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Lim DS, Ahn SH, Gwon HJ, Cho W, Abd El-Aty AM, Aydemir HA, Sharma N, Hong SA, Jung TW, Jeong JH. Resolvin D5: A lipid mediator with a therapeutic effect on hepatic steatosis through SIRT6/autophagy. Tissue Cell 2025; 96:102980. [PMID: 40398078 DOI: 10.1016/j.tice.2025.102980] [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: 03/24/2025] [Revised: 05/06/2025] [Accepted: 05/16/2025] [Indexed: 05/23/2025]
Abstract
Resolvin D5 (RD5), a lipid mediator derived from DHA via 5-lipoxygenase signaling, has been shown to resolve inflammation in various disease models. This study aimed to investigate the role of RD5 in the development of hepatic steatosis in individuals with obesity and explore the detailed mechanisms involved. Protein expression was evaluated via Western blot analysis, whereas hepatic lipid deposition was examined via Oil Red O staining and triglyceride quantification. Autophagosomes were detected via MDC staining. Our findings indicated that RD5 treatment normalized lipogenic lipid accumulation, fatty acid uptake, oxidation, apoptosis, and endoplasmic reticulum (ER) stress in palmitate-treated primary hepatocytes. As a cytoprotective signaling pathway, RD5 treatment increased the expression of SIRT6 and autophagy markers, such as those involved in LC3 conversion and p62 degradation. The beneficial effects of RD5 on hepatic lipid metabolism, apoptosis, and ER stress were negated by SIRT6 small interfering RNA or 3-methyladenine, an inhibitor of autophagy. Furthermore, RD5 administration decreased hepatic steatosis, apoptosis, and ER stress in the livers of high-fat diet (HFD)-fed mice. In line with the in vitro results, RD5 treatment elevated SIRT6 and autophagy levels in the livers of HFD-fed mice. These novel findings suggest that RD5 improves hepatic lipid metabolism, apoptosis and ER stress through SIRT6/autophagy signaling, thereby attenuating hepatic steatosis. RD5 may have therapeutic potential for treating nonalcoholic fatty liver disease with minimal side effects.
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Affiliation(s)
- Do Su Lim
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Sung Ho Ahn
- Department of Family Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyeon Ji Gwon
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Wonjun Cho
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum 25240, Turkey.
| | - Haci Ahmet Aydemir
- Department of Family Medicine, Erzurum Regional Training and Research Hospital, Erzurum 25000, Turkey
| | - Naveen Sharma
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Soon Auck Hong
- Department of Pathology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Tae Woo Jung
- Department of Pharmacology, 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; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea.
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Ahn SH, Lee YJ, Lim DS, Cho W, Gwon HJ, Abd El-Aty AM, Jeong JH, Jung TW. Upadacitinib counteracts hepatic lipid deposition via the repression of JAK1/STAT3 signaling and AMPK/autophagy-mediated suppression of ER stress. Biochem Biophys Res Commun 2024; 735:150829. [PMID: 39406018 DOI: 10.1016/j.bbrc.2024.150829] [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: 10/05/2024] [Accepted: 10/11/2024] [Indexed: 11/05/2024]
Abstract
Upadacitinib (UPA) has been utilized to treat conditions such as rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, and axial spondyloarthritis by modulating inflammation via the JAK pathway. However, its impact on hepatic lipogenesis remains insufficiently studied. This research evaluated protein expression through Western blotting, lipid accumulation with oil red O staining, autophagosomes in hepatocytes via MDC staining, and hepatic apoptosis via cell viability and caspase 3 activity assays. This study aimed to explore the effects of UPA on hepatic lipogenesis and the underlying molecular mechanisms in in vitro models of hepatic steatosis. These findings demonstrated that UPA reduced lipid deposition, apoptosis, and ER stress in palmitate-treated hepatocytes. UPA treatment inhibited phosphorylated JAK1 and STAT3 while promoting the expression of phosphorylated AMPK and autophagy markers. AMPK siRNA negated the effects of UPA on lipogenic lipid deposition, apoptosis, JAK1/STAT3 phosphorylation, and ER stress. These results reveal that UPAmitigates ER stress through the JAK1/STAT3/AMPK pathway, thereby reducing lipid deposition and apoptosis in hyperlipidemic hepatocytes, supporting its potential as a therapeutic strategy for treating hepatic steatosis in obese individuals.
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Affiliation(s)
- Sung Ho Ahn
- Department of Family Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong-Jik Lee
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Do Su Lim
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Wonjun Cho
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Hyeon Ji Gwon
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, 12211-Giza, Egypt; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey.
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea.
| | - Tae Woo Jung
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
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Li D, Cai D, Xie D, Wang L, Zhang Y, Ruan G, Zhang Q, Yan B, Zhang H, Lai P, Liao Z, Jiang Y, Yu D, Ding C, Yang C. Dynamic control of mTORC1 facilitates bone healing in mice. Bone 2024; 190:117285. [PMID: 39426581 DOI: 10.1016/j.bone.2024.117285] [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: 08/27/2024] [Revised: 10/10/2024] [Accepted: 10/12/2024] [Indexed: 10/21/2024]
Abstract
Bone healing requires well-orchestrated sequential actions of osteoblasts and osteoclasts. Previous studies have demonstrated that the mechanistic target of rapamycin complex 1 (mTORC1) plays a critical role in the metabolism of osteoblasts and osteoclasts. However, the role of mTORC1 in bone healing remains unclear. Here, we showed that a dynamic change in mTORC1 activity during the process was essential for proper healing and can be harnessed therapeutically for treatment of bone fractures. Low mTORC1 activity induced by osteoblastic Raptor knockout or rapamycin treatment promoted osteoblast-mediated osteogenesis, thus leading to better bone formation and shorter bone union time. Rapamycin treatment in vitro also revealed that low mTORC1 activity enhanced osteoblast differentiation and maturation. However, rapamycin treatment affected the recruitment of osteoclasts to new bone sites, thus resulting in delayed callus absorption in bone marrow cavity. Mechanistically, decreased mTORC1 activity inhibited the recruitment of osteoclast progenitor cells to healing sites through a decrease in osteoblastic expression of monocyte chemoattractant protein-1, thus inhibiting osteoclast-mediated remodeling. Therefore, normal mTORC1 activity was necessary for bone remodeling stage. Furthermore, through the use of sustained-release materials at the bone defect, we confirmed that localized application of rapamycin in early stages accelerated bone healing without affecting bone remodeling. Together, these findings revealed that the activity of mTORC1 continually changed during bone healing, and staged rapamycin treatment could be used to promote bone healing.
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Affiliation(s)
- Delong Li
- Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China
| | - Daozhang Cai
- Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China
| | - Denghui Xie
- Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China
| | - Liang Wang
- Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China
| | - Yan Zhang
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Guangfeng Ruan
- Clinical Research Centre, Guangzhou First People's Hospital, Guangzhou 510180, China
| | - Qun Zhang
- Office of Clinical Trial of Drug, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China
| | - Bo Yan
- Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China
| | - Haiyan Zhang
- Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China
| | - Pinglin Lai
- Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China
| | - Zhengquan Liao
- Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China
| | - Yu Jiang
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Dianbo Yu
- Department of Sports Medicine, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, China; Guangxi Biomedical Materials Engineering Research Center for Bone and Joint Degenerative Diseases, Baise, Guangxi 533000, China
| | - Changhai Ding
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; Menzies Institute for Medical Research, University of Tasmania, Hobart 7000, Australia.
| | - Chengliang Yang
- Department of Orthopedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, China; Guangxi Health Commission Key Laboratory of Biomedical Materials Research, Baise, Guangxi 533000, China.
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Park SS, Cho W, Lim DS, Gwon HJ, Choi SW, Abd El-Aty AM, Aydemir HA, Jeong JH, Jung TW. AMPK/autophagy-mediated alleviation of tendinopathy by IL-38: A novel strategy for the treatment of obesity-related tendinopathy. Tissue Cell 2024; 88:102392. [PMID: 38643674 DOI: 10.1016/j.tice.2024.102392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/14/2024] [Accepted: 04/18/2024] [Indexed: 04/23/2024]
Abstract
The effect of interleukin-38 (IL-38), a recently identified member of the IL-1 family with potential applications in various inflammation-related conditions, on ER stress has not been explored. Furthermore, its role in obesity-associated tendinopathy has not been investigated. In this study, human primary tenocytes were treated with palmitate (200 or 400 μM) and palmitate plus IL-38 (0-50 ng/mL) for 24 h. Western blotting was used to assess ER stress and tendinopathogenic markers in tenocytes. Monodansylcadaverine (MDC) staining was used to evaluate autophagosomes. Apoptosis was determined by cell viability assays, caspase 3 activity assays and TUNEL assays. Cell migration was evaluated by a cell scratch assay. Small interfering (si) RNA transfection was used for target gene silencing. Treatment of tenocytes with IL-38 attenuated apoptosis, restored the balance between MMPs and TIMP-1, and alleviated ER stress under palmitate conditions. IL-38 treatment enhanced AMPK phosphorylation and promoted the expression of autophagy markers related to LC3 conversion, p62 degradation, and autophagosome formation in cultured tenocytes. The effects of IL-38 on ER stress, apoptosis, and MMP-9, MMP-13, and TIMP-1 expression in palmitate-treated tenocytes were abrogated by AMPK siRNA or 3-methyladenine (3MA). These results suggest that IL-38 alleviates ER stress through the AMPK/autophagy pathway, thereby reducing apoptosis and preventing extracellular matrix (ECM) degradation in tenocytes under hyperlipidemic conditions. This study provides a promising therapeutic avenue for treating obesity-related tendinopathy using an endogenous compound such as IL-38.
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Affiliation(s)
- Sung Su Park
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, the Republic of Korea
| | - Wonjun Cho
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, the Republic of Korea
| | - Do Su Lim
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, the Republic of Korea
| | - Hyeon Ji Gwon
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, the Republic of Korea
| | - Sung Woo Choi
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, the Republic of Korea
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum 25240, Turkey.
| | - Hacı Ahmet Aydemir
- Dr. Filiz Dolunay Family Health Center, Unit Number:59, Yakutiye, Erzurum, Turkey
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, the Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, the Republic of Korea
| | - Tae Woo Jung
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, the Republic of Korea.
