proinflammatory macrophage polarization status, thus protecting against the development of metabolic inflammation and insulin resistance. Serum from HFD-fed mice activated NOD1 signaling ex vivo; however, the molecular identity of the activating factors remains unclear. Many have proposed that an HFD changes the gut permeability, resulting in increased translocation of bacterial fragments and increased circulating NOD1 ligands. In contrast, others have suggested that NOD1 ligands are endogenous and potentially lipid-derived metabolites produced during states of nutrient overload. Nevertheless, that NOD1 contributes to the development of insulin resistance, and that NOD1-based therapy might provide benefit, is an exciting advancement in metabolic research.
Collapse
Affiliation(s)
- Sydney L Rivers
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Amira Klip
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Adria Giacca
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
- Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Correspondence: Adria Giacca, MD, Department of Physiology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King’s College Circle, No. 3336, Toronto, Ontario M5S 1A8, Canada. E-mail:
| |
Collapse
|
|
44
|
Jung TW, Kim H, Kim HU, Park T, Park J, Kim U, Kim MK, Jeong JH. Asprosin attenuates insulin signaling pathway through PKCδ‐activated ER stress and inflammation in skeletal muscle. J Cell Physiol 2019; 234:20888-20899. [DOI: 10.1002/jcp.28694] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 03/30/2019] [Accepted: 04/05/2019] [Indexed: 12/17/2022]
Affiliation(s)
- Tae Woo Jung
- Department of Pharmacology College of Medicine, Chung‐Ang University Seoul Republic of Korea
| | - Hyoung‐Chun Kim
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University Chunchon Republic of Korea
| | - Ho Ung Kim
- Department of Pharmacology College of Medicine, Chung‐Ang University Seoul Republic of Korea
| | - Taekwang Park
- Department of Pharmacology College of Medicine, Chung‐Ang University Seoul Republic of Korea
| | - Jinwoo Park
- Department of Pharmacology College of Medicine, Chung‐Ang University Seoul Republic of Korea
| | - Uiseok Kim
- Department of Pharmacology College of Medicine, Chung‐Ang University Seoul Republic of Korea
| | - Min Kyoon Kim
- Department of Surgery Chung‐Ang University College of Medicine, Chung‐Ang University Seoul Republic of Korea
| | - Ji Hoon Jeong
- Department of Pharmacology College of Medicine, Chung‐Ang University Seoul Republic of Korea
| |
Collapse
|
|
45
|
Xu M, Liu PP, Li H. Innate Immune Signaling and Its Role in Metabolic and Cardiovascular Diseases. Physiol Rev 2019; 99:893-948. [PMID: 30565509 DOI: 10.1152/physrev.00065.2017] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The innate immune system is an evolutionarily conserved system that senses and defends against infection and irritation. Innate immune signaling is a complex cascade that quickly recognizes infectious threats through multiple germline-encoded cell surface or cytoplasmic receptors and transmits signals for the deployment of proper countermeasures through adaptors, kinases, and transcription factors, resulting in the production of cytokines. As the first response of the innate immune system to pathogenic signals, inflammatory responses must be rapid and specific to establish a physical barrier against the spread of infection and must subsequently be terminated once the pathogens have been cleared. Long-lasting and low-grade chronic inflammation is a distinguishing feature of type 2 diabetes and cardiovascular diseases, which are currently major public health problems. Cardiometabolic stress-induced inflammatory responses activate innate immune signaling, which directly contributes to the development of cardiometabolic diseases. Additionally, although the innate immune elements are highly conserved in higher-order jawed vertebrates, lower-grade jawless vertebrates lack several transcription factors and inflammatory cytokine genes downstream of the Toll-like receptors (TLRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) pathways, suggesting that innate immune signaling components may additionally function in an immune-independent way. Notably, recent studies from our group and others have revealed that innate immune signaling can function as a vital regulator of cardiometabolic homeostasis independent of its immune function. Therefore, further investigation of innate immune signaling in cardiometabolic systems may facilitate the discovery of new strategies to manage the initiation and progression of cardiometabolic disorders, leading to better treatments for these diseases. In this review, we summarize the current progress in innate immune signaling studies and the regulatory function of innate immunity in cardiometabolic diseases. Notably, we highlight the immune-independent effects of innate immune signaling components on the development of cardiometabolic disorders.
