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Gagnani R, Srivastava M, Suri M, Singh H, Shanker Navik U, Bali A. A focus on c-Jun-N-terminal kinase signaling in sepsis-associated multiple organ dysfunction: Mechanisms and therapeutic strategies. Int Immunopharmacol 2024; 143:113552. [PMID: 39536486 DOI: 10.1016/j.intimp.2024.113552] [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: 07/31/2024] [Revised: 09/19/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024]
Abstract
Sepsis is a life-threatening condition characterized by a widespread inflammatory response to infection, inevitably leading to multiple organ dysfunctions. Extensive research, both in vivo and in vitro, has revealed key factors contributing to sepsis, such as apoptosis, inflammation, cytokine release, oxidative stress, and systemic stress. The changes observed during sepsis-induced conditions are mainly attributed to altered signal transduction pathways, which play a critical role in cell proliferation, migration, and apoptosis. C-Jun N-terminal kinases, JNKs, and serine/threonine protein kinases in the mitogen-activated super family have gained considerable interest for their contribution to cellular events under sepsis conditions. JNK1 and JNK2 are present in various tissues like the lungs, liver, and intestine, while JNK3 is found in neurons. The JNK pathway plays a crucial role in the signal transduction of cytokines related to sepsis development, notably TNF-α and IL-1β. Activated JNK leads to apoptosis, causing tissue damage and organ dysfunction. Further, JNK activation is significant in several inflammatory conditions. Pharmacologically inhibiting JNK has been shown to prevent sepsis-associated damage across multiple organs, including the lungs, liver, intestines, heart, and kidneys. Multiple signaling pathways have been implicated in sepsis, including JNK/c-Myc, Mst1-JNK, MKK4-JNK, JNK-dependent autophagy, and Sirt1/FoxO3a. The review examines the role of JNK signaling in the development of sepsis-induced multiple-organ dysfunction through specific mechanisms. It also discusses different therapeutic approaches to target JNK. This review emphasizes the potential of JNKs as targets for the development of therapeutic agents for sepsis and the associated specific organ damage.
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Affiliation(s)
- Riya Gagnani
- Laboratory of Neuroendocrinology, Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, India.
| | - Mukul Srivastava
- Laboratory of Neuroendocrinology, Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, India
| | - Manisha Suri
- Laboratory of Neuroendocrinology, Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, India
| | - Harshita Singh
- Laboratory of Neuroendocrinology, Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, India
| | - Uma Shanker Navik
- Laboratory of Neuroendocrinology, Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, India
| | - Anjana Bali
- Laboratory of Neuroendocrinology, Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, India.
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Gao W, Wang Y, Liu S, Li G, Shao Q, Zhang C, Cao L, Liu K, Gao W, Yang Z, Dong Y, Du X, Lei L, Liu G, Li X. Inositol-requiring enzyme 1α and c-Jun N-terminal kinase axis activation contributes to intracellular lipid accumulation in calf hepatocytes. J Dairy Sci 2024; 107:3127-3139. [PMID: 37939835 DOI: 10.3168/jds.2022-23189] [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: 12/22/2022] [Accepted: 10/13/2023] [Indexed: 11/10/2023]
Abstract
During the perinatal period, dairy cows undergo negative energy balance, resulting in elevated circulating levels of nonesterified fatty acids (NEFA). Although increased blood NEFA concentrations are a physiological adaptation of early lactation, excessive NEFA in dairy cows is a major cause of fatty liver. Aberrant lipid metabolism leads to hepatic lipid accumulation and subsequently the development of fatty liver. Both inositol-requiring enzyme 1α (IRE1α) and c-Jun N-terminal kinase (JNK) have been validated for their association with hepatic lipid accumulation, including their regulatory functions in calf hepatocyte insulin resistance, oxidative stress, and apoptosis. Meanwhile, both IRE1α and JNK are involved in lipid metabolism in nonruminants. Therefore, the aim of this study was to investigate how IRE1α and JNK regulate lipid metabolism in bovine hepatocytes. An experiment was conducted on randomly selected 10 healthy cows (hepatic triglyceride [TG] content <1%) and 10 cows with fatty liver (hepatic TG content >5%). Liver tissue and blood samples were collected from experimental cows. Serum concentrations of NEFA and β-hydroxybutyrate (BHB) were greater, whereas serum concentrations of glucose and milk production were lower in cows with fatty liver. The western blot results revealed that dairy cows with fatty liver had higher phosphorylation levels of JNK, c-Jun, and IRE1α in the liver tissue. Three in vitro experiments were conducted using primary calf hepatocytes isolated from 5 healthy calves (body weight: 30-40 kg; 1 d old). First, hepatocytes were treated with NEFA (1.2 mM) for 0.5, 1, 2, 3, 5, 7, 9, or 12 h, which showed that the phosphorylated levels of JNK, c-Jun, and IRE1α increased in both linear and quadratic effects. In the second experiment, hepatocytes were treated with high concentrations of NEFA (1.2 mM) for 12 h with or without SP600125, a canonical inhibitor of JNK. Western blot results showed that SP600125 treatment could decrease the expression of lipogenesis-associated proteins (PPARγ and SREBP-1c) and increase the expression of fatty acid oxidation (FAO)-associated proteins (CPT1A and PPARα) in NEFA-treated hepatocytes. The perturbed expression of lipogenesis-associated genes (FASN, ACACA, and CD36) and FAO-associated gene ACOX1 were also recovered by JNK inhibition, indicating that JNK reduced excessive NEFA-induced lipogenesis and FAO dysregulation in calf hepatocytes. Third, short hairpin RNA targeting IRE1α (sh-IRE1α) was transfected into calf hepatocytes to silence IRE1α, and KIRA6 was used to inhibit the kinase activity of IRE1α. The blockage of IRE1α could at least partially suppressed NEFA-induced JNK activation. Moreover, the blockage of IRE1α downregulated the expression of lipogenesis genes and upregulated the expression of FAO genes in NEFA-treated hepatocytes. In conclusion, these findings indicate that targeting the IRE1α-JNK axis can reduce NEFA-induced lipid accumulation in bovine hepatocytes by modulating lipogenesis and FAO. This may offer a prospective therapeutic target for fatty liver in dairy cows.
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Affiliation(s)
- Wenwen Gao
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Yanxi Wang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Siyu Liu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Guojin Li
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Qi Shao
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Cai Zhang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471003, China
| | - Liguang Cao
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Kai Liu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Wenrui Gao
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Zifeng Yang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Yifei Dong
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Xiliang Du
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Lin Lei
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Guowen Liu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Xinwei Li
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China.