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Cho W, Oh H, Abd El-Aty AM, Özten Ö, Jeong JH, Jung TW. Interleukin-27 as a novel player in alleviating hepatic steatosis: Mechanistic insights from an in vitro analysis. Biochem Biophys Res Commun 2024; 703:149671. [PMID: 38367515 DOI: 10.1016/j.bbrc.2024.149671] [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: 02/04/2024] [Revised: 02/05/2024] [Accepted: 02/09/2024] [Indexed: 02/19/2024]
Abstract
Interleukin-27 (IL-27) is a recently discovered cytokine that has been implicated in inflammatory and metabolic conditions, such as atherosclerosis and insulin resistance. However, the mechanisms by which IL-27 attenuates hepatic lipid accumulation in hyperlipidemic conditions and counteracts endoplasmic reticulum (ER) stress, a known risk factor for impaired hepatic lipid metabolism, have not been elucidated. This in vitro study was designed to examine the effect of IL-27 on hepatic lipid metabolism. The study included the evaluation of lipogenesis-associated proteins and ER stress markers by Western blotting, the determination of hepatic lipid accumulation by Oil Red O staining, and the examination of autophagosome formation by MDC staining. The results showed that IL-27 treatment reduced lipogenic lipid deposition and the expression of ER stress markers in cultured hepatocytes exposed to palmitate. Moreover, treatment with IL-27 suppressed CD36 expression and enhanced fatty acid oxidation in palmitate-treated hepatocytes. The effects of IL-27 on hyperlipidemic hepatocytes were attenuated when adenosine monophosphate-activated protein kinase (AMPK) or 3-methyladenine (3 MA) were inhibited by small interfering RNA (siRNA). These results suggest that IL-27 attenuates hepatic ER stress and fatty acid uptake and stimulates fatty acid oxidation via AMPK/autophagy signaling, thereby alleviating hepatic steatosis. In conclusion, this study identified IL-27 as a promising therapeutic target for nonalcoholic fatty liver disease (NAFLD).
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Affiliation(s)
- Wonjun Cho
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Heeseung Oh
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, 12211, Giza, Egypt; Department of Medical Pharmacology, Medical Faculty, Ataturk University, 25240 Erzurum, Turkey.
| | - Ömer Özten
- Department of Pharmacy Services, Vocational School of Health Services, Bayburt University, Bayburt, 69010, Turkey
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Tae Woo Jung
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
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Sun Y, Zhang Y, Zhang J, Chen YE, Jin JP, Zhang K, Mou H, Liang X, Xu J. XBP1-mediated transcriptional regulation of SLC5A1 in human epithelial cells in disease conditions. Cell Biosci 2024; 14:27. [PMID: 38388523 PMCID: PMC10885492 DOI: 10.1186/s13578-024-01203-x] [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: 06/27/2023] [Accepted: 02/01/2024] [Indexed: 02/24/2024] Open
Abstract
BACKGROUND Sodium-Glucose cotransporter 1 and 2 (SGLT1/2) belong to the family of glucose transporters, encoded by SLC5A1 and SLC5A2, respectively. SGLT2 is almost exclusively expressed in the renal proximal convoluted tubule cells. SGLT1 is expressed in the kidneys but also in other organs throughout the body. Many SGLT inhibitor drugs have been developed based on the mechanism of blocking glucose (re)absorption mediated by SGLT1/2, and several have gained major regulatory agencies' approval for treating diabetes. Intriguingly these drugs are also effective in treating diseases beyond diabetes, for example heart failure and chronic kidney disease. We recently discovered that SGLT1 is upregulated in the airway epithelial cells derived from patients of cystic fibrosis (CF), a devastating genetic disease affecting greater than 70,000 worldwide. RESULTS In the present work, we show that the SGLT1 upregulation is coupled with elevated endoplasmic reticulum (ER) stress response, indicated by activation of the primary ER stress senor inositol-requiring protein 1α (IRE1α) and the ER stress-induced transcription factor X-box binding protein 1 (XBP1), in CF epithelial cells, and in epithelial cells of other stress conditions. Through biochemistry experiments, we demonstrated that the spliced form of XBP1 (XBP1s) acts as a transcription factor for SLC5A1 by directly binding to its promoter region. Targeting this ER stress → SLC5A1 axis by either the ER stress inhibitor Rapamycin or the SGLT1 inhibitor Sotagliflozin was effective in attenuating the ER stress response and reducing the SGLT1 level in these cellular model systems. CONCLUSIONS The present work establishes a causal relationship between ER stress and SGLT1 upregulation and provides a mechanistic explanation why SGLT inhibitor drugs benefit diseases beyond diabetes.
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Affiliation(s)
- Yifei Sun
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Yihan Zhang
- The Mucosal Immunology & Biology Research Center, Massachusetts General Hospital, 55 Fruit Street, Jackson, 1402, Boston, MA, 02114, USA
| | - Jifeng Zhang
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Y Eugene Chen
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Jian-Ping Jin
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Kezhong Zhang
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Hongmei Mou
- The Mucosal Immunology & Biology Research Center, Massachusetts General Hospital, 55 Fruit Street, Jackson, 1402, Boston, MA, 02114, USA.
| | - Xiubin Liang
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Jie Xu
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, Ann Arbor, MI, USA.
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Engin AB. Mechanism of Obesity-Related Lipotoxicity and Clinical Perspective. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:131-166. [PMID: 39287851 DOI: 10.1007/978-3-031-63657-8_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
The link between cellular exposure to fatty acid species and toxicity phenotypes remains poorly understood. However, structural characterization and functional profiling of human plasma free fatty acids (FFAs) analysis has revealed that FFAs are located either in the toxic cluster or in the cluster that is transcriptionally responsive to lipotoxic stress and creates genetic risk factors. Genome-wide short hairpin RNA screen has identified more than 350 genes modulating lipotoxicity. Hypertrophic adipocytes in obese adipose are both unable to expand further to store excess lipids in the diet and are resistant to the antilipolytic action of insulin. In addition to lipolysis, the inability of packaging the excess lipids into lipid droplets causes circulating fatty acids to reach toxic levels in non-adipose tissues. Deleterious effects of accumulated lipid in non-adipose tissues are known as lipotoxicity. Although triglycerides serve a storage function for long-chain non-esterified fatty acid and their products such as ceramide and diacylglycerols (DAGs), overloading of palmitic acid fraction of saturated fatty acids (SFAs) raises ceramide levels. The excess DAG and ceramide load create harmful effects on multiple organs and systems, inducing chronic inflammation in obesity. Thus, lipotoxic inflammation results in β cells death and pancreatic islets dysfunction. Endoplasmic reticulum stress stimuli induce lipolysis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and extracellular signal-regulated kinase (Erk) 1/2 signaling in adipocytes. However, palmitic acid-induced endoplasmic reticulum stress-c-Jun N-terminal kinase (JNK)-autophagy axis in hypertrophic adipocytes is a pro-survival mechanism against endoplasmic reticulum stress and cell death induced by SFAs. Endoplasmic reticulum-localized acyl-coenzyme A (CoA): glycerol-3-phosphate acyltransferase (GPAT) enzymes are mediators of lipotoxicity, and inhibiting these enzymes has therapeutic potential for lipotoxicity. Lipotoxicity increases the number of autophagosomes, which engulf palmitic acid, and thus suppress the autophagic turnover. Fatty acid desaturation promotes palmitate detoxification and storages into triglycerides. As therapeutic targets of glucolipotoxicity, in addition to caloric restriction and exercise, there are four different pharmacological approaches, which consist of metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, peroxisome proliferator-activated receptor-gamma (PPARγ) ligands thiazolidinediones, and chaperones are still used in clinical practice. Furthermore, induction of the brown fat-like phenotype with the mixture of eicosapentanoic acid and docosahexaenoic acid appears as a potential therapeutic application for treatment of lipotoxicity.
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
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Cho W, Oh H, Choi SW, Abd El-Aty AM, Birdal O, Jeong JH, Song JH, Jung TW. CTRP4 attenuates apoptosis and epithelial-mesenchymal transition markers in podocytes through an AMPK/autophagy-dependent pathway. Biochem Biophys Res Commun 2023; 682:104-110. [PMID: 37806247 DOI: 10.1016/j.bbrc.2023.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 09/28/2023] [Accepted: 10/01/2023] [Indexed: 10/10/2023]
Abstract
Hyperglycemia, characterized by high blood glucose levels resulting from pancreatic beta cell dysfunction or impaired insulin signaling, is a contributing factor in the development of diabetic nephropathy. This study aimed to investigate the effects of C1q/TNF-related protein 4 (CTRP4), known for its anti-obesity and anti-inflammatory properties in various disease models, on podocyte apoptosis and endoplasmic reticulum (ER) stress in the presence of elevated glucose levels. The expression levels of various proteins in podocytes and adipocytes were evaluated by Western blotting. Autophagosomes in podocytes were stained by MDC. Chromatin condensation in podocytes was examined by Hoechst staining. The research revealed increased expression of CTRP4 in 3T3-L1 adipocytes and CIHP-1 podocytes exposed to high glucose (HG) conditions. Treatment with CTRP4 effectively mitigated HG-induced apoptosis and ER stress and normalized epithelial-to-mesenchymal transition (EMT) markers in CIHP-1 cells. Furthermore, elevated levels of AMPK phosphorylation and autophagy were observed in CIHP-1 cells treated with CTRP4. Silencing of AMPK or the use of 3-methyl adenine (3 MA) reduced the impacts of CTRP4 on apoptosis, EMT markers and ER stress in CIHP-1 cells. In conclusion, these findings suggest that CTRP4 alleviates ER stress in podocytes under hyperglycemic conditions, leading to the suppression of apoptosis and the restoration of EMT through AMPK/autophagy-mediated signaling. These insights provide valuable information for the development of therapeutic strategies for diabetic nephropathy.
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Affiliation(s)
- Wonjun Cho
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Heeseung Oh
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Sung Woo Choi
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, 12211, Giza, Egypt; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey.
| | - Oğuzhan Birdal
- Department of Cardiology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Jin-Ho Song
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
| | - Tae Woo Jung
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
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Choi SW, Cho W, Oh H, Abd El-Aty AM, Hong SA, Hong M, Jeong JH, Jung TW. Madecassoside ameliorates hepatic steatosis in high-fat diet-fed mice through AMPK/autophagy-mediated suppression of ER stress. Biochem Pharmacol 2023; 217:115815. [PMID: 37741512 DOI: 10.1016/j.bcp.2023.115815] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 09/18/2023] [Accepted: 09/20/2023] [Indexed: 09/25/2023]
Abstract
Hepatic endoplasmic reticulum (ER) stress is a contributing factor in the development of hepatic steatosis in obesity. Madecassoside (MA), a pentacyclic triterpene derived from Centella asiatica, is known for its anti-inflammatory properties in the treatment of skin wounds. However, the impact of MA on hepatic ER stress and lipid metabolism in experimental obesity models has not been investigated. In this study, we examined the effects of MA on primary hepatocytes treated with palmitate and the livers of mice fed a high-fat diet (HFD). Our findings demonstrated that MA treatment reduced lipogenic lipid accumulation, apoptosis, and ER stress in hepatocytes. Additionally, MA treatment increased the phosphorylation of AMP-activated protein kinase (AMPK) and markers of autophagy. Importantly, when AMPK was inhibited by small interfering RNA (siRNA) or autophagy was blocked by 3-methyladenine (3MA), the protective effects of MA against ER stress, lipogenic lipid deposition, and apoptosis in palmitate-treated hepatocytes were abolished. These results suggest that MA mitigates hepatic steatosis in obesity through an AMPK/autophagy-dependent pathway. The present study highlights the potential of MA as a promising therapeutic candidate for hepatic steatosis.