Collapse
Affiliation(s)
- Meng Xu
- Department of Cardiology, Renmin Hospital of Wuhan University , Wuhan , China ; Medical Research Center, Zhongnan Hospital of Wuhan University , Wuhan , China ; Animal Experiment Center, Wuhan University , Wuhan , China ; Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Ontario , Canada
| | - Peter P Liu
- Department of Cardiology, Renmin Hospital of Wuhan University , Wuhan , China ; Medical Research Center, Zhongnan Hospital of Wuhan University , Wuhan , China ; Animal Experiment Center, Wuhan University , Wuhan , China ; Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Ontario , Canada
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University , Wuhan , China ; Medical Research Center, Zhongnan Hospital of Wuhan University , Wuhan , China ; Animal Experiment Center, Wuhan University , Wuhan , China ; Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Ontario , Canada
| |
Collapse
|
|
46
|
Diallo K, Oppong AK, Lim GE. Can 14-3-3 proteins serve as therapeutic targets for the treatment of metabolic diseases? Pharmacol Res 2019; 139:199-206. [DOI: 10.1016/j.phrs.2018.11.021] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 11/14/2018] [Accepted: 11/15/2018] [Indexed: 12/12/2022]
|
|
47
|
Rao TN, Gupta MK, Softic S, Wang LD, Jang YC, Thomou T, Bezy O, Kulkarni RN, Kahn CR, Wagers AJ. Attenuation of PKCδ enhances metabolic activity and promotes expansion of blood progenitors. EMBO J 2018; 37:embj.2018100409. [PMID: 30446598 PMCID: PMC6293338 DOI: 10.15252/embj.2018100409] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 09/08/2018] [Accepted: 09/12/2018] [Indexed: 12/21/2022] Open
Abstract
A finely tuned balance of self‐renewal, differentiation, proliferation, and survival governs the pool size and regenerative capacity of blood‐forming hematopoietic stem and progenitor cells (HSPCs). Here, we report that protein kinase C delta (PKCδ) is a critical regulator of adult HSPC number and function that couples the proliferative and metabolic activities of HSPCs. PKCδ‐deficient mice showed a pronounced increase in HSPC numbers, increased competence in reconstituting lethally irradiated recipients, enhanced long‐term competitive advantage in serial transplantation studies, and an augmented HSPC recovery during stress. PKCδ‐deficient HSPCs also showed accelerated proliferation and reduced apoptosis, but did not exhaust in serial transplant assays or induce leukemia. Using inducible knockout and transplantation models, we further found that PKCδ acts in a hematopoietic cell‐intrinsic manner to restrict HSPC number and bone marrow regenerative function. Mechanistically, PKCδ regulates HSPC energy metabolism and coordinately governs multiple regulators within signaling pathways implicated in HSPC homeostasis. Together, these data identify PKCδ as a critical regulator of HSPC signaling and metabolism that acts to limit HSPC expansion in response to physiological and regenerative demands.