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Luo TT, Wu YJ, Yin Q, Chen WG, Zuo J. The Involvement of Glucose and Lipid Metabolism Alteration in Rheumatoid Arthritis and Its Clinical Implication. J Inflamm Res 2023; 16:1837-1852. [PMID: 37131409 PMCID: PMC10149064 DOI: 10.2147/jir.s398291] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 04/19/2023] [Indexed: 05/04/2023] Open
Abstract
Obviously, immune cells like T cells and macrophages play a major role in rheumatoid arthritis (RA). On one hand, the breakdown of immune homeostasis directly induces systemic inflammation; on the other hand, these cells initiate and perpetuate synovitis and tissue damages through the interaction with fibroblast-like synoviocytes (FLS). In recent years, the pathological link between metabolic disorders and immune imbalance has received increasing attention. High energy demand of immune cells leads to the accumulation of metabolic byproducts and inflammatory mediators. They act on various metabolism-sensitive signal pathways as well as relevant transcription factors, such as HIF-1α, and STATs. These molecular events will impact RA-related effectors like circulating immune cells and joint-resident cells in return, allowing the continuous progression of systemic inflammation, arthritic manifestations, and life-threatening complications. In other words, metabolic complications are secondary pathological factors for the progression of RA. Therefore, the status of energy metabolism may be an important indicator to evaluate RA severity, and in-depth explorations of the mechanisms underlying the mystery of how RA-related metabolic disorders develop will provide useful clues to further clarify the etiology of RA, and inspire the discovery of new anti-rheumatic targets. This article reviews the latest research progress on the interactions between immune and metabolism systems in the context of RA. Great importance is attached to the changes in certain pathways controlling both immune and metabolism functions during RA progression.
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Affiliation(s)
- Ting-Ting Luo
- Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China
- Xin’an Medical Research Center, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China
| | - Yi-Jin Wu
- Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China
- Xin’an Medical Research Center, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China
| | - Qin Yin
- Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China
| | - Wen-Gang Chen
- Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China
| | - Jian Zuo
- Xin’an Medical Research Center, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China
- Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China
- Correspondence: Jian Zuo, Email
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Alshehade S, Alshawsh MA, Murugaiyah V, Asif M, Alshehade O, Almoustafa H, Al Zarzour RH. The role of protein kinases as key drivers of metabolic dysfunction-associated fatty liver disease progression: New insights and future directions. Life Sci 2022; 305:120732. [PMID: 35760093 DOI: 10.1016/j.lfs.2022.120732] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 06/08/2022] [Accepted: 06/21/2022] [Indexed: 02/07/2023]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD), proposed in 2020 is a novel term for non-alcoholic fatty liver disease (NAFLD) which was coined for the first time in 1980. It is a leading cause of the most chronic liver disease and hepatic failure all over the world, and unfortunately, with no licensed drugs for treatment yet. The progress of the disease is driven by the triggered inflammatory process, oxidative stress, and insulin resistance in many pathways, starting with simple hepatic steatosis to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and liver cancer. Protein kinases (PKs), such as MAPK, ErbB, PKC, PI3K/Akt, and mTOR, govern most of the pathological pathways by acting on various downstream key points in MAFLD and regulating both hepatic gluco- lipo-neogenesis and inflammation. Therefore, modulating the function of those potential protein kinases that are effectively involved in MAFLD might be a promising therapeutic approach for tackling this disease. In the current review, we have discussed the key role of protein kinases in the pathogenesis of MAFLD and performed a protein-protein interaction (PPI) network among the main proteins of each kinase pathway with MAFLD-related proteins to predict the most likely targets of the PKs in MAFLD. Moreover, we have reported the experimental, pre-clinical, and clinical data for the most recent investigated molecules that are activating p38-MAPK and AMPK proteins and inhibiting the other PKs to improve MAFLD condition by regulating oxidation and inflammation signalling.
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Affiliation(s)
- Salah Alshehade
- Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia; Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | | | - Vikneswaran Murugaiyah
- Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia
| | - Muhammad Asif
- Department of Pharmacology, Faculty of Pharmacy, The Islamia University of Bahawalpur, 63100, Punjab, Pakistan
| | - Omayma Alshehade
- Department of Paediatrics, Faculty of Medicine, Damascus University, Damascus, Syria
| | - Hassan Almoustafa
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Raghdaa Hamdan Al Zarzour
- Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia; Department of Pharmacology, Faculty of Pharmacy, Arab International University, Damascus, Syria.
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Keating MF, Drew BG, Calkin AC. Antisense Oligonucleotide Technologies to Combat Obesity and Fatty Liver Disease. Front Physiol 2022; 13:839471. [PMID: 35295579 PMCID: PMC8918623 DOI: 10.3389/fphys.2022.839471] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 01/21/2022] [Indexed: 11/24/2022] Open
Abstract
Synthetic oligonucleotide technologies are DNA or RNA based molecular compounds that are utilized to disrupt gene transcription or translation in target tissues or cells. Optimally, oligonucleotides are 10–30 base pairs in length, and mediate target gene suppression through directed sequence homology with messenger RNA (mRNA), leading to mRNA degradation. Examples of specific oligonucleotide technologies include antisense oligonucleotides (ASO), short hairpin RNAs (shRNA), and small interfering RNAs (siRNA). In vitro and in vivo studies that model obesity related disorders have demonstrated that oligonucleotide technologies can be implemented to improve the metabolism of cells and tissues, exemplified by improvements in fat utilization and hepatic insulin signaling, respectively. Oligonucleotide therapy has also been associated with reductions in lipid accumulation in both the liver and adipose tissue in models of diet-induced obesity. Recent advances in oligonucleotide technologies include the addition of chemical modifications such as N-acetylgalactosamine (GalNAc) conjugates that have been successful at achieving affinity for the liver, in turn improving specificity, and thus reducing off target effects. However, some challenges are still yet to be overcome relating to hepatic injury and off-target effects that have been reported with some compounds, including ASOs. In summary, oligonucleotide-based therapies are an effective tool to elucidate mechanistic insights into metabolic pathways and provide an attractive avenue for translational research into the clinic.