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Affiliation(s)
- Sung Woo Choi
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Wonjun Cho
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Heeseung Oh
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, 12211 Giza, Egypt; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum 25240, Turkey.
| | - Soon Auck Hong
- Department of Pathology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Mineui Hong
- Department of Pathology, 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; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Tae Woo Jung
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
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10
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Choi SW, Oh H, Park SY, Cho W, Abd El-Aty AM, Hacimuftuoglu A, Jeong JH, Jung TW. Adipokine gremlin-1 promotes hepatic steatosis via upregulation of ER stress by suppressing autophagy-mediated signaling. J Cell Physiol 2023; 238:966-975. [PMID: 36890751 DOI: 10.1002/jcp.30982] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 02/01/2023] [Accepted: 02/10/2023] [Indexed: 03/10/2023]
Abstract
Gremlin-1 (GR1) is a novel adipokine that is highly expressed in human adipocytes and has been shown to inhibit the BMP2/4-TGFb signaling pathway. It has an effect on insulin sensitivity. Elevated levels of Gremlin have been shown to lead to insulin resistance in skeletal muscle, adipocytes, and hepatocytes. In this study, we investigated the effect of GR1 on hepatic lipid metabolism under hyperlipidemic conditions and explored the molecular mechanisms associated with GR1 by in vitro and in vivo studies. We found that palmitate increased GR1 expression in visceral adipocytes. Recombinant GR1 increased lipid accumulation, lipogenesis, and ER stress markers in cultured primary hepatocytes. Treatment with GR1 increased EGFR expression and mTOR phosphorylation and reduced autophagy markers. EGFR or rapamycin siRNA reduced the effects of GR1 on lipogenic lipid deposition and ER stress in cultured hepatocytes. Administration of GR1 via the tail vein induced lipogenic proteins and ER stress while suppressing autophagy in the livers of experimental mice. Suppression of GR1 by in vivo transfection reduced the effects of a high-fat diet on hepatic lipid metabolism, ER stress, and autophagy in mice. These results suggest that the adipokine GR1 promotes hepatic ER stress due to the impairment of autophagy, ultimately causing hepatic steatosis in the obese state. The current study demonstrated that targeting GR1 may be a potential therapeutic approach for treating metabolic diseases, including metabolic-associated fatty liver disease (MAFLD).
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Affiliation(s)
- Sung Woo Choi
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Heeseung Oh
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Seung Yeon Park
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.,Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Wonjun Cho
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.,Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey
| | - Ahmet Hacimuftuoglu
- Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey.,Vaccine Development Application and Research Center, Ataturk University, Erzurum, Turkey
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.,Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Tae Woo Jung
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
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11
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Cho W, Choi SW, Oh H, Baygutalp F, Abd El-Aty A, Jeong JH, Song JH, Shin YK, Jung TW. Musclin attenuates lipid deposition in hepatocytes through SIRT7/autophagy-mediated suppression of ER stress. Biochem Biophys Res Commun 2023; 658:62-68. [PMID: 37023616 DOI: 10.1016/j.bbrc.2023.03.065] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 03/25/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023]
Abstract
Musclin, an exercise-responsive myokine, has the ability to attenuate inflammation, oxidative stress, and apoptosis in cardiomyocytes under pathogenic conditions. While the potential benefits of musclin in the cardiovascular system have been well documented, its effects on hepatic endoplasmic reticulum (ER) stress and lipid metabolism are not fully understood. The present study showed that musclin treatment reduced lipid accumulation and lipogenic protein expression in primary hepatocytes exposed to palmitate. Palmitate treatment led to an increase in markers of ER stress, which was reversed by musclin treatment. Musclin treatment increased SIRT7 expression and markers of autophagy in a dose-dependent manner. Small interfering (si) RNA of SIRT7 or 3-methyladenine (3 MA) reduced the effects of musclin on lipogenic lipid deposition in hepatocytes under hyperlipidemic conditions. These findings suggest that musclin can suppress palmitate-induced ER stress by upregulating SIRT7 and autophagy signaling, thereby alleviating lipid accumulation in primary hepatocytes. The current study provides a potential therapeutic strategy for the treatment of liver diseases characterized by lipid accumulation and ER stress, such as nonalcoholic fatty liver disease (NAFLD).
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12
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Fatty Acids as Potent Modulators of Autophagy Activity in White Adipose Tissue. Biomolecules 2023; 13:biom13020255. [PMID: 36830623 PMCID: PMC9953325 DOI: 10.3390/biom13020255] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/26/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
A high-fat diet is one of the causative factors of obesity. The dietary profile of fatty acids is also an important variable in developing obesity, as saturated fatty acids are more obesogenic than monounsaturated and polyunsaturated fatty acids. Overweight and obesity are inseparably connected with the excess of adipose tissue in the body, characterized by hypertrophy and hyperplasia of fat cells, which increases the risk of developing metabolic syndrome. Changes observed within hypertrophic adipocytes result in elevated oxidative stress, unfolded protein accumulation, and increased endoplasmic reticulum (ER) stress. One of the processes involved in preservation of cellular homeostasis is autophagy, which is defined as an intracellular lysosome-dependent degradation system that serves to recycle available macromolecules and eliminate damaged organelles. In obesity, activation of autophagy is increased and the process appears to be regulated by different types of dietary fatty acids. This review describes the role of autophagy in adipose tissue and summarizes the current understanding of the effects of saturated and unsaturated fatty acids in autophagy modulation in adipocytes.
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13
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Zheng W, Sun Q, Li L, Cheng Y, Chen Y, Lv M, Xiang X. Role of endoplasmic reticulum stress in hepatic glucose and lipid metabolism and therapeutic strategies for metabolic liver disease. Int Immunopharmacol 2022; 113:109458. [DOI: 10.1016/j.intimp.2022.109458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/22/2022] [Accepted: 11/10/2022] [Indexed: 11/18/2022]
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14
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Sharma MK, Priyam K, Kumar P, Garg PK, Roy TS, Jacob TG. Effect of calorie-restriction and rapamycin on autophagy and the severity of caerulein-induced experimental acute pancreatitis in mice. FRONTIERS IN GASTROENTEROLOGY 2022; 1. [DOI: 10.3389/fgstr.2022.977169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
BackgroundImpaired autophagy contributes to development of acute pancreatitis (AP). We studied the effect of inducing autophagy by calorie-restriction and rapamycin, separately, in the caerulein-induced model of severe AP.MethodsAdult, male, Swiss albino mice were given eight, hourly, intraperitoneal injections of caerulein (Ce) (50µg/Kg/dose). The interventions were calorie restriction (CR) and rapamycin (2mg/Kg). Mice were sacrificed at the 9th hour. Pancreas was harvested for histopathology and immunoblotting. Amylase activity and the levels of cytokines were measured in plasma.ResultsThe histopathological score and amylase activity were significantly lower in calorie-restricted caerulein-induced AP (CRCeAP) in comparison to animals that had unrestricted access to chow. In the CRCeAP group, levels of IL-6 and GM-CSF in plasma were lower and the expression of LC3II and Beclin-1 were higher. On transmission electron-microscopy, the area occupied by autophagic vacuoles was higher in CRCeAP. The expression of caspase-8 and caspase-9 was also higher in CRCeAP. In rapamycin with caerulein-induced AP (Rapa+CeAP), the histopathological score and amylase activity were significantly lower than caerulein-induced AP (CeAP). In Rapa+CeAP, the expression of LC3II and Beclin-1 were higher, whereas; SQSTM1 was decreased. The number of autophagic vacuoles in Rapa+CeAP group was fewer. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) were lower in Rapa+CeAP. Caspase-3 increased and high mobility group box 1 (HMGB1) decreased in Rapa+CeAP.ConclusionCalorie-restriction and rapamycin can individually decrease the severity of injury in the caerulein-induced model of severe AP.
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15
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Woo Jung T, Hee Chung Y, Yeon Park S, Cho W, Oh H, Hacimuftuoglu A, Abd El-Aty A, Seok Bang J, Hoon Jeong J. The aqueous extract of Phragmites rhizome improves hepatic steatosis in obese mice via the AMPK-mediated inhibition of ER stress. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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16
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Resolvin D3 improves the impairment of insulin signaling in skeletal muscle and nonalcoholic fatty liver disease through AMPK/autophagy-associated attenuation of ER stress. Biochem Pharmacol 2022; 203:115203. [DOI: 10.1016/j.bcp.2022.115203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/30/2022] [Accepted: 08/02/2022] [Indexed: 11/17/2022]
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17
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Jung TW, Jeong JC, Park SY, Cho W, Oh H, Lee HJ, Hacimuftuoglu A, Abd El-Aty A, Bang JS, Jeong JH. Abietic acid alleviates endoplasmic reticulum stress and lipid accumulation in human primary hepatocytes through the AMPK/ORP150 signaling. Biochem Biophys Res Commun 2022; 608:142-148. [DOI: 10.1016/j.bbrc.2022.04.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 04/02/2022] [Indexed: 02/06/2023]
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18
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Park TJ, Park SY, Lee HJ, Abd El-Aty A, Jeong JH, Jung TW. α-ketoisocaproic acid promotes ER stress through impairment of autophagy, thereby provoking lipid accumulation and insulin resistance in murine preadipocytes. Biochem Biophys Res Commun 2022; 603:109-115. [DOI: 10.1016/j.bbrc.2022.03.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/01/2022] [Indexed: 01/03/2023]
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19
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Yeon Park S, Cho W, Abd El-Aty A, Hacimuftuoglu A, Hoon Jeong J, Woo Jung T. Valdecoxib attenuates lipid-induced hepatic steatosis through autophagy-mediated suppression of endoplasmic reticulum stress. Biochem Pharmacol 2022; 199:115022. [DOI: 10.1016/j.bcp.2022.115022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 03/22/2022] [Accepted: 03/23/2022] [Indexed: 02/09/2023]
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20
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Zhang LS, Zhang JS, Hou YL, Lu WW, Ni XQ, Lin F, Liu XY, Wang XJ, Yu YR, Jia MZ, Tang CS, Han L, Chai SB, Qi YF. Intermedin 1-53 Inhibits NLRP3 Inflammasome Activation by Targeting IRE1α in Cardiac Fibrosis. Inflammation 2022; 45:1568-1584. [PMID: 35175495 DOI: 10.1007/s10753-022-01642-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 01/27/2022] [Accepted: 01/29/2022] [Indexed: 11/24/2022]
Abstract
Intermedin (IMD), a paracrine/autocrine peptide, protects against cardiac fibrosis. However, the underlying mechanism remains poorly understood. Previous study reports that activation of nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome contributes to cardiac fibrosis. In this study, we aimed to investigate whether IMD mitigated cardiac fibrosis by inhibiting NLRP3. Cardiac fibrosis was induced by angiotensin II (Ang II) infusion for 2 weeks in rats. Western blot, real-time PCR, histological staining, immunofluorescence assay, RNA sequencing, echocardiography, and hemodynamics were used to detect the role and the mechanism of IMD in cardiac fibrosis. Ang II infusion resulted in rat cardiac fibrosis, shown as over-deposition of myocardial interstitial collagen and cardiac dysfunction. Importantly, NLRP3 activation and endoplasmic reticulum stress (ERS) were found in Ang II-treated rat myocardium. Ang II infusion decreased the expression of IMD and increased the expression of the receptor system of IMD in the fibrotic rat myocardium. IMD treatment attenuated the cardiac fibrosis and improved cardiac function. In addition, IMD inhibited the upregulation of NLRP3 markers and ERS markers induced by Ang II. In vitro, IMD knockdown by small interfering RNA significantly promoted the Ang II-induced cardiac fibroblast and NLRP3 activation. Moreover, silencing of inositol requiring enzyme 1 α (IRE1α) blocked the effects of IMD inhibiting fibroblast and NLRP3 activation. Pre-incubation with PKA pathway inhibitor H89 blocked the effects of IMD on the anti-ERS, anti-NLRP3, and anti-fibrotic response. In conclusion, IMD alleviated cardiac fibrosis by inhibiting NLRP3 inflammasome activation through suppressing IRE1α via the cAMP/PKA pathway.