Collapse
Affiliation(s)
- Tata Nageswara Rao
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA .,Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Manoj K Gupta
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Samir Softic
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA, USA.,Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA
| | - Leo D Wang
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.,Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA.,Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Dana-Farber/Boston Children's Center for Cancer and Blood Disorders, Boston, MA, USA
| | - Young C Jang
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.,Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Thomas Thomou
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA, USA
| | - Olivier Bezy
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA, USA
| | - Rohit N Kulkarni
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - C Ronald Kahn
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA, USA
| | - Amy J Wagers
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA .,Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| |
Collapse
|
|
48
|
Maslov LN, Naryzhnaya NV, Boshchenko AA, Popov SV, Ivanov VV, Oeltgen PR. Is oxidative stress of adipocytes a cause or a consequence of the metabolic syndrome? JOURNAL OF CLINICAL AND TRANSLATIONAL ENDOCRINOLOGY 2018; 15:1-5. [PMID: 30479968 PMCID: PMC6240632 DOI: 10.1016/j.jcte.2018.11.001] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 11/02/2018] [Accepted: 11/08/2018] [Indexed: 01/17/2023]
Abstract
Metabolic syndrome is accompanied by oxidative stress in animals and humans. The main source of ROS in experimental metabolic syndrome is NADPH oxidase and possibly adipocyte mitochondria. It is now documented that oxidative stress induces insulin resistance of adipocytes and increases secretion of leptin, MCP-1, IL-6, and TNF-α by adipocytes. It was established that oxidative stress induces a decrease in adiponectin production by adipocytes. It has also been shown that obesity itself can induce oxidative stress. Oxidative stress can cause an alteration of intracellular signaling in adipocytes that apparently leads to the formation of insulin resistance of adipocytes. Chronic stress, glucocorticoids, mineralocorticoids, angiotensin-II, TNF-α also play an important role in the pathogenesis of oxidative stress of adipocytes. Oxidative stress is not only a consequence of metabolic syndrome, but also a reason and a foundational link in the pathogenesis of the metabolic syndrome.
Collapse
Affiliation(s)
- Leonid N Maslov
- Cardiology Research Institute, Tomsk National Research Medical Centre, Russian Academy of Sciences, Tomsk, Russia
| | - Natalia V Naryzhnaya
- Cardiology Research Institute, Tomsk National Research Medical Centre, Russian Academy of Sciences, Tomsk, Russia
| | - Alla A Boshchenko
- Cardiology Research Institute, Tomsk National Research Medical Centre, Russian Academy of Sciences, Tomsk, Russia
| | - Sergey V Popov
- Cardiology Research Institute, Tomsk National Research Medical Centre, Russian Academy of Sciences, Tomsk, Russia
| | | | - Peter R Oeltgen
- Department of Pathology, University of Kentucky College of Medicine, Lexington, KY, USA
| |
Collapse
|
|
49
|
Mulcahy MJ, Paulo JA, Hawrot E. Proteomic Investigation of Murine Neuronal α7-Nicotinic Acetylcholine Receptor Interacting Proteins. J Proteome Res 2018; 17:3959-3975. [PMID: 30285449 DOI: 10.1021/acs.jproteome.8b00618] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The α7-nicotinic acetylcholine receptor (α7-nAChR) is a ligand-gated ion channel that is expressed widely in vertebrates and is the principal high-affinity α-bungarotoxin (α-bgtx) binding protein in the mammalian CNS. α7-nAChRs associate with proteins that can modulate its properties. The α7-nAChR interactome is the summation of proteins interacting or associating with α7-nAChRs in a protein complex. To identify an α7-nAChR interactome in neural tissue, we isolated α-bgtx-affinity protein complexes from wild-type and α7-nAChR knockout (α7 KO) mouse whole brain tissue homogenates using α-bgtx-affinity beads. Affinity precipitated proteins were trypsinized and analyzed with an Orbitrap Fusion mass spectrometer. Proteins isolated with the α7-nAChR specific ligand, α-bgtx, were determined to be α7-nAChR associated proteins. The α7-nAChR subunit and 120 additional proteins were identified. Additionally, 369 proteins were identified as binding to α-bgtx in the absence of α7-nAChR expression, thereby identifying nonspecific proteins for α7-nAChR investigations using α-bgtx enrichment. These results expand on our previous investigations of α7-nAChR interacting proteins using α-bgtx-affinity bead isolation by controlling for differences between α7-nAChR and α-bgtx-specific proteins, developing an improved protein isolation methodology, and incorporating the latest technology in mass spectrometry. The α7-nAChR interactome identified in this study includes proteins associated with the expression, localization, function, or modulation of α7-nAChRs, and it provides a foundation for future studies to elucidate how these interactions contribute to human disease.