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Affiliation(s)
- Michael F Keating
- Lipid Metabolism and Cardiometabolic Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Molecular Metabolism and Ageing Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Baker Department of Cardiometabolic Disease, University of Melbourne, Parkville, VIC, Australia
| | - Brian G Drew
- Molecular Metabolism and Ageing Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Baker Department of Cardiometabolic Disease, University of Melbourne, Parkville, VIC, Australia.,Central Clinical School, Department of Medicine, Monash University, Melbourne, VIC, Australia
| | - Anna C Calkin
- Lipid Metabolism and Cardiometabolic Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Baker Department of Cardiometabolic Disease, University of Melbourne, Parkville, VIC, Australia.,Central Clinical School, Department of Medicine, Monash University, Melbourne, VIC, Australia
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6
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Xie D, Zhao H, Lu J, He F, Liu W, Yu W, Wang Q, Hisatome I, Yamamoto T, Koyama H, Cheng J. High uric acid induces liver fat accumulation via ROS/JNK/AP-1 signaling. Am J Physiol Endocrinol Metab 2021; 320:E1032-E1043. [PMID: 33900847 DOI: 10.1152/ajpendo.00518.2020] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Uric acid is the end metabolite derived from the oxidation of purine compounds. Overwhelming evidence shows the vital interrelationship between hyperuricemia (HUA) and nonalcoholic fatty liver disease (NAFLD). However, the mechanisms for this association remain unclear. In this study, we established a urate oxidase-knockout (Uox-KO) mouse model by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 technology. To study the correlation between HUA and NAFLD, human HepG2 hepatoma cells were treated in culture medium with high level of uric acid. In vivo, the Uox-KO mice spontaneously developed hyperuricemia and aberrant lipid-metabolism, concomitant with abnormal hepatic fat accumulation. HUA activated c-Jun N-terminal kinase (JNK) in vivo and in vitro. Furthermore, inhibiting JNK activation by a JNK-specific inhibitor, SP600125, decreased fat accumulation and lipogenic gene expression induced by HUA. Overexpression of the lipogenic enzymes fatty acid synthase and acetyl-CoA carboxylase 1 was via activation of JNK, which was blocked by the JNK inhibitor SP600125. HUA activated AP-1 to upregulate lipogenic gene expression via JNK activation. In addition, HUA caused mitochondrial dysfunction and reactive oxygen species production. Pretreatment with the antioxidant N-acetyl-l-cysteine could ameliorate HUA-activated JNK and hepatic steatosis. These data suggest that ROS/JNK/AP-1 signaling plays an important role in HUA-mediated fat accumulation in liver.NEW & NOTEWORTHY Hyperuricemia and nonalcoholic fatty liver disease are global public health problems, which are strongly associated with metabolic syndrome. In this study, we demonstrate that uric acid induces hepatic fat accumulation via the ROS/JNK/AP-1 pathway. This study identifies a new mechanism of NAFLD pathogenesis and new potential therapeutic strategies for HUA-induced NAFLD.
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Affiliation(s)
- De Xie
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China
| | - Hairong Zhao
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China
| | - Jiaming Lu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China
| | - Furong He
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China
| | - Weidong Liu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China
| | - Wei Yu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China
| | - Qiang Wang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China
| | - Ichiro Hisatome
- Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Yonago, Japan
| | - Tetsuya Yamamoto
- Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hidenori Koyama
- Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Jidong Cheng
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China
- Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Nishinomiya, Japan
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Garg R, Kumariya S, Katekar R, Verma S, Goand UK, Gayen JR. JNK signaling pathway in metabolic disorders: An emerging therapeutic target. Eur J Pharmacol 2021; 901:174079. [PMID: 33812885 DOI: 10.1016/j.ejphar.2021.174079] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/18/2021] [Accepted: 03/25/2021] [Indexed: 02/08/2023]
Abstract
Metabolic Syndrome is a multifactorial disease associated with increased risk of cardiovascular disorders, type 2 diabetes mellitus, fatty liver disease, etc. Various stress stimuli such as reactive oxygen species, endoplasmic reticulum stress, mitochondrial dysfunction, increased cytokines, or free fatty acids are known to aggravate progressive development of hyperglycemia and hyperlipidemia. Although the exact mechanism contributing to altered metabolism is unclear. Evidence suggests stress kinase role to be a crucial one in metabolic syndrome. Stress kinase, c-jun N-terminal kinase activation (JNK) is involved in various metabolic manifestations including obesity, insulin resistance, fatty liver disease as well as cardiometabolic disorders. It emerged as a foremost mediator in regulating metabolism in the liver, skeletal muscle, adipose tissue as well as pancreatic β cells. It has three isoforms each having a unique and tissue-specific role in altered metabolism. Current findings based on genetic manipulation or chemical inhibition studies identified JNK isoforms to play a central role in the regulation of whole-body metabolism, suggesting it to be a novel therapeutic target. Hence, it is imperative to elucidate its role in metabolic syndrome onset and progression. The purpose of this review is to elucidate in vitro and in vivo implications of JNK signaling along with the therapeutic strategy to inhibit specific isoform. Since metabolic syndrome is an array of diseases and complex pathway, carefully examining each tissue will be important for specific treatment strategies.
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Affiliation(s)
- Richa Garg
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Sanjana Kumariya
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India
| | - Roshan Katekar
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Saurabh Verma
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Umesh K Goand
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Pharmacology Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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8
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Cicuéndez B, Ruiz-Garrido I, Mora A, Sabio G. Stress kinases in the development of liver steatosis and hepatocellular carcinoma. Mol Metab 2021; 50:101190. [PMID: 33588102 PMCID: PMC8324677 DOI: 10.1016/j.molmet.2021.101190] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/31/2020] [Accepted: 02/09/2021] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an important component of metabolic syndrome and one of the most prevalent liver diseases worldwide. This disorder is closely linked to hepatic insulin resistance, lipotoxicity, and inflammation. Although the mechanisms that cause steatosis and chronic liver injury in NAFLD remain unclear, a key component of this process is the activation of stress-activated kinases (SAPKs), including p38 and JNK in the liver and immune system. This review summarizes findings which indicate that the dysregulation of stress kinases plays a fundamental role in the development of steatosis and are important players in inducing liver fibrosis. To avoid the development of steatohepatitis and liver cancer, SAPK activity must be tightly regulated not only in the hepatocytes but also in other tissues, including cells of the immune system. Possible cellular mechanisms of SAPK actions are discussed.
Hepatic JNK triggers steatosis and insulin resistance, decreasing lipid oxidation and ketogenesis in HFD-fed mice. Decreased liver expression of p38α/β in HFD increases lipogenesis. Hepatic p38γ/δ drive insulin resistance and inhibit autophagy, which may lead to steatosis. Macrophage p38α/β promote cytokine production and M1 polarization, leading to lipid accumulation in hepatocytes. Myeloid p38γ/δ contribute to cytokine production and neutrophil migration, protecting against steatosis, diabetes and NAFLD. JNK1 and p38γ induce HCC while p38α blocks it. However, deletion of hepatic JNK1/2 induces cholangiocarcinoma. SAPK are potential therapeutic target for metabolic disorders, steatohepatitis and liver cancer.