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Affiliation(s)
- Lin-Shuang Zhang
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China.,Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, HaidianDistrict, No. 38 Xueyuan Road, Beijing, 100083, China.,School of Nursing, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jin-Sheng Zhang
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China.,Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, HaidianDistrict, No. 38 Xueyuan Road, Beijing, 100083, China
| | - Yue-Long Hou
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China
| | - Wei-Wei Lu
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China.,Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, HaidianDistrict, No. 38 Xueyuan Road, Beijing, 100083, China
| | - Xian-Qiang Ni
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China.,Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, HaidianDistrict, No. 38 Xueyuan Road, Beijing, 100083, China
| | - Fan Lin
- Department of Respiratory Disease, Peking University Third Hospital, Beijing, China
| | - Xiu-Ying Liu
- Key Laboratory of Genetic Network Biology, Collaborative Innovation Center of Genetics and Development, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Xiu-Jie Wang
- Key Laboratory of Genetic Network Biology, Collaborative Innovation Center of Genetics and Development, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Yan-Rong Yu
- Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, HaidianDistrict, No. 38 Xueyuan Road, Beijing, 100083, China
| | - Mo-Zhi Jia
- Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, HaidianDistrict, No. 38 Xueyuan Road, Beijing, 100083, China
| | - Chao-Shu Tang
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China
| | - Ling Han
- Department of Cardiology, Fu Xing Hospital, Capital Medical University, A20 Fuxingmenwai Street, Xicheng District, Beijing, 100038, China.
| | - San-Bao Chai
- Department of Endocrinology, Peking University International Hospital, Life Park Road No. 1, Zhongguancun Life Science Park, Changping District, Beijing, 102206, China.
| | - Yong-Fen Qi
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China. .,Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, HaidianDistrict, No. 38 Xueyuan Road, Beijing, 100083, China.
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21
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Carnosic Acid Attenuates the Free Fatty Acid-Induced Insulin Resistance in Muscle Cells and Adipocytes. Cells 2022; 11:cells11010167. [PMID: 35011728 PMCID: PMC8750606 DOI: 10.3390/cells11010167] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 12/10/2021] [Accepted: 12/28/2021] [Indexed: 12/12/2022] Open
Abstract
Elevated blood free fatty acids (FFAs), as seen in obesity, impair insulin action leading to insulin resistance and Type 2 diabetes mellitus. Several serine/threonine kinases including JNK, mTOR, and p70 S6K cause serine phosphorylation of the insulin receptor substrate (IRS) and have been implicated in insulin resistance. Activation of AMP-activated protein kinase (AMPK) increases glucose uptake, and in recent years, AMPK has been viewed as an important target to counteract insulin resistance. We reported previously that carnosic acid (CA) found in rosemary extract (RE) and RE increased glucose uptake and activated AMPK in muscle cells. In the present study, we examined the effects of CA on palmitate-induced insulin-resistant L6 myotubes and 3T3L1 adipocytes. Exposure of cells to palmitate reduced the insulin-stimulated glucose uptake, GLUT4 transporter levels on the plasma membrane, and Akt activation. Importantly, CA attenuated the deleterious effect of palmitate and restored the insulin-stimulated glucose uptake, the activation of Akt, and GLUT4 levels. Additionally, CA markedly attenuated the palmitate-induced phosphorylation/activation of JNK, mTOR, and p70S6K and activated AMPK. Our data indicate that CA has the potential to counteract the palmitate-induced muscle and fat cell insulin resistance.
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22
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Yang L, Yu P, Chen M, Lei B. Mammalian Target of Rapamycin Inhibitor Rapamycin Alleviates 7-Ketocholesterol Induced Inflammatory Responses and Vascular Endothelial Growth Factor Elevation by Regulating MAPK Pathway in Human Retinal Pigment Epithelium Cells. J Ocul Pharmacol Ther 2021; 38:189-200. [PMID: 34936813 DOI: 10.1089/jop.2021.0082] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Purpose: To validate the protective effect of a mammalian target of rapamycin (mTOR) inhibitor on human retinal pigment epithelium (RPE) cells challenged with 7-ketocholesterol (7-KC) and explored the underlying mechanisms. Methods: Human primary RPE (hRPE) cells and ARPE-19 cells were cultured with or without 10 nM of rapamycin for 6 h before being exposed to 10 μM of 7-KC for 24 h. The transcriptome of 7-KC challenged ARPE-19 cells was investigated by RNA sequencing (RNA-seq). The effects of 7-KC and rapamycin on the viability of ARPE-19 cells were measured with CCK-8. Gene expression was verified by real-time PCR, and protein levels were determined by ELISA or Western blotting. Results: The expression of IL-6, IL-8, and vascular endothelial growth factor (VEGF) in RPE cells was markedly increased after stimulation with 7-KC for 12/24 h compared with the controls. RNA-seq showed that a total of 10,243 genes were differentially expressed, with 5,518 genes upregulated and 4,725 genes downregulated between the 7-KC treated and the control group. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that 7-KC stimulation activated mTOR signaling and other pathways, including adherent junction, MAPK, and Wnt signalings. mTOR inhibitor rapamycin significantly suppressed the elevation of IL-6, IL-8, and VEGF stimulated by 7-KC. Rapamycin not only decreased the level of phosphorylated mTOR, P70S6K, 4EBP1 but also inhibited the activation of MAPK pathway. Conclusions: Inhibition of mTOR signaling pathway suppressed the elevation of inflammatory cytokines IL-6, IL-8, and the angiogenic agent VEGF induced by 7-KC. The protective effect of rapamycin was associated with its downregulation on MAPK pathway.
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Affiliation(s)
- Lin Yang
- Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Peng Yu
- Department of Ophthalmology, People's Hospital of Changshou District, Chongqing, China
| | - Mei Chen
- Centre for Experimental Medicine, Queen's University, Belfast, United Kingdom
| | - Bo Lei
- Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
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23
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Hou Y, Li M, Jin Y, Xu F, Liang S, Xue C, Wang K, Zhao W. Protective effects of tetramethylpyrazine on dysfunction of the locus coeruleus in rats exposed to single prolonged stress by anti-ER stress mechanism. Psychopharmacology (Berl) 2021; 238:2923-2936. [PMID: 34231002 DOI: 10.1007/s00213-021-05908-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 06/21/2021] [Indexed: 10/20/2022]
Abstract
Post-traumatic stress disorder (PTSD) is a serious stress-related neuropsychiatric disorder caused by major traumatic events. Abnormal activity of the locus coeruleus (LC)-noradrenergic system is related to the development of PTSD-like symptoms. Our previous studies have indicated that endoplasmic reticulum (ER) stress induced neuronal apoptosis of LC in rats with PTSD. The purpose of this study was to further investigate the role of ER stress pathways in LC neuronal dysfunction and elucidate the effect of the bioactive component tetramethylpyrazine (TMP) against ER stress response. We used an acute exposure to single prolonged stress (SPS) to model PTSD in rats. There were higher norepinephrine (NE) levels in the brain, increased tyrosine hydroxylase expression in LC, and enhanced anxiety-like behaviors in rats exposed to SPS, which were observed by enzyme-linked immunosorbent assay, western blot analysis and elevated plus maze test, respectively. In addition, the three major pathways of ER stress were activated by SPS exposure, which may be involved in the dysregulation of the LC-noradrenergic system of rats with PTSD. Furthermore, we found that TMP administration significantly suppressed the increased responsiveness of LC-noradrenergic system, effectively reduced the anxiety response of SPS rats, and selectively attenuated the activation of pro-apoptotic ER stress pathways. The results suggest that TMP was efficient in improving the LC-NE dysfunction induced by excessive ER stress. TMP exhibited a significant neuroprotective effect and potential therapeutics on PTSD-like symptoms.
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Affiliation(s)
- Yun Hou
- Department of Histology and Embryology, Binzhou Medical University, No. 346 Guanhai Road, Yantai, 264003, Shandong, China
| | - Meifeng Li
- Department of Intensive Care Unit, Yantai Yuhuangding Hospital Qingdao University, Yantai, 264000, Shandong, China
| | - Yinchuan Jin
- Department of Medical Psychology, Fourth Military Medical University, No. 169 West Changle Road, Xi'an, 710032, China
| | - Feibo Xu
- Department of Histology and Embryology, Binzhou Medical University, No. 346 Guanhai Road, Yantai, 264003, Shandong, China
| | - Shaohua Liang
- Department of Anatomy, Binzhou Medical University, No. 346 Guanhai Road, Yantai, 264003, Shandong, China
| | - Chen Xue
- Clinical Medicine College, Binzhou Medical University, No. 346 Guanhai Road, Yantai, 264003, Shandong, China
| | - Kaili Wang
- Clinical Medicine College, Binzhou Medical University, No. 346 Guanhai Road, Yantai, 264003, Shandong, China
| | - Wei Zhao
- Department of Histology and Embryology, Binzhou Medical University, No. 346 Guanhai Road, Yantai, 264003, Shandong, China.
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24
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Mechanisms linking endoplasmic reticulum (ER) stress and microRNAs to adipose tissue dysfunction in obesity. Crit Rev Biochem Mol Biol 2021; 56:455-481. [PMID: 34182855 DOI: 10.1080/10409238.2021.1925219] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Over accumulation of lipids in adipose tissue disrupts metabolic homeostasis by affecting cellular processes. Endoplasmic reticulum (ER) stress is one such process affected by obesity. Biochemical and physiological alterations in adipose tissue due to obesity interfere with adipose ER functions causing ER stress. This is in line with increased irregularities in other cellular processes such as inflammation and autophagy, affecting overall metabolic integrity within adipocytes. Additionally, microRNAs (miRNAs), which can post-transcriptionally regulate genes, are differentially modulated in obesity. A better understanding and identification of such miRNAs could be used as novel therapeutic targets to fight against diseases. In this review, we discuss ways in which ER stress participates as a common molecular process in the pathogenesis of obesity-associated metabolic disorders. Moreover, our review discusses detailed underlying mechanisms through which ER stress and miRNAs contribute to metabolic alteration in adipose tissue in obesity. Hence, identifying mechanistic involvement of miRNAs-ER stress cross-talk in regulating adipose function during obesity could be used as a potential therapeutic approach to combat chronic diseases, including obesity.