Collapse
Affiliation(s)
- Matthew J Mulcahy
- Division of Biology and Biological Engineering , California Institute of Technology , 1200 East California Boulevard , Pasadena , California 91125-2900 , United States.,Department of Molecular Pharmacology, Physiology and Biotechnology , Brown University , Providence , Rhode Island 02912 , United States
| | - Joao A Paulo
- Department of Cell Biology , Harvard Medical School , 240 Longwood Avenue , Boston , Massachusetts 02115 , United States
| | - Edward Hawrot
- Department of Molecular Pharmacology, Physiology and Biotechnology , Brown University , Providence , Rhode Island 02912 , United States
| |
Collapse
|
|
50
|
Petersen MC, Shulman GI. Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev 2018; 98:2133-2223. [PMID: 30067154 PMCID: PMC6170977 DOI: 10.1152/physrev.00063.2017] [Citation(s) in RCA: 1678] [Impact Index Per Article: 239.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 03/22/2018] [Accepted: 03/24/2018] [Indexed: 12/15/2022] Open
Abstract
The 1921 discovery of insulin was a Big Bang from which a vast and expanding universe of research into insulin action and resistance has issued. In the intervening century, some discoveries have matured, coalescing into solid and fertile ground for clinical application; others remain incompletely investigated and scientifically controversial. Here, we attempt to synthesize this work to guide further mechanistic investigation and to inform the development of novel therapies for type 2 diabetes (T2D). The rational development of such therapies necessitates detailed knowledge of one of the key pathophysiological processes involved in T2D: insulin resistance. Understanding insulin resistance, in turn, requires knowledge of normal insulin action. In this review, both the physiology of insulin action and the pathophysiology of insulin resistance are described, focusing on three key insulin target tissues: skeletal muscle, liver, and white adipose tissue. We aim to develop an integrated physiological perspective, placing the intricate signaling effectors that carry out the cell-autonomous response to insulin in the context of the tissue-specific functions that generate the coordinated organismal response. First, in section II, the effectors and effects of direct, cell-autonomous insulin action in muscle, liver, and white adipose tissue are reviewed, beginning at the insulin receptor and working downstream. Section III considers the critical and underappreciated role of tissue crosstalk in whole body insulin action, especially the essential interaction between adipose lipolysis and hepatic gluconeogenesis. The pathophysiology of insulin resistance is then described in section IV. Special attention is given to which signaling pathways and functions become insulin resistant in the setting of chronic overnutrition, and an alternative explanation for the phenomenon of ‟selective hepatic insulin resistanceˮ is presented. Sections V, VI, and VII critically examine the evidence for and against several putative mediators of insulin resistance. Section V reviews work linking the bioactive lipids diacylglycerol, ceramide, and acylcarnitine to insulin resistance; section VI considers the impact of nutrient stresses in the endoplasmic reticulum and mitochondria on insulin resistance; and section VII discusses non-cell autonomous factors proposed to induce insulin resistance, including inflammatory mediators, branched-chain amino acids, adipokines, and hepatokines. Finally, in section VIII, we propose an integrated model of insulin resistance that links these mediators to final common pathways of metabolite-driven gluconeogenesis and ectopic lipid accumulation.
Collapse
Affiliation(s)
- Max C Petersen
- Departments of Internal Medicine and Cellular & Molecular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine , New Haven, Connecticut
| | - Gerald I Shulman
- Departments of Internal Medicine and Cellular & Molecular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine , New Haven, Connecticut
| |
Collapse
|