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Affiliation(s)
- Beatriz Cicuéndez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Irene Ruiz-Garrido
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Alfonso Mora
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
| | - Guadalupe Sabio
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
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Rana R, Shearer AM, Fletcher EK, Nguyen N, Guha S, Cox DH, Abdelmalek M, Wang Y, Baleja JD, Covic L, Kuliopulos A. PAR2 controls cholesterol homeostasis and lipid metabolism in nonalcoholic fatty liver disease. Mol Metab 2019; 29:99-113. [PMID: 31668396 PMCID: PMC6742970 DOI: 10.1016/j.molmet.2019.08.019] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 08/16/2019] [Accepted: 08/24/2019] [Indexed: 01/04/2023] Open
Abstract
OBJECTIVE Increases in hepatic and plasma cholesterol occur in patients with nonalcoholic fatty liver disease (NAFLD), although the reason for this is not well understood. We investigated whether Protease-Activated Receptor 2 (PAR2) plays a role in cholesterol and lipid homeostasis in NAFLD. METHODS Human liver biopsies (n = 108) were quantified for PAR2 expression from NAFLD cases randomly selected and stratified by liver fibrosis stage, the primary predictor for clinical outcomes, while controlling for age, gender, and BMI between fibrosis groups. Demographic data and laboratory studies on plasma samples were obtained within 6 months of liver biopsy. Wild-type and PAR2-KO (C57BL/6 F2rl1-/-) mice were fed either normal or high fat diet for 16 weeks and plasma and liver assayed for lipids and soluble metabolites. RESULTS Severity of NAFLD and plasma cholesterol levels significantly correlated with hepatocyte PAR2 expression in NAFLD patients. Conversely, PAR2 deficiency in mice resulted in reduced expression of key hepatic genes involved in cholesterol synthesis, a 50% drop in plasma and total liver cholesterol, and induced a reverse cholesterol transport system that culminated in 25% higher fecal bile acid output. PAR2-deficient mice exhibited enhanced fatty acid β-oxidation with a ketogenic shift and an unexpected increase in liver glycogenesis. Mechanistic studies identified Gi-Jnk1/2 as key downstream effectors of protease-activated PAR2 in the regulation of lipid and cholesterol homeostasis in liver. CONCLUSIONS These data indicate that PAR2 may be a new target for the suppression of plasma cholesterol and hepatic fat accumulation in NAFLD and related metabolic conditions.
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Affiliation(s)
- Rajashree Rana
- Center for Hemostasis and Thrombosis Research, Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA
| | - Andrew M Shearer
- Center for Hemostasis and Thrombosis Research, Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA; Tufts University School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, 02111, USA
| | - Elizabeth K Fletcher
- Center for Hemostasis and Thrombosis Research, Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA
| | - Nga Nguyen
- Center for Hemostasis and Thrombosis Research, Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA
| | - Srijoy Guha
- Center for Hemostasis and Thrombosis Research, Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA
| | - Daniel H Cox
- Tufts University School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, 02111, USA
| | - Manal Abdelmalek
- Division of Gastroenterology and Hepatology, Duke University Medical Center, Durham, NC, 27710, USA
| | - Ying Wang
- Division of Gastroenterology and Hepatology, Duke University Medical Center, Durham, NC, 27710, USA
| | - James D Baleja
- Tufts University School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, 02111, USA
| | - Lidija Covic
- Center for Hemostasis and Thrombosis Research, Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA; Tufts University School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, 02111, USA
| | - Athan Kuliopulos
- Center for Hemostasis and Thrombosis Research, Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA; Tufts University School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, 02111, USA.
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10
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Xue H, Chen D, Zhong Y, Zhou Z, Fang S, Li M, Guo C. Deferoxamine ameliorates hepatosteatosis via several mechanisms in
ob/ob
mice. Ann N Y Acad Sci 2016; 1375:52-65. [DOI: 10.1111/nyas.13174] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Revised: 05/31/2016] [Accepted: 06/14/2016] [Indexed: 01/12/2023]
Affiliation(s)
- Han Xue
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Di Chen
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Yan‐Ke Zhong
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Zhen‐Diao Zhou
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Shi‐Xin Fang
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Ming‐Yao Li
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Chuang Guo
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
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11
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Song XS, Zhang J, Chen X, Palyha O, Chung C, Sonatore LM, Wilsie L, Stout S, McLaren DG, Taggart A, Imbriglio JE, Pinto S, Garcia-Calvo M, Addona GH. Identification of DGAT2 Inhibitors Using Mass Spectrometry. ACTA ACUST UNITED AC 2015; 21:117-26. [DOI: 10.1177/1087057115607463] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 08/23/2015] [Indexed: 11/17/2022]
Abstract
Mass spectrometry offers significant advantages over other detection technologies in the areas of hit finding, hit validation, and medicinal chemistry compound optimization. The foremost obvious advantage is the ability to directly measure enzymatic product formation. In addition, the inherent sensitivity of the liquid chromatography/mass spectrometry (LC/MS) approach allows the execution of enzymatic assays at substrate concentrations typically at or below substrate Km. Another advantage of the LC/MS approach is the ability to assay impure enzyme systems that would otherwise be difficult to prosecute with traditional labeled methods. This approach was used to identify inhibitors of diacylglycerol O-acyltransferase-2 (DGAT2), a transmembrane enzyme involved in the triglyceride (TG) production pathway. The LC/MS approach was employed because of its increased assay window (compared with control membranes) of more than sevenfold compared with less than twofold with a conventional fluorogenic assay. The ability to generate thousands of dose-dependent IC50 data was made possible by the use of a staggered parallel LC/MS system with fast elution gradients. From the hit-deconvolution efforts, several structural scaffold series were identified that inhibit DGAT2 activity. Additional profiling of one chemotype in particular identified two promising reversible and selective compounds (compound 15 and compound 16) that effectively inhibit TG production in mouse primary hepatocytes.