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25
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Yang M, Chang Z, Ji H. Characterization and expression analysis of ATG4 paralogs in response to the palmitic acid induced-ER stress in Ctenopharyngodon idellus kidney cells. Comp Biochem Physiol B Biochem Mol Biol 2021; 252:110525. [DOI: 10.1016/j.cbpb.2020.110525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 08/22/2020] [Accepted: 10/21/2020] [Indexed: 02/08/2023]
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26
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Pyun DH, Kim TJ, Kim MJ, Hong SA, Abd El-Aty AM, Jeong JH, Jung TW. Endogenous metabolite, kynurenic acid, attenuates nonalcoholic fatty liver disease via AMPK/autophagy- and AMPK/ORP150-mediated signaling. J Cell Physiol 2020; 236:4902-4912. [PMID: 33283879 DOI: 10.1002/jcp.30199] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 11/03/2020] [Accepted: 11/23/2020] [Indexed: 02/06/2023]
Abstract
Endoplasmic reticulum (ER) stress plays a causative role in the development of nonalcoholic fatty liver disease (NAFLD). Kynurenic acid (KA) is a tryptophan metabolite that has been shown to exert anti-inflammatory effects in macrophages and endothelial cells. However, the role of KA in ER stress-associated development of NAFLD has not been fully explored. In the current study, we observed decreased KA levels in the serum of obese subjects. Treated hepatocytes with KA attenuated palmitate-induced lipid accumulation and downregulated lipogenesis-associated genes as well as ER stress markers in a dose-dependent manner. Furthermore, KA augmented AMP-activated protein kinase (AMPK) phosphorylation, oxygen-regulated protein 150 (ORP150) expression, and autophagy markers. The small interfering RNA-mediated suppression of AMPK and ORP150, or 3-methyladenine also abrogated the effects of KA on ER stress and lipid accumulation in hepatocytes. In accordance with in vitro observations, KA administration to mice fed a high-fat diet ameliorated hepatic lipid accumulation and decreased the expression of lipogenic genes as well as ER stress. Moreover, KA treatment increased hepatic AMPK phosphorylation, ORP150 expression, and autophagy related markers in mouse livers. Knockdown of AMPK using in vivo transfection mitigated the effects of KA on hepatic steatosis and ER stress as well as autophagy and ORP150 expression. These results suggest that KA ameliorates hepatic steatosis via the AMPK/autophagy- and AMPK/ORP150-mediated suppression of ER stress. In sum, KA might be used as a promising therapeutic agent for treatment of NAFLD.
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Affiliation(s)
- Do Hyeon Pyun
- Department of Pharmacology, Chung-Ang University, Seoul, Republic of Korea
| | - Tae Jin Kim
- Department of Pharmacology, Chung-Ang University, Seoul, Republic of Korea
| | - Myeong Jun Kim
- Department of Pharmacology, Chung-Ang University, Seoul, Republic of Korea
| | - Soon Auck Hong
- Department of Pathology, Chung-Ang University, Seoul, Republic of Korea
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.,State Key Laboratory of Biobased Material and Green Papermaking, College of Food Science and Engineering, Shandong Academy of Science, Qilu University of Technology, Jinan, China.,Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey
| | - Ji Hoon Jeong
- Department of Pharmacology, Chung-Ang University, Seoul, Republic of Korea.,Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Tae Woo Jung
- Department of Pharmacology, Chung-Ang University, Seoul, Republic of Korea
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Ganesan D, Ramaian Santhaseela A, Rajasekaran S, Selvam S, Jayavelu T. Astroglial biotin deprivation under endoplasmic reticulum stress uncouples BCAA‐mTORC1 role in lipid synthesis to prolong autophagy inhibition in the aging brain. J Neurochem 2020; 154:562-575. [DOI: 10.1111/jnc.14979] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 01/21/2020] [Accepted: 02/04/2020] [Indexed: 01/10/2023]
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28
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Hydrogen alleviated organ injury and dysfunction in sepsis: The role of cross-talk between autophagy and endoplasmic reticulum stress: Experimental research. Int Immunopharmacol 2020; 78:106049. [PMID: 31830624 DOI: 10.1016/j.intimp.2019.106049] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 11/10/2019] [Accepted: 11/11/2019] [Indexed: 01/26/2023]
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29
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Korbecki J, Bajdak-Rusinek K. The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms. Inflamm Res 2019; 68:915-932. [PMID: 31363792 PMCID: PMC6813288 DOI: 10.1007/s00011-019-01273-5] [Citation(s) in RCA: 296] [Impact Index Per Article: 49.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 07/22/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023] Open
Abstract
Palmitic acid is a saturated fatty acid whose blood concentration is elevated in obese patients. This causes inflammatory responses, where toll-like receptors (TLR), TLR2 and TLR4, play an important role. Nevertheless, palmitic acid is not only a TLR agonist. In the cell, this fatty acid is converted into phospholipids, diacylglycerol and ceramides. They trigger the activation of various signaling pathways that are common for LPS-mediated TLR4 activation. In particular, metabolic products of palmitic acid affect the activation of various PKCs, ER stress and cause an increase in ROS generation. Thanks to this, palmitic acid also strengthens the TLR4-induced signaling. In this review, we discuss the mechanisms of inflammatory response induced by palmitic acid. In particular, we focus on describing its effect on ER stress and IRE1α, and the mechanisms of NF-κB activation. We also present the mechanisms of inflammasome NLRP3 activation and the effect of palmitic acid on enhanced inflammatory response by increasing the expression of FABP4/aP2. Finally, we focus on the consequences of inflammatory responses, in particular, the effect of TNF-α, IL-1β and IL-6 on insulin resistance. Due to the high importance of macrophages and the production of proinflammatory cytokines by them, this work mainly focuses on these cells.
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Affiliation(s)
- Jan Korbecki
- Department of Molecular Biology, School of Medicine in Katowice, Medical University of Silesia, Medyków 18 St., 40-752, Katowice, Poland.
| | - Karolina Bajdak-Rusinek
- Department of Medical Genetics, School of Medicine in Katowice, Medical University of Silesia, Medyków 18 St., 40-752, Katowice, Poland
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30
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Ding J, He J, Zhang ZQ, Wu ZK, Jin FC. Effect of Hemiepiphysiodesis on the Growth Plate: The Histopathological Changes and Mechanism Exploration of Recurrence in Mini Pig Model. BIOMED RESEARCH INTERNATIONAL 2018; 2018:6348171. [PMID: 30687754 PMCID: PMC6330884 DOI: 10.1155/2018/6348171] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 12/10/2018] [Indexed: 01/02/2023]
Abstract
PURPOSE Hemiepiphysiodesis has been widely used to correct angular deformity of long bone in immature patients. However, there is a limited knowledge about the biomechanical effect of this technique on the histopathological changes of the growth plate and the mechanism of recurrence of malformation after implant removal. We aimed to evaluate the biomechanical effect of hemiepiphysiodesis on the histopathological changes of the growth plate and the mechanism of recurrence of malformation after implant removal in Bama miniature pigs, and to explore the role of asymmetric stress during this procedure. METHODS Eight 3-month-old male Bama miniature pigs sustained surgeries on the bilateral medial hind leg proximal tibia as the intervention group (n=16), and four pigs sustained bilateral sham surgeries as the control (n=8). In the 18th week after surgeries, hardware was removed in the unilateral leg of each animal in the intervention group. In the 24th week of the study, all animals were euthanized. A total of 24 samples were obtained and stained with H&E, TUNEL, and immunohistochemistry. Sixteen samples in the intervention group were divided into two subgroups. The tibias without an implant were included in the implant removal group (IR group), while the tibias with an implant were included in the implant persist group (IP group). The proximal tibia specimens were divided into 3 equidistant parts from medial to lateral, named as area A, area B, and area C, respectively. The change of thickness of growth plates, chondral apoptosis index, and the expression of Caspase-3, Caspase-9, CHOP, and P65 were compared. RESULTS H&E staining showed the thickness of growth plate to be varied in different areas. In the IP group, the thickness of growth plate in areas A and B was statistically significantly thinner than that in area C (p<0.05). In the IR group, the thickness of growth plate in areas A and B was statistically significantly thicker than that in area C (p<0.05). TUNEL staining showed that the apoptosis rate increased significantly after hemiepiphysiodesis and declined after implant removal (p<0.05). Immunohistochemical staining suggested that the expression of Caspase-3, Caspase-9, P65, and CHOP protein was upregulated in the experimental group and downregulated after implant removal. CONCLUSION The thickness parameter of the growth plate changes with asymmetric pressure. When the pressure is relieved, the recurrence of malformation is related to the thickening of the growth plate.
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Affiliation(s)
- Jing Ding
- Department of Pediatric Orthopaedics, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, No. 1665, Kongjiang Road, Shanghai 200092, China
| | - Jin He
- Department of Pediatric Orthopaedics, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, No. 1665, Kongjiang Road, Shanghai 200092, China
| | - Zhi-Qiang Zhang
- Department of Pediatric Orthopaedics, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, No. 1665, Kongjiang Road, Shanghai 200092, China
| | - Zhen-Kai Wu
- Department of Pediatric Orthopaedics, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, No. 1665, Kongjiang Road, Shanghai 200092, China
- Division of Orthopaedic Surgery, Children's Mercy Kansas City, 2401 Gillham Road, Kansas City, MO 64108, USA
| | - Fang-Chun Jin
- Department of Pediatric Orthopaedics, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, No. 1665, Kongjiang Road, Shanghai 200092, China
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31
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Xie W, Zhou J. Aberrant regulation of autophagy in mammalian diseases. Biol Lett 2018; 14:rsbl.2017.0540. [PMID: 29321247 DOI: 10.1098/rsbl.2017.0540] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 12/13/2017] [Indexed: 12/11/2022] Open
Abstract
Autophagy is a major cellular metabolic pathway that facilitates degradation of a subset of long-lived proteins and cytoplasmic organelles in eukaryotic cells. This pathway plays a vital role in preserving the cellular homeostasis of the cells themselves, in addition to maintaining the normal physiological state of cell renewal. Many stressors, such as starvation, ischaemia and oxidative stress can induce autophagy. In addition to its physiological roles, autophagy also occurs in a wide variety of pathological processes, including tumour progression, metabolic disorders, and neurodegenerative and lung diseases. In recent years, a growing body of evidence has shown that autophagy also plays a key role in the development of mammalian diseases, a function that has garnered substantial attention and study. An in-depth understanding of the molecular role that autophagy plays in pathological settings is vital for both the diagnosis and treatment of mammalian diseases and will aid in the search for novel targets for therapeutic drug intervention. Here, we provide an integrated review of recent studies implicating autophagy dysfunction in the progression of mammalian disorders and summarize research suggesting that the molecular pathways involved in autophagy could serve as potential therapeutic targets.
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Affiliation(s)
- Wei Xie
- Shandong Provincial Key Laboratory of Animal Resistance Biology, Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, Jinan 250014, P. R. China
| | - Jun Zhou
- Shandong Provincial Key Laboratory of Animal Resistance Biology, Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, Jinan 250014, P. R. China
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32
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Asiatic acid from Potentilla chinensis alleviates non-alcoholic fatty liver by regulating endoplasmic reticulum stress and lipid metabolism. Int Immunopharmacol 2018; 65:256-267. [DOI: 10.1016/j.intimp.2018.10.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 10/09/2018] [Accepted: 10/09/2018] [Indexed: 12/17/2022]
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33
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Miao YF, Li J, Zhang YM, Zhu L, Chen H, Yuan L, Hu J, Yi XL, Wu QT, Wan MH, Tang WF. Sheng-jiang powder ameliorates obesity-induced pancreatic inflammatory injury via stimulating activation of the AMPK signalling pathway in rats. World J Gastroenterol 2018; 24:4448-4461. [PMID: 30356974 PMCID: PMC6196332 DOI: 10.3748/wjg.v24.i39.4448] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 09/12/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the mechanisms by which Sheng-jiang powder (SJP) ameliorates obesity-induced pancreatic inflammatory injury.
METHODS Sprague-Dawley rats were randomized into three groups: normal group (NG), obese group (HLG), or SJP treatment group (HSG). Obesity was induced by feeding a high-fat diet in the HLG and HSG, while the NG received standard chow. Rats were euthanized after 12 wk, and blood and pancreatic tissues were collected for histopathological analyses. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transforming growth factor beta (TGF-β) expression, serum triglyceride and adiponectin levels, and apoptosis in pancreatic acinar cells were assessed. A high-fat AR42J acinar cell injury model was established using very low-density lipoprotein (VLDL). AR42J acinar cell culture supernatant, treated with different interventions, was applied to seven groups of pancreatic stellate cells (PSCs). The proliferation of PSCs and the expression of fibronectin and type I collagenase were assessed.
RESULTS Compared with the NG, we found higher pathological scores for pancreatic tissues, lower serum adiponectin levels, higher expression levels of NF-κB in pancreatic tissues and TGF-β in pancreatic inflammatory cells, and increased apoptosis among pancreatic acinar cells for the HLG (P < 0.05). Compared with the HLG, we found reduced body weight, Lee’s index scores, serum triglyceride levels, and pathological scores for pancreatic tissues; higher serum adiponectin levels; and lower expression levels of NF-κB, in pancreatic tissue and TGF-β in pancreatic inflammatory cells for the HSG (P < 0.05). The in vitro studies showed enhanced PSC activation and increased expression levels of fibronectin and type I collagenase after SJP treatment. An adenosine 5‘-monophosphate-activated protein kinase (AMPK) inhibitor inhibited PSC activation.
CONCLUSION SJP may ameliorate obesity-induced pancreatic inflammatory injury in rats by regulating key molecules of the adiponectin-AMPK signalling pathway.
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Affiliation(s)
- Yi-Fan Miao
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Juan Li
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yu-Mei Zhang
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lv Zhu
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Huan Chen
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ling Yuan
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jing Hu
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xiao-Lin Yi
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Qiu-Ting Wu
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Mei-Hua Wan
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wen-Fu Tang
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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34
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Jiang Y, Wang Z, Ma B, Fan L, Yi N, Lu B, Wang Q, Liu R. GLP-1 Improves Adipocyte Insulin Sensitivity Following Induction of Endoplasmic Reticulum Stress. Front Pharmacol 2018; 9:1168. [PMID: 30459598 PMCID: PMC6232689 DOI: 10.3389/fphar.2018.01168] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 09/26/2018] [Indexed: 01/05/2023] Open
Abstract
Glucagon-like peptide 1 (GLP-1) improves insulin resistance of adipose tissue in obese humans. However, the mechanism of this effect is unclear. Perturbation of endoplasmic reticulum (ER) homeostasis impairs insulin signaling. We hypothesized that GLP-1 could directly improve insulin signaling in ER-stressed adipocytes. Here, we examined the effects of GLP-1 on ER stress response in fat cells in an obese and insulin-resistant murine model. We found that GLP-1 analog liraglutide reduced ER stress related gene expression in visceral fat cells accompanied by improved systemic insulin tolerance. Consistently, GLP-1 decreased CHOP expression and increased insulin stimulated AKT phosphorylation (p-AKT) in thapsigargin, a ER stress inducer, treated white fat cells differentiated from visceral stromal vascular fraction. We further found blocking CHOP expression increased insulin stimulated p-AKT in ER-stressed fat cells. Of note, we found mTOR signaling pathway contributed to the expression of ATF4 and subsequently the CHOP expression in ER stress response, while GLP-1 inhibited mTOR activity as exemplified by elevated autophagosome formation and increased LC3II/LC3I ratio. These findings suggest that GLP-1 directly modulates the ER stress response partially via inhibiting mTOR signaling pathway, leading to increased insulin sensitivity in adipocytes.
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Affiliation(s)
- Yaojing Jiang
- Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhihong Wang
- Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China
| | - Bo Ma
- Department of Obstetrics and Gynecology, Tianjin Central Hospital of Gynecology Obstetrics, Tianjin, China
| | - Linling Fan
- Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China
| | - Na Yi
- Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China
| | - Bin Lu
- Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China
| | - Qinghua Wang
- Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China.,Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, University of Toronto, Toronto, ON, Canada
| | - Rui Liu
- Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China
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35
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Chen Z, Nie SD, Qu ML, Zhou D, Wu LY, Shi XJ, Ma LR, Li X, Zhou SL, Wang S, Wu J. The autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes. Cell Death Dis 2018; 9:771. [PMID: 29991726 PMCID: PMC6039485 DOI: 10.1038/s41419-018-0795-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 06/04/2018] [Accepted: 06/06/2018] [Indexed: 12/23/2022]
Abstract
The accumulation of palmitic acid (PA), implicated in obesity, can induce apoptotic cell death and inflammation of astrocytes. Caveolin-1 (Cav-1), an essential protein for astrocytes survival, can be degraded by autophagy, which is a double-edge sword that can either promote cell survival or cell death. The aim of this study was to delineate whether the autophagic degradation of Cav-1 is involved in PA-induced apoptosis and inflammation in hippocampal astrocytes. In this study we found that: (1) PA caused apoptotic death and inflammation by autophagic induction; (2) Cav-1 was degraded by PA-induced autophagy and PA induced autophagy in a Cav-1-independent manner; (3) the degradation of Cav-1 was responsible for PA-induced autophagy-dependent apoptotic cell death and inflammation; (4) chronic high-fat diet (HFD) induced Cav-1 degradation, apoptosis, autophagy, and inflammation in the hippocampal astrocytes of rats. Our results suggest that the autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes. Therefore, Cav-1 may be a potential therapeutic target for central nervous system injuries caused by PA accumulation.
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Affiliation(s)
- Zi Chen
- Department of Endocrinology, Xiang-Ya Hospital, Central South University, Changsha, China
| | - Sheng-Dan Nie
- Institute of Clinical Medicine, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Min-Li Qu
- Department of Endocrinology, Xiang-Ya Hospital, Central South University, Changsha, China
| | - Di Zhou
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China
| | - Liang-Yan Wu
- Department of Endocrinology, Xiang-Ya Hospital, Central South University, Changsha, China
| | - Xia-Jie Shi
- Department of Endocrinology, Xiang-Ya Hospital, Central South University, Changsha, China
| | - Ling-Ran Ma
- Institute of Clinical Medicine, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Xin Li
- Institute of Clinical Medicine, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Shan-Lei Zhou
- Department of Endocrinology, Xiang-Ya Hospital, Central South University, Changsha, China
| | - Shan Wang
- Department of Endocrinology, Xiang-Ya Hospital, Central South University, Changsha, China.
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China.
| | - Jing Wu
- Department of Endocrinology, Xiang-Ya Hospital, Central South University, Changsha, China.
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36
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He L, Zhang J, Zhao J, Ma N, Kim SW, Qiao S, Ma X. Autophagy: The Last Defense against Cellular Nutritional Stress. Adv Nutr 2018; 9:493-504. [PMID: 30032222 PMCID: PMC6054220 DOI: 10.1093/advances/nmy011] [Citation(s) in RCA: 123] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Homeostasis of nutrient metabolism is critical for maintenance of the normal physiologic status of the cell and the integral health of humans and mammals. In vivo, there is a highly efficient and precise process involved in nutrient recycling and organelle cleaning. This process is named autophagy, and it can be induced in response to the dynamic change of nutrients. When cells face nutritional stress, such as stress caused by nutrient deficiency or nutrient excess, the autophagy pathway will be activated. Generally, when nutrients are withdrawn, cells will sense the signs of starvation and respond. AMP-activated protein kinase and the mammalian target of rapamycin, two of the major metabolic kinases, are responsible for monitoring cellular energy and the concentration of amino acids, respectively. Nutrient excess also induces autophagy, mainly via the reactive oxygen species and endoplasmic reticulum stress pathway. When nutritional stress activates the autophagy pathway, the nutrients or damaged organelles will be recycled for cell survival. However, if autophagy is overwhelmingly induced, autophagic cell death will possibly occur. The balance of the autophagy induction is the crucial factor for cell survival or death. Herein, we summarize the current knowledge on the induction of autophagy, the autophagy response under nutritional stresses, and autophagic cell death and related diseases, which will highlight the process of nutritional stress-induced autophagy and its important physiologic and/or pathologic roles in cell metabolism and diseases, and shed light on the research into the mechanism and clinical applications of autophagy induced by nutritional stresses.
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Affiliation(s)
- Long He
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, Beijing, China
| | - Jie Zhang
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, Beijing, China
| | - Jinshan Zhao
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao, China
| | - Ning Ma
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, Beijing, China
| | - Sung Woo Kim
- Department of Animal Science, North Carolina State University, Raleigh, NC
| | - Shiyan Qiao
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, Beijing, China
| | - Xi Ma
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, Beijing, China,College of Animal Science and Technology, Qingdao Agricultural University, Qingdao, China,Department of Internal Medicine, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX,Address correspondence to XM (e-mail: )
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37
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Abstract
Cellular signaling pathways are often interconnected. They accurately and efficiently regulate essential cell functions such as protein synthesis, cell growth, and survival. The target of rapamycin (TOR) signaling pathway and the endoplasmic reticulum (ER) stress response pathway regulate similar cellular processes. However, the crosstalk between them has not been appreciated until recently and the detailed mechanisms remain unclear. Here, we show that ER stress-inducing drugs activate the TOR signaling pathway in S2R+ Drosophila cells. Activating transcription factor 6 (Atf6), a major stress-responsive ER transmembrane protein, is responsible for ER stress-induced TOR activation. Supporting the finding, we further show that knocking down of both site-1/2 proteases (S1P/S2P), Atf6 processing enzymes, are necessary to connect the two pathways.