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Affiliation(s)
- Xuelei S. Song
- Department of Pharmacology, Merck Research Laboratories, Boston, MA, USA
| | - Jiaping Zhang
- Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ, USA
| | - Xun Chen
- Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ, USA
| | - Oksana Palyha
- Atherosclerosis, Merck Research Laboratories, Kenilworth, NJ, USA
| | - Christine Chung
- Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ, USA
| | - Lisa M. Sonatore
- Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ, USA
| | - Larissa Wilsie
- Atherosclerosis, Merck Research Laboratories, Kenilworth, NJ, USA
| | - Steven Stout
- Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ, USA
| | - David G. McLaren
- Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ, USA
| | - Andrew Taggart
- Atherosclerosis, Merck Research Laboratories, Kenilworth, NJ, USA
| | | | - Shirly Pinto
- Atherosclerosis, Merck Research Laboratories, Kenilworth, NJ, USA
| | | | - George H. Addona
- Department of Pharmacology, Merck Research Laboratories, Boston, MA, USA
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12
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Abstract
Adipose tissue plays a major role in metabolic homeostasis, which it coordinates through a number of local and systemic effectors. The burgeoning epidemic of metabolic disease, especially obesity and type 2 diabetes, has focused attention on the adipocyte. In this chapter, we review strategies for genetic overexpression and knockout of specific genes in adipose tissue. We also discuss these strategies in the context of different types of adipocytes, including brown, beige, and white fat cells.
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Affiliation(s)
- Sona Kang
- Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Xingxing Kong
- Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Evan D Rosen
- Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
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13
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Abstract
Diabetes and obesity are both associated with lipotoxic cardiomyopathy exclusive of coronary artery disease and hypertension. Lipotoxicities have become a public health concern and are responsible for a significant portion of clinical cardiac disease. These abnormalities may be the result of a toxic metabolic shift to more fatty acid and less glucose oxidation with concomitant accumulation of toxic lipids. Lipids can directly alter cellular structures and activate downstream pathways leading to toxicity. Recent data have implicated fatty acids and fatty acyl coenzyme A, diacylglycerol, and ceramide in cellular lipotoxicity, which may be caused by apoptosis, defective insulin signaling, endoplasmic reticulum stress, activation of protein kinase C, MAPK activation, or modulation of PPARs.
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14
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Danai LV, Guilherme A, Guntur KV, Straubhaar J, Nicoloro SM, Czech MP. Map4k4 suppresses Srebp-1 and adipocyte lipogenesis independent of JNK signaling. J Lipid Res 2013; 54:2697-707. [PMID: 23924694 PMCID: PMC3770083 DOI: 10.1194/jlr.m038802] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 08/05/2013] [Indexed: 11/20/2022] Open
Abstract
Adipose tissue lipogenesis is paradoxically impaired in human obesity, promoting ectopic triglyceride (TG) deposition, lipotoxicity, and insulin resistance. We previously identified mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4), a sterile 20 protein kinase reported to be upstream of c-Jun NH2-terminal kinase (JNK) signaling, as a novel negative regulator of insulin-stimulated glucose transport in adipocytes. Using full-genome microarray analysis we uncovered a novel role for Map4k4 as a suppressor of lipid synthesis. We further report here the surprising finding that Map4k4 suppresses adipocyte lipogenesis independently of JNK. Thus, while Map4k4 silencing in adipocytes enhances the expression of lipogenic enzymes, concomitant with increased conversion of (14)C-glucose and (14)C-acetate into TGs and fatty acids, JNK1 and JNK2 depletion causes the opposite effects. Furthermore, high expression of Map4k4 fails to activate endogenous JNK, while Map4k4 depletion does not attenuate JNK activation by tumor necrosis factor α. Map4k4 silencing in cultured adipocytes elevates both the total protein expression and cleavage of sterol-regulated element binding protein-1 (Srebp-1) in a rapamycin-sensitive manner, consistent with Map4k4 signaling via mechanistic target of rapamycin complex 1 (mTORC1). We show Map4k4 depletion requires Srebp-1 upregulation to increase lipogenesis and further show that Map4k4 promotes AMP-protein kinase (AMPK) signaling and the phosphorylation of mTORC1 binding partner raptor (Ser792) to inhibit mTORC1. Our results indicate that Map4k4 inhibits adipose lipogenesis by suppression of Srebp-1 in an AMPK- and mTOR-dependent but JNK-independent mechanism.
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Affiliation(s)
- Laura V. Danai
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
| | - Adilson Guilherme
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
| | | | - Juerg Straubhaar
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
| | - Sarah M. Nicoloro
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
| | - Michael P. Czech
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
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15
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Peripheral reduction of FGFR4 with antisense oligonucleotides increases metabolic rate and lowers adiposity in diet-induced obese mice. PLoS One 2013; 8:e66923. [PMID: 23922646 PMCID: PMC3726752 DOI: 10.1371/journal.pone.0066923] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Accepted: 05/13/2013] [Indexed: 12/26/2022] Open
Abstract
Obesity is a primary risk factor for multiple metabolic disorders. Many drugs for the treatment of obesity, which mainly act through CNS as appetite suppressants, have failed during development or been removed from the market due to unacceptable adverse effects. Thus, there are very few efficacious drugs available and remains a great unmet medical need for anti-obesity drugs that increase energy expenditure by acting on peripheral tissues without severe side effects. Here, we report a novel approach involving antisense inhibition of fibroblast growth factor receptor 4 (FGFR4) in peripheral tissues. Treatment of diet-induce obese (DIO) mice with FGFR4 antisense oligonucleotides (ASO) specifically reduced liver FGFR4 expression that not only resulted in decrease in body weight (BW) and adiposity in free-feeding conditions, but also lowered BW and adiposity under caloric restriction. In addition, combination treatment with FGFR4 ASO and rimonabant showed additive reduction in BW and adiposity. FGFR4 ASO treatment increased basal metabolic rate during free-feeding conditions and, more importantly, prevented adaptive decreases of metabolic rate induced by caloric restriction. The treatment increased fatty acid oxidation while decreased lipogenesis in both liver and fat. Mechanistic studies indicated that anti-obesity effect of FGFR4 ASO was mediated at least in part through an induction of plasma FGF15 level resulted from reduction of hepatic FGFR4 expression. The anti-obesity effect was accompanied by improvement in plasma glycemia, whole body insulin sensitivity, plasma lipid levels and liver steatosis. Therefore, FGFR4 could be a potential novel target and antisense reduction of hepatic FGFR4 expression could be an efficacious therapy as an adjunct to diet restriction or to an appetite suppressant for the treatment of obesity and related metabolic disorders.
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16
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Abstract
The main approach to obesity and type-II diabetes is to unravel the mechanisms involved in nutrient absorption and fuel allocation. In conditions of over-nutrition, cells must cope with a multitude of extracellular signals generated by changes in nutrient load, hormonal milieu, adverse cytokine/adipokine profile, and apoptosis/anti-apoptosis processes. To date studies have demonstrate that among all nutrients, lipids and carbohydrates play a major regulatory role in the gene transcription of glycolytic and lipogenic enzymes, insulin, and adipokines. These nutrients mainly exert their effects through the gene expression of sterol responsive binding protein 1 and 2 (SREBP) and the mammalian target of rapamycin (mTOR). Excess of adipose tissue is known to confer a significantly higher risk of coronary artery disease. Administration of rapamycin effectively attenuated inflammation, inhibited progression, and enhanced stability of atherosclerotic plaques in animal models. Herein we discuss the mTOR pathway and the molecular mechanisms of mTOR inhibitors, hypothesizing a possible protective role in atherosclerosis, taking into account also previous clinical studies emphasizing their opposite role.
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Affiliation(s)
- Giovanni Tarantino
- Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, Italy.
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17
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Josekutty J, Iqbal J, Iwawaki T, Kohno K, Hussain MM. Microsomal triglyceride transfer protein inhibition induces endoplasmic reticulum stress and increases gene transcription via Ire1α/cJun to enhance plasma ALT/AST. J Biol Chem 2013; 288:14372-14383. [PMID: 23532846 DOI: 10.1074/jbc.m113.459602] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Microsomal triglyceride transfer protein (MTP) is a target to reduce plasma lipids because of its indispensable role in triglyceride-rich lipoprotein biosynthesis. MTP inhibition in Western diet fed mice decreased plasma triglycerides/cholesterol, whereas increasing plasma alanine/aspartate aminotransferases (ALT/AST) and hepatic triglycerides/free cholesterol. Free cholesterol accumulated in the endoplasmic reticulum (ER) and mitochondria resulting in ER and oxidative stresses. Mechanistic studies revealed that MTP inhibition increased transcription of the GPT/GOT1 genes through up-regulation of the IRE1α/cJun pathway leading to increased synthesis and release of ALT1/AST1. Thus, transcriptional up-regulation of GPT/GOT1 genes is a major mechanism, in response to ER stress, elevating plasma transaminases. Increases in plasma and tissue transaminases might represent a normal response to stress for survival.
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Affiliation(s)
- Joby Josekutty
- School of Graduate Studies, Molecular and Cell Biology Program, State University of New York Downstate Medical Center, Brooklyn, New York 11203; Departments of Cell Biology and Pediatrics, State University of New York Downstate Medical Center, Brooklyn, New York 11203
| | - Jahangir Iqbal
- Departments of Cell Biology and Pediatrics, State University of New York Downstate Medical Center, Brooklyn, New York 11203
| | - Takao Iwawaki
- Advanced Scientific Research Leaders Development Unit, Gunma University, Gunma, Japan
| | - Kenji Kohno
- Nara Institute of Science and Technology, Nara, Japan
| | - M Mahmood Hussain
- Departments of Cell Biology and Pediatrics, State University of New York Downstate Medical Center, Brooklyn, New York 11203.
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18
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Ngoei KRW, Ng DCH, Gooley PR, Fairlie DP, Stoermer MJ, Bogoyevitch MA. Identification and characterization of bi-thiazole-2,2'-diamines as kinase inhibitory scaffolds. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2013; 1834:1077-88. [PMID: 23410953 DOI: 10.1016/j.bbapap.2013.02.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Revised: 01/30/2013] [Accepted: 02/03/2013] [Indexed: 11/18/2022]
Abstract
Based on bioinformatics interrogation of the genome, >500 mammalian protein kinases can be clustered within seven different groups. Of these kinases, the mitogen-activated protein kinase (MAPK) family forms part of the CMGC group of serine/threonine kinases that includes extracellular signal regulated kinases (ERKs), cJun N-terminal kinases (JNKs), and p38 MAPKs. With the JNKs considered attractive targets in the treatment of pathologies including diabetes and stroke, efforts have been directed to the discovery of new JNK inhibitory molecules that can be further developed as new therapeutics. Capitalizing on our biochemical understanding of JNK, we performed in silico screens of commercially available chemical databases to identify JNK1-interacting compounds and tested their in vitro JNK inhibitory activity. With in vitro and cell culture studies, we showed that the compound, 4'-methyl-N(2)-3-pyridinyl-4,5'-bi-1,3-thiazole-2,2'-diamine (JNK Docking (JD) compound 123, but not the related compound (4'-methyl-N~2~-(6-methyl-2-pyridinyl)-4,5'-bi-1,3-thiazole-2,2'-diamine (JD124), inhibited JNK1 activity towards a range of substrates. Molecular docking, saturation transfer difference NMR experiments and enzyme kinetic analyses revealed both ATP- and substrate-competitive inhibition of JNK by JD123. In characterizing JD123 further, we noted its ATP-competitive inhibition of the related p38-γ MAPK, but not ERK1, ERK2, or p38-α, p38-β or p38-δ. Further screening of a broad panel of kinases using 10μM JD123, identified inhibition of kinases including protein kinase Bβ (PKBβ/Aktβ). Appropriately modified thiazole diamines, as typified by JD123, thus provide a new chemical scaffold for development of inhibitors for the JNK and p38-γ MAPKs as well as other kinases that are also potential therapeutic targets such as PKBβ/Aktβ.
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Affiliation(s)
- Kevin R W Ngoei
- Department of Biochemistry and Molecular Biology, University of Melbourne, Victoria, Australia
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19
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Díaz-Delfín J, Hondares E, Iglesias R, Giralt M, Caelles C, Villarroya F. TNF-α represses β-Klotho expression and impairs FGF21 action in adipose cells: involvement of JNK1 in the FGF21 pathway. Endocrinology 2012; 153:4238-45. [PMID: 22778214 DOI: 10.1210/en.2012-1193] [Citation(s) in RCA: 165] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Fibroblast growth factor 21 (FGF21) is a member of the FGF family that reduces glycemia and ameliorates insulin resistance. Adipose tissue is a main target of FGF21 action. Obesity is associated with a chronic proinflammatory state. Here, we analyzed the role of proinflammatory signals in the FGF21 pathway in adipocytes, evaluating the effects of TNF-α on β-Klotho and FGF receptor-1 expression and FGF21 action in adipocytes. We also determined the effects of rosiglitazone on β-Klotho and FGF receptor-1 expression in models of proinflammatory signal induction in vitro and in vivo (high-fat diet-induced obesity). Because c-Jun NH(2)-terminal kinase 1 (JNK1) serves as a sensing juncture for inflammatory status, we also evaluated the involvement of JNK1 in the FGF21 pathway. TNF-α repressed β-Klotho expression and impaired FGF21 action in adipocytes. Rosiglitazone prevented the reduction in β-Klotho expression elicited by TNF-α. Moreover, β-Klotho levels were reduced in adipose tissue from high-fat diet-induced obese mice, whereas rosiglitazone restored β-Klotho to near-normal levels. β-Klotho expression was increased in white fat from JNK1(-/-) mice. The absence of JNK1 increased the responsiveness of mouse embryonic fibroblast-derived adipocytes and brown adipocytes to FGF21. In conclusion, we show that proinflammatory signaling impairs β-Klotho expression and FGF21 responsiveness in adipocytes. We also show that JNK1 activity is involved in modulating FGF21 effects in adipocytes. The impairment in the FGF21 response machinery in adipocytes and the reduction in FGF21 action in response to proinflammatory signals may play important roles in metabolic alterations in obesity and other diseases associated with enhanced inflammation.