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38
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Xu J, Pan S, Gan F, Hao S, Liu D, Xu H, Huang K. Selenium deficiency aggravates T-2 toxin-induced injury of primary neonatal rat cardiomyocytes through ER stress. Chem Biol Interact 2018; 285:96-105. [DOI: 10.1016/j.cbi.2018.01.021] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Revised: 12/11/2017] [Accepted: 01/24/2018] [Indexed: 02/01/2023]
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39
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RostamiRad A, Ebrahimi SSS, Sadeghi A, Taghikhani M, Meshkani R. Palmitate-induced impairment of autophagy turnover leads to increased apoptosis and inflammation in peripheral blood mononuclear cells. Immunobiology 2018; 223:269-278. [DOI: 10.1016/j.imbio.2017.10.041] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 10/14/2017] [Indexed: 12/20/2022]
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40
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Zhou Y, Wu Y, Liu Y, He Z, Zou S, Wang Q, Li J, Zheng Z, Chen J, Wu F, Gong F, Zhang H, Xu H, Xiao J. The cross-talk between autophagy and endoplasmic reticulum stress in blood-spinal cord barrier disruption after spinal cord injury. Oncotarget 2018; 8:1688-1702. [PMID: 27926492 PMCID: PMC5352089 DOI: 10.18632/oncotarget.13777] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 11/07/2016] [Indexed: 01/07/2023] Open
Abstract
Spinal cord injury induces the disruption of blood-spinal cord barrier and triggers a complex array of tissue responses, including endoplasmic reticulum (ER) stress and autophagy. However, the roles of ER stress and autophagy in blood-spinal cord barrier disruption have not been discussed in acute spinal cord trauma. In the present study, we respectively detected the roles of ER stress and autophagy in blood-spinal cord barrier disruption after spinal cord injury. Besides, we also detected the cross-talking between autophagy and ER stress both in vivo and in vitro. ER stress inhibitor, 4-phenylbutyric acid, and autophagy inhibitor, chloroquine, were respectively or combinedly administrated in the model of acute spinal cord injury rats. At day 1 after spinal cord injury, blood-spinal cord barrier was disrupted and activation of ER stress and autophagy were involved in the rat model of trauma. Inhibition of ER stress by treating with 4-phenylbutyric acid decreased blood-spinal cord barrier permeability, prevented the loss of tight junction (TJ) proteins and reduced autophagy activation after spinal cord injury. On the contrary, inhibition of autophagy by treating with chloroquine exacerbated blood-spinal cord barrier permeability, promoted the loss of TJ proteins and enhanced ER stress after spinal cord injury. When 4-phenylbutyric acid and chloroquine were combinedly administrated in spinal cord injury rats, chloroquine abolished the blood-spinal cord barrier protective effect of 4-phenylbutyric acid by exacerbating ER stress after spinal cord injury, indicating that the cross-talking between autophagy and ER stress may play a central role on blood-spinal cord barrier integrity in acute spinal cord injury. The present study illustrates that ER stress induced by spinal cord injury plays a detrimental role on blood-spinal cord barrier integrity, on the contrary, autophagy induced by spinal cord injury plays a furthersome role in blood-spinal cord barrier integrity in acute spinal cord injury.
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Affiliation(s)
- Yulong Zhou
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China.,Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China
| | - Yanqing Wu
- The Institute of Life Sciences, Wenzhou University, Wenzhou 325035, China
| | - Yanlong Liu
- Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China
| | - Zili He
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China.,Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China
| | - Shuang Zou
- Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China
| | - Qingqing Wang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China.,Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China
| | - Jiawei Li
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China.,Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China
| | - Zengming Zheng
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China.,Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China
| | - Jian Chen
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China.,Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China
| | - Fenzan Wu
- Department of Neurosurgery, Affiliated Cixi People's Hospital, Wenzhou Medical University, Ningbo, 315300, China
| | - Fanhua Gong
- The Institute of Life Sciences, Wenzhou University, Wenzhou 325035, China
| | - Hongyu Zhang
- Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China
| | - Huazi Xu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China
| | - Jian Xiao
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China.,Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China
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41
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Progesterone suppresses Aβ 42-induced neuroinflammation by enhancing autophagy in astrocytes. Int Immunopharmacol 2017; 54:336-343. [PMID: 29197800 DOI: 10.1016/j.intimp.2017.11.044] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 11/13/2017] [Accepted: 11/28/2017] [Indexed: 12/24/2022]
Abstract
Autophagy is an intracellular catabolic mechanism essential for recycling intracellular unfolding protein and eliminating toxic protein aggregates. Several studies have shown that deficient autophagy is implicated in the development of Alzheimer's disease (AD) progression. To date, rapidly emerging evidence suggests that neurosteroid progesterone (PG) may play an important role in ameliorating AD. However, the role of PG and its neuroprotective mechanism in regulating autophagy still require further investigation. Here, we investigated the protective effects of PG against Aβ-induced inflammatory responses in astrocytes and its underlying mechanism in mediating autophagy. Remarkably, Aβ induced astrocyte dysfunction in autophagic activation and up-regulated inflammatory secretion. However, the autophagy inducer rapamycin (RAPA) significantly suppressed Aβ-induced inflammation in astrocytes. In astrocytes, treatment with Aβ caused autophagy deficiency, whereas PG significantly increased autophagy activation. Finally, PG suppressed Aβ-induced neuroinflammatory production via enhancing autophagy together with regulating mTOR signaling. Taken together, these results show that autophagy is a vital mechanism against Aβ-induced neuroinflammatory responses in astrocytes and demonstrate the potential neuroprotective mechanism of PG in suppressing neuroinflammatory responses by enhancing autophagy. Therefore, uncovering the neuroprotective mechanism of PG may provide new insight into novel therapies for the amelioration of AD.
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42
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Diet-induced obesity impairs spermatogenesis: a potential role for autophagy. Sci Rep 2017; 7:43475. [PMID: 28276438 PMCID: PMC5343591 DOI: 10.1038/srep43475] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 01/25/2017] [Indexed: 12/11/2022] Open
Abstract
Autophagy is an evolutionarily conserved process that plays a crucial role in maintaining a series of cellular functions. It has been found that autophagy is closely involved in the physiological process of spermatogenesis and the regulation of sperm survival and motility. However, the role of autophagy in high-fat diet (HFD)-induced impaired spermatogenesis remains unknown. This study was designed to investigate the role of autophagy in HFD-induced spermatogenesis deficiency and employed chloroquine (CQ) to inhibit autophagy and rapamycin (RAP) to induce autophagy. 3-methyladenine (3-MA) and CQ were administered via intratesticular injection in vivo. The effects of CQ and 3-MA on the parameters of spermatozoa co-cultured with palmitic acid (PA) in vitro were also investigated. Human semen samples from obese, subfertile male patients were also collected to examine the level of autophagy. The results suggested that HFD mice subjected to CQ showed improved spermatogenesis. Inhibiting autophagy with CQ improved the decreased fertility of HFD male mice. Moreover, the in vivo and in vitro results indicated that both CQ and 3-MA could suppress the pathological changes in spermatozoa caused by HFD or PA treatment. Additionally, the excessive activation of autophagy was also observed in sperm samples from obese, subfertile male patients.
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43
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Tschurtschenthaler M, Adolph TE, Ashcroft JW, Niederreiter L, Bharti R, Saveljeva S, Bhattacharyya J, Flak MB, Shih DQ, Fuhler GM, Parkes M, Kohno K, Iwawaki T, Janneke van der Woude C, Harding HP, Smith AM, Peppelenbosch MP, Targan SR, Ron D, Rosenstiel P, Blumberg RS, Kaser A. Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis. J Exp Med 2017; 214:401-422. [PMID: 28082357 PMCID: PMC5294857 DOI: 10.1084/jem.20160791] [Citation(s) in RCA: 142] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Revised: 10/02/2016] [Accepted: 12/07/2016] [Indexed: 02/02/2023] Open
Abstract
ATG16L1T300A, a major risk polymorphism in Crohn's disease (CD), causes impaired autophagy, but it has remained unclear how this predisposes to CD. In this study, we report that mice with Atg16l1 deletion in intestinal epithelial cells (IECs) spontaneously develop transmural ileitis phenocopying ileal CD in an age-dependent manner, driven by the endoplasmic reticulum (ER) stress sensor IRE1α. IRE1α accumulates in Paneth cells of Atg16l1ΔIEC mice, and humans homozygous for ATG16L1T300A exhibit a corresponding increase of IRE1α in intestinal epithelial crypts. In contrast to a protective role of the IRE1β isoform, hyperactivated IRE1α also drives a similar ileitis developing earlier in life in Atg16l1;Xbp1ΔIEC mice, in which ER stress is induced by deletion of the unfolded protein response transcription factor XBP1. The selective autophagy receptor optineurin interacts with IRE1α, and optineurin deficiency amplifies IRE1α levels during ER stress. Furthermore, although dysbiosis of the ileal microbiota is present in Atg16l1;Xbp1ΔIEC mice as predicted from impaired Paneth cell antimicrobial function, such structural alteration of the microbiota does not trigger ileitis but, rather, aggravates dextran sodium sulfate-induced colitis. Hence, we conclude that defective autophagy in IECs may predispose to CD ileitis via impaired clearance of IRE1α aggregates during ER stress at this site.
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Affiliation(s)
- Markus Tschurtschenthaler
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK
| | - Timon E. Adolph
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK
| | - Jonathan W. Ashcroft
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK
| | - Lukas Niederreiter
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK
| | - Richa Bharti
- Institute for Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel, Germany
| | - Svetlana Saveljeva
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK
| | - Joya Bhattacharyya
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK
| | - Magdalena B. Flak
- Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - David Q. Shih
- Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
| | - Gwenny M. Fuhler
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, 3015 CE Rotterdam, Netherlands
| | - Miles Parkes
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK
| | - Kenji Kohno
- Laboratory of Molecular and Cell Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan
| | - Takao Iwawaki
- Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Kahoku, Ishikawa 920-0293, Japan
| | - C. Janneke van der Woude
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, 3015 CE Rotterdam, Netherlands
| | - Heather P. Harding
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0QQ, England, UK
| | - Andrew M. Smith
- Eastman Dental Institute, University College London, London WC1E 6BT, England, UK
| | - Maikel P. Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, 3015 CE Rotterdam, Netherlands
| | - Stephan R. Targan
- Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
| | - David Ron
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0QQ, England, UK
| | - Philip Rosenstiel
- Institute for Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel, Germany
| | - Richard S. Blumberg
- Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Arthur Kaser
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK
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44
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Li S, Li H, Yang D, Yu X, Irwin DM, Niu G, Tan H. Excessive Autophagy Activation and Increased Apoptosis Are Associated with Palmitic Acid-Induced Cardiomyocyte Insulin Resistance. J Diabetes Res 2017; 2017:2376893. [PMID: 29318158 PMCID: PMC5727752 DOI: 10.1155/2017/2376893] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 08/26/2017] [Accepted: 09/12/2017] [Indexed: 12/13/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) remains the major cause of death associated with diabetes. Researchers have demonstrated the importance of impaired cardiac insulin signaling in this process. Insulin resistance (IR) is an important predictor of DCM. Previous studies examining the dynamic changes in autophagy during IR have yielded inconsistent results. This study aimed to investigate the dynamic changes in autophagy and apoptosis in the rat H9c2 cardiomyocyte IR model. H9c2 cells were treated with 500 μM palmitic acid (PA) for 24 hours, resulting in the induction of IR. To examine autophagy, monodansylcadaverine staining, GFP-LC3 puncta confocal observation, and Western blot analysis of LC3I-to-LC3II conversion were used. Results of these studies showed that autophagic acid vesicles increased in numbers during the first 24 hours and then decreased by 36 hours after PA treatment. Western blot analysis showed that treatment of H9c2 cells with 500 μM PA for 24 hours decreased the expression of Atg12-Atg5, Atg16L1, Atg3, and PI3Kp85. Annexin V/PI flow cytometry revealed that PA exposure for 24 hours increased the rate of apoptosis. Together, this study demonstrates that PA induces IR in H9c2 cells and that this process is accompanied by excessive activation of autophagy and increases in apoptosis.