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Affiliation(s)
- Julieta Díaz-Delfín
- Department of Biochemistry and Molecular Biology, University of Barcelona, Avda Diagonal 643, 08028-Barcelona, Spain.
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20
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Park YS, David AE, Huang Y, Park JB, He H, Byun Y, Yang VC. In vivo delivery of cell-permeable antisense hypoxia-inducible factor 1α oligonucleotide to adipose tissue reduces adiposity in obese mice. J Control Release 2012; 161:1-9. [PMID: 22546680 PMCID: PMC3378795 DOI: 10.1016/j.jconrel.2012.04.026] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Revised: 04/13/2012] [Accepted: 04/18/2012] [Indexed: 01/06/2023]
Abstract
Ongoing research has gradually recognized and understood the importance of adipose tissue (AT) angiogenesis as a key modulating factor of adipogenesis in the development of obesity. Previously, we carried out the first in vitro demonstration of the down-regulation of hypoxic angiogenesis during adipogenesis using cell-permeable chemical conjugates composed of antisense hypoxia-inducible factor 1α (HIF1α) oligonucleotide (ASO) and low-molecular weight protamine (LMWP). To further confirm the in vivo feasibility, we administered ASO-LMWP conjugates (AL) to diet-induced obese (DIO) mice by intraperitoneal injection (IP). Results showed that the AL conjugates significantly reduced the body weight, total fat tissue weight, and plasma lipid concentrations in the mice. Moreover, the AL conjugates not only decreased liver weight and hepatic triglyceride concentration but also significantly attenuated subcutaneous adipocyte cell size, which was conversely increased in the AL-untreated high-fat diet (HFD) group. Interestingly, more blood vessels were observed in the HFD group than in the lean group, indicating that blood vessel development could induce growth of the fat mass. This pattern was reversed in the AL-treated groups, which displayed a decrease in blood vessel density compared to the AL-untreated HFD group. This study presents the first in vivo evidence, in an obese mouse model, of the feasibility of achieving a biological treatment modality for obesity by blocking the angiogenic transcriptional factor HIF1α, thereby limiting angiogenesis, via the use of an adipose tissue-permeable ASO-LMWP.
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Affiliation(s)
- Yoon Shin Park
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109-1065, USA
| | - Allan E. David
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109-1065, USA
| | - Yongzhuo Huang
- Shanghai Institute of Material Medica, Chinese Academy of Sciences, 501 Hai-ke Road, Shanghai, 201203, China
| | - Jun-Beom Park
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea
| | - Huining He
- School of Pharmacy, Tianjin Medical University & Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, Tianjin 300070, China
| | - Youngro Byun
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea
| | - Victor C. Yang
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109-1065, USA
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea
- School of Pharmacy, Tianjin Medical University & Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, Tianjin 300070, China
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21
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Crooke RM, Graham MJ. Therapeutic potential of antisense oligonucleotides for the management of dyslipidemia. ACTA ACUST UNITED AC 2011. [DOI: 10.2217/clp.11.59] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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22
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Tarantino G, Caputi A. JNKs, insulin resistance and inflammation: A possible link between NAFLD and coronary artery disease. World J Gastroenterol 2011; 17:3785-3794. [PMID: 21987620 PMCID: PMC3181439 DOI: 10.3748/wjg.v17.i33.3785] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2010] [Revised: 02/19/2011] [Accepted: 02/26/2011] [Indexed: 02/06/2023] Open
Abstract
The incidence of obesity has dramatically increased in recent years. Consequently, obesity and associated disorders such as nonalcoholic fatty liver disease constitute a serious problem. Therefore, the contribution of adipose tissue to metabolic homeostasis has become a focus of interest. In this review, we discuss the latest discoveries that support the role of lipids in nonalcoholic fatty liver disease. We describe the common mechanisms (c-Jun amino-terminal kinases, endoplasmic reticulum stress, unfolded protein response, ceramide, low-grade chronic inflammation) by which lipids and their derivatives impair insulin responsiveness and contribute to inflammatory liver and promote plaque instability in the arterial wall. Presenting the molecular mechanism of lipid activation of pro-inflammatory pathways, we attempt to find a link between nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular diseases. Describing the common mechanisms by which lipid derivatives, through modulation of macrophage function, promote plaque instability in the arterial wall, impair insulin responsiveness and contribute to inflammatory liver and discussing the molecular mechanism of lipid activation of pro-inflammatory pathways, the key roles played by the proliferator-activated receptor and liver X receptor α, nuclear receptors-lipid sensors that link lipid metabolism and inflammation, should be emphasized. Further studies are warranted of anti-inflammatory drugs such as aspirin, anti-interleukin-6 receptors, immune-modulators (calcineurin inhibitors), substances enhancing the expression of heat shock proteins (which protect cells from endoplasmic reticulum stress-induced apoptosis), and anti- c-Jun amino-terminal kinases in well-designed trials to try to minimize the high impact of these illnesses, and the different expressions of the diseases, on the whole population.