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Affiliation(s)
- Shanxin Li
- Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, China
| | - Hui Li
- Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, China
| | - Di Yang
- Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, China
| | - Xiuyan Yu
- Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, China
| | - David M. Irwin
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 1A8
| | - Gang Niu
- Beijing N&N Genetech Company, Beijing 100082, China
| | - Huanran Tan
- Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, China
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45
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Sekar S, Crawford R, Xiao Y, Prasadam I. Dietary Fats and Osteoarthritis: Insights, Evidences, and New Horizons. J Cell Biochem 2016; 118:453-463. [DOI: 10.1002/jcb.25758] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Accepted: 10/10/2016] [Indexed: 12/11/2022]
Affiliation(s)
- Sunderajhan Sekar
- Institute of Health and Biomedical Innovation; Queensland University of Technology; Brisbane Australia
| | - Ross Crawford
- Institute of Health and Biomedical Innovation; Queensland University of Technology; Brisbane Australia
- The Prince Charles Hospital; Orthopedic Department; Brisbane Australia
| | - Yin Xiao
- Institute of Health and Biomedical Innovation; Queensland University of Technology; Brisbane Australia
| | - Indira Prasadam
- Institute of Health and Biomedical Innovation; Queensland University of Technology; Brisbane Australia
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46
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Regulation of Autophagy-Related Protein and Cell Differentiation by High Mobility Group Box 1 Protein in Adipocytes. Mediators Inflamm 2016; 2016:1936386. [PMID: 27843198 PMCID: PMC5098089 DOI: 10.1155/2016/1936386] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 09/11/2016] [Accepted: 10/04/2016] [Indexed: 12/27/2022] Open
Abstract
High mobility group box 1 protein (HMGB1) is a molecule related to the development of inflammation. Autophagy is vital to maintain cellular homeostasis and protect against inflammation of adipocyte injury. Our recent work focused on the relationship of HMGB1 and autophagy in 3T3-L1 cells. In vivo experimental results showed that, compared with the normal-diet group, the high-fat diet mice displayed an increase in adipocyte size in the epididymal adipose tissues. The expression levels of HMGB1 and LC3II also increased in epididymal adipose tissues in high-fat diet group compared to the normal-diet mice. The in vitro results indicated that HMGB1 protein treatment increased LC3II formation in 3T3-L1 preadipocytes in contrast to that in the control group. Furthermore, LC3II formation was inhibited through HMGB1 knockdown by siRNA. Treatment with the HMGB1 protein enhanced LC3II expression after 2 and 4 days but decreased the expression after 8 and 10 days among various differentiation stages of adipocytes. By contrast, FABP4 expression decreased on the fourth day and increased on the eighth day. Hence, the HMGB1 protein modulated autophagy-related proteins and lipid-metabolism-related genes in adipocytes and could be a new target for treatment of obesity and related metabolic diseases.
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47
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Zhao W, Han F, Shi Y. IRE1α pathway of endoplasmic reticulum stress induces neuronal apoptosis in the locus coeruleus of rats under single prolonged stress. Prog Neuropsychopharmacol Biol Psychiatry 2016; 69:11-8. [PMID: 27059130 DOI: 10.1016/j.pnpbp.2016.03.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 03/21/2016] [Accepted: 03/26/2016] [Indexed: 10/22/2022]
Abstract
Our previous studies have shown evidence of endoplasmic reticulum (ER) stress-induced apoptosis in the hippocampus and mPFC in an animal model of post- traumatic stress disorder (PTSD). Inositol-requiring enzyme 1α (IRE1α) and its downstream molecule X-box binding protein 1 (XBP1) play key roles in the ER-related apoptosis pathway. Dysregulation of the locus coeruleus (LC) has been reported to contribute to cognitive and/or arousal impairments associated with PTSD. The aim of the present study was to explore the role of IRE1α pathway in neuronal apoptosis in the LC of rat models of PTSD. We used an acute exposure to prolonged stress (single prolonged stress, SPS) to model PTSD in rats and examined the effects related to the IRE1α pathway. Neuronal apoptosis in LC was detected by transmission electron microscopy and TUNEL staining. The results showed that the level of LC neuronal apoptosis was markedly increased after SPS. SPS exposure triggered IRE1α pathway, as evidenced by the increased activity of IRE1α, specific splicing of XBP1, and up-regulated expression of binding immunoglobulin protein/78kDa glucose-regulated protein (BiP/GRP78), and C/EBP-homologous protein (CHOP). Treatment with STF-083010, an IRE1α RNase-specific inhibitor, successfully attenuated the above changes. These results indicate that excessive activation of the ER stress-associated IRE1α pathway is involved in LC neuronal apoptosis induced by SPS exposure; this may be a crucial mechanism of the pathogenesis of PTSD.
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Affiliation(s)
- Wei Zhao
- PTSD Laboratory, Department of Histology and Embryology, Basic Medical Science College, China Medical University, Shenyang, China; Department of Histology and Embryology, Binzhou Medical University, Yantai, China
| | - Fang Han
- PTSD Laboratory, Department of Histology and Embryology, Basic Medical Science College, China Medical University, Shenyang, China
| | - Yuxiu Shi
- PTSD Laboratory, Department of Histology and Embryology, Basic Medical Science College, China Medical University, Shenyang, China.
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48
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Trudeau KM, Colby AH, Zeng J, Las G, Feng JH, Grinstaff MW, Shirihai OS. Lysosome acidification by photoactivated nanoparticles restores autophagy under lipotoxicity. J Cell Biol 2016; 214:25-34. [PMID: 27377248 PMCID: PMC4932370 DOI: 10.1083/jcb.201511042] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 06/15/2016] [Indexed: 12/11/2022] Open
Abstract
In pancreatic β-cells, liver hepatocytes, and cardiomyocytes, chronic exposure to high levels of fatty acids (lipotoxicity) inhibits autophagic flux and concomitantly decreases lysosomal acidity. Whether impaired lysosomal acidification is causally inhibiting autophagic flux and cellular functions could not, up to the present, be determined because of the lack of an approach to modify lysosomal acidity. To address this question, lysosome-localizing nanoparticles are described that, upon UV photoactivation, enable controlled acidification of impaired lysosomes. The photoactivatable, acidifying nanoparticles (paNPs) demonstrate lysosomal uptake in INS1 and mouse β-cells. Photoactivation of paNPs in fatty acid-treated INS1 cells enhances lysosomal acidity and function while decreasing p62 and LC3-II levels, indicating rescue of autophagic flux upon acute lysosomal acidification. Furthermore, paNPs improve glucose-stimulated insulin secretion that is reduced under lipotoxicity in INS1 cells and mouse islets. These results establish a causative role for impaired lysosomal acidification in the deregulation of autophagy and β-cell function under lipotoxicity.
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Affiliation(s)
- Kyle M Trudeau
- Obesity and Nutrition Section, Department of Medicine, Evans Biomedical Research Center, Boston University School of Medicine, Boston, MA 02118
| | - Aaron H Colby
- Departments of Biomedical Engineering, Chemistry, and Medicine, Boston University, Boston, MA 02215 Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215
| | - Jialiu Zeng
- Departments of Biomedical Engineering, Chemistry, and Medicine, Boston University, Boston, MA 02215
| | - Guy Las
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84103, Israel
| | - Jiazuo H Feng
- Departments of Biomedical Engineering, Chemistry, and Medicine, Boston University, Boston, MA 02215
| | - Mark W Grinstaff
- Departments of Biomedical Engineering, Chemistry, and Medicine, Boston University, Boston, MA 02215
| | - Orian S Shirihai
- Obesity and Nutrition Section, Department of Medicine, Evans Biomedical Research Center, Boston University School of Medicine, Boston, MA 02118 Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84103, Israel Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90045
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Yu X, Jin D, Yu A, Sun J, Chen X, Yang Z. p65 down-regulates DEPTOR expression in response to LPS stimulation in hepatocytes. Gene 2016; 589:12-19. [PMID: 27179948 DOI: 10.1016/j.gene.2016.05.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Revised: 05/09/2016] [Accepted: 05/10/2016] [Indexed: 01/16/2023]
Abstract
DEPTOR, a novel endogenous inhibitor of mTOR, plays an important role in regulating the inflammatory response in vascular endothelial cells (ECs) and in mouse skeletal muscle. However, the regulatory mechanism of DEPTOR transcription and its effects on liver inflammation are unknown presently. Here we reported the role of DEPTOR in regulating inflammatory response in mouse liver-derived Hepa1-6 cells and in a mouse model with LPS-induced hepatic inflammation. The results revealed that DEPTOR over-expression in Hepa1-6 liver cells increased the mRNA levels of the pro-inflammatory cytokines interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1). Contrasting results were observed in Hepa1-6 cells with DEPTOR interference. Treatment Hepa1-6 cells with rapamycin, a specific inhibitor of mTORC1, increased MCP-1 mRNA, but have no significant effect on IL-6 mRNA. DEPTOR expression was down-regulated in Hepa1-6 cells with the treatment of inflammatory stimuli LPS or the over-expression of p65/NF-κB, a key inflammatory transcription factor. NF-κB antagonist (PDTC) and inhibitor (IκBα) blocked the effect of LPS on DEPTOR expression. The study in vivo showed that DEPTOR mRNA and protein were significantly reduced in a mouse model with LPS-induced hepatic inflammation, which was accompanied by a concurrent activation of the mTOR signaling pathway. Further, the transcriptional regulation of DEPTOR was explored, which revealed that DEPTOR promoter activity was significantly down-regulated by NF-κB. The progressive deletions and mutations demonstrated that the NF-κB binding motif situated at -145/-127 region is an essential component required for the DEPTOR promoter activity. Chromatin immunoprecipitation (ChIP) assays determined that p65 can directly interact with the DEPTOR promoter DNA. Those results indicate DEPTOR regulates liver inflammation at least partially via mTORC1 pathway, and is down-regulated by LPS through p65.
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Affiliation(s)
- Xiaoling Yu
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Dan Jin
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - An Yu
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jun Sun
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Xiaodong Chen
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Zaiqing Yang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
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50
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Jung TW, Choi KM. Pharmacological Modulators of Endoplasmic Reticulum Stress in Metabolic Diseases. Int J Mol Sci 2016; 17:ijms17020192. [PMID: 26840310 PMCID: PMC4783926 DOI: 10.3390/ijms17020192] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Revised: 01/20/2016] [Accepted: 01/27/2016] [Indexed: 01/23/2023] Open
Abstract
The endoplasmic reticulum (ER) is the principal organelle responsible for correct protein folding, a step in protein synthesis that is critical for the functional conformation of proteins. ER stress is a primary feature of secretory cells and is involved in the pathogenesis of numerous human diseases, such as certain neurodegenerative and cardiometabolic disorders. The unfolded protein response (UPR) is a defense mechanism to attenuate ER stress and maintain the homeostasis of the organism. Two major degradation systems, including the proteasome and autophagy, are involved in this defense system. If ER stress overwhelms the capacity of the cell's defense mechanisms, apoptotic death may result. This review is focused on the various pharmacological modulators that can protect cells from damage induced by ER stress. The possible mechanisms for cytoprotection are also discussed.
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Affiliation(s)
- Tae Woo Jung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul 152-703, Korea.
| | - Kyung Mook Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul 152-703, Korea.
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