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23
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Drosatos K, Drosatos-Tampakaki Z, Khan R, Homma S, Schulze PC, Zannis VI, Goldberg IJ. Inhibition of c-Jun-N-terminal kinase increases cardiac peroxisome proliferator-activated receptor alpha expression and fatty acid oxidation and prevents lipopolysaccharide-induced heart dysfunction. J Biol Chem 2011; 286:36331-9. [PMID: 21873422 DOI: 10.1074/jbc.m111.272146] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Septic shock results from bacterial infection and is associated with multi-organ failure, high mortality, and cardiac dysfunction. Sepsis causes both myocardial inflammation and energy depletion. We hypothesized that reduced cardiac energy production is a primary cause of ventricular dysfunction in sepsis. The JNK pathway is activated in sepsis and has also been implicated in impaired fatty acid oxidation in several tissues. Therefore, we tested whether JNK activation inhibits cardiac fatty acid oxidation and whether blocking JNK would restore fatty acid oxidation during LPS treatment. LPS treatment of C57BL/6 mice and adenovirus-mediated activation of the JNK pathway in cardiomyocytes inhibited peroxisome proliferator-activated receptor α expression and fatty acid oxidation. Surprisingly, none of the adaptive responses that have been described in other types of heart failure, such as increased glucose utilization, reduced αMHC:βMHC ratio or induction of certain microRNAs, occurred in LPS-treated mice. Treatment of C57BL/6 mice with a general JNK inhibitor (SP600125) increased fatty acid oxidation in mice and a cardiomyocyte-derived cell line. JNK inhibition also prevented LPS-mediated reduction in fatty acid oxidation and cardiac dysfunction. Inflammation was not alleviated in LPS-treated mice that received the JNK inhibitor. We conclude that activation of JNK signaling reduces fatty acid oxidation and prevents the peroxisome proliferator-activated receptor α down-regulation that occurs with LPS.
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Affiliation(s)
- Konstantinos Drosatos
- Division of Preventive Medicine and Nutrition, Columbia University College of Physicians and Surgeons, New York, New York, USA
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Czaja MJ. JNK regulation of hepatic manifestations of the metabolic syndrome. Trends Endocrinol Metab 2010; 21:707-13. [PMID: 20888782 PMCID: PMC2991513 DOI: 10.1016/j.tem.2010.08.010] [Citation(s) in RCA: 101] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2010] [Revised: 08/20/2010] [Accepted: 08/30/2010] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is now recognized as both an important component of the metabolic syndrome and the most prevalent liver disease in the United States. Although the mechanisms for development of steatosis and chronic liver injury in NAFLD remain unclear, recent investigations have indicated that overactivation of c-Jun N-terminal kinase (JNK) is crucial to this process. These findings, together with evidence for the involvement of JNK signaling in other manifestations of the metabolic syndrome such as obesity and insulin resistance, have suggested that JNK could be a novel therapeutic target in this disorder. This review details findings that JNK mediates lipid accumulation and cell injury in fatty liver disease and discusses the possible cellular mechanisms of JNK actions.
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Affiliation(s)
- Mark J Czaja
- Department of Medicine, Marion Bessin Liver Research Center and Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
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Cubero FJ, Drvarov O, Trautwein C. c-Jun NH(2)-terminal kinase 1 in hepatocytes: an essential mediator of insulin resistance. Hepatology 2010; 51:2221-3. [PMID: 20513007 DOI: 10.1002/hep.23737] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Garcia-Garcia J, Guney E, Aragues R, Planas-Iglesias J, Oliva B. Biana: a software framework for compiling biological interactions and analyzing networks. BMC Bioinformatics 2010; 11:56. [PMID: 20105306 PMCID: PMC3098100 DOI: 10.1186/1471-2105-11-56] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2009] [Accepted: 01/27/2010] [Indexed: 12/13/2022] Open
Abstract
Background The analysis and usage of biological data is hindered by the spread of information across multiple repositories and the difficulties posed by different nomenclature systems and storage formats. In particular, there is an important need for data unification in the study and use of protein-protein interactions. Without good integration strategies, it is difficult to analyze the whole set of available data and its properties. Results We introduce BIANA (Biologic Interactions and Network Analysis), a tool for biological information integration and network management. BIANA is a Python framework designed to achieve two major goals: i) the integration of multiple sources of biological information, including biological entities and their relationships, and ii) the management of biological information as a network where entities are nodes and relationships are edges. Moreover, BIANA uses properties of proteins and genes to infer latent biomolecular relationships by transferring edges to entities sharing similar properties. BIANA is also provided as a plugin for Cytoscape, which allows users to visualize and interactively manage the data. A web interface to BIANA providing basic functionalities is also available. The software can be downloaded under GNU GPL license from http://sbi.imim.es/web/BIANA.php. Conclusions BIANA's approach to data unification solves many of the nomenclature issues common to systems dealing with biological data. BIANA can easily be extended to handle new specific data repositories and new specific data types. The unification protocol allows BIANA to be a flexible tool suitable for different user requirements: non-expert users can use a suggested unification protocol while expert users can define their own specific unification rules.
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Affiliation(s)
- Javier Garcia-Garcia
- Structural Bioinformatics Lab, Universitat Pompeu Fabra-IMIM, Barcelona Research Park of Biomedicine, Barcelona, Catalonia, Spain
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Kodama Y, Brenner DA. c-Jun N-terminal kinase signaling in the pathogenesis of nonalcoholic fatty liver disease: Multiple roles in multiple steps. Hepatology 2009; 49:6-8. [PMID: 19111006 DOI: 10.1002/hep.22710] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Nasse J, Terman D, Venugopal S, Hermann G, Rogers R, Travers JB. Local circuit input to the medullary reticular formation from the rostral nucleus of the solitary tract. Am J Physiol Regul Integr Comp Physiol 2008; 295:R1391-408. [PMID: 18716034 DOI: 10.1152/ajpregu.90457.2008] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The intermediate reticular formation (IRt) subjacent to the rostral (gustatory) nucleus of the solitary tract (rNST) receives projections from the rNST and appears essential to the expression of taste-elicited ingestion and rejection responses. We used whole cell patch-clamp recording and calcium imaging to characterize responses from an identified population of prehypoglossal neurons in the IRt to electrical stimulation of the rNST in a neonatal rat pup slice preparation. The calcium imaging studies indicated that IRt neurons could be activated by rNST stimulation and that many neurons were under tonic inhibition. Whole cell patch-clamp recording revealed mono- and polysynaptic projections from the rNST to identified prehypoglossal neurons. The projection was primarily excitatory and glutamatergic; however, there were some inhibitory GABAergic projections, and many neurons received excitatory and inhibitory inputs. There was also evidence of disinhibition. Overall, bath application of GABA(A) antagonists increased the amplitude of excitatory currents, and, in several neurons, stimulation of the rNST systematically decreased inhibitory currents. We have hypothesized that the transition from licks to gapes by natural stimuli, such as quinine monohydrochloride, could occur via such disinhibition. We present an updated dynamic model that summarizes the complex synaptic interface between the rNST and the IRt and demonstrates how inhibition could contribute to the transition from ingestion to rejection.
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Affiliation(s)
- J Nasse
- College of Dentistry, Ohio State Univ., 305 W. 12th Ave., Columbus, OH 43201, USA
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