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Li X, Chen Y, Gong S, Chen H, Liu H, Li X, Hao J. Emerging roles of TFE3 in metabolic regulation. Cell Death Discov 2023; 9:93. [PMID: 36906611 PMCID: PMC10008649 DOI: 10.1038/s41420-023-01395-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/27/2023] [Accepted: 03/01/2023] [Indexed: 03/13/2023] Open
Abstract
TFE3 is a member of the MiT family of the bHLH-leucine zipper transcription factor. We previously focused on the role of TFE3 in autophagy and cancer. Recently, an increasing number of studies have revealed that TFE3 plays an important role in metabolic regulation. TFE3 participates in the metabolism of energy in the body by regulating pathways such as glucose and lipid metabolism, mitochondrial metabolism, and autophagy. This review summarizes and discusses the specific regulatory mechanisms of TFE3 in metabolism. We determined both the direct regulation of TFE3 on metabolically active cells, such as hepatocytes and skeletal muscle cells, and the indirect regulation of TFE3 through mitochondrial quality control and the autophagy-lysosome pathway. The role of TFE3 in tumor cell metabolism is also summarized in this review. Understanding the diverse roles of TFE3 in metabolic processes can provide new avenues for the treatment of some metabolism-related disorders.
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Affiliation(s)
- Xingyu Li
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Yongming Chen
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Siqiao Gong
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Huixia Chen
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Huafeng Liu
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
| | - Xiaoyu Li
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
| | - Junfeng Hao
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
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Cheng H, Wang M, Su J, Li Y, Long J, Chu J, Wan X, Cao Y, Li Q. Lipid Metabolism and Cancer. Life (Basel) 2022; 12:life12060784. [PMID: 35743814 PMCID: PMC9224822 DOI: 10.3390/life12060784] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/16/2022] [Accepted: 05/18/2022] [Indexed: 11/16/2022] Open
Abstract
Lipid metabolism is involved in the regulation of numerous cellular processes, such as cell growth, proliferation, differentiation, survival, apoptosis, inflammation, movement, membrane homeostasis, chemotherapy response, and drug resistance. Reprogramming of lipid metabolism is a typical feature of malignant tumors. In a variety of cancers, fat uptake, storage and fat production are up-regulated, which in turn promotes the rapid growth, invasion, and migration of tumors. This paper systematically summarizes the key signal transduction pathways and molecules of lipid metabolism regulating tumors, and the role of lipid metabolism in programmed cell death. In conclusion, understanding the potential molecular mechanism of lipid metabolism and the functions of different lipid molecules may facilitate elucidating the mechanisms underlying the occurrence of cancer in order to discover new potential targets for the development of effective antitumor drugs.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Qinglin Li
- Correspondence: ; Tel.: +86-0551-65169051
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Kamoshita K, Tsugane H, Ishii KA, Takayama H, Yao X, Abuduwaili H, Tanida R, Taniguchi Y, Oo HK, Gafiyatullina G, Kaneko S, Matsugo S, Takamura T. Lauric acid impairs insulin-induced Akt phosphorylation by upregulating SELENOP expression via HNF4α induction. Am J Physiol Endocrinol Metab 2022; 322:E556-E568. [PMID: 35499234 DOI: 10.1152/ajpendo.00163.2021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 04/06/2022] [Accepted: 04/25/2022] [Indexed: 11/22/2022]
Abstract
Selenoprotein P (SeP; encoded by SELENOP in humans, Selenop in rodents) is a hepatokine that is upregulated in the liver of humans with type 2 diabetes. Excess SeP contributes to the onset of insulin resistance and various type 2 diabetes-related complications. We have previously reported that the long-chain saturated fatty acid, palmitic acid, upregulates Selenop expression, whereas the polyunsaturated fatty acids (PUFAs) downregulate it in hepatocytes. However, the effect of medium-chain fatty acids (MCFAs) on Selenop is unknown. Here we report novel mechanisms that underlie the lauric acid-mediated Selenop gene regulation in hepatocytes. Lauric acid upregulated Selenop expression in Hepa1-6 hepatocytes and mice liver. A luciferase promoter assay and computational analysis of transcription factor-binding sites identified the hepatic nuclear factor 4α (HNF4α) binding site in the SELENOP promoter. A chromatin immunoprecipitation (ChIP) assay showed that lauric acid increased the binding of HNF4α to the SELENOP promoter. The knockdown of Hnf4α using siRNA canceled the upregulation of lauric acid-induced Selenop. Thus, the lauric acid-induced impairment of Akt phosphorylation brought about by insulin was rescued by the knockdown of either Hnf4α or Selenop. These results provide new insights into the regulation of SeP by fatty acids and suggest that SeP may mediate MCFA-induced hepatic insulin signal reduction.
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Affiliation(s)
- Kyoko Kamoshita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Hirohiko Tsugane
- Institute of Science and Engineering, Faculty of Natural System, Kanazawa University, Kanazawa, Japan
| | - Kiyo-Aki Ishii
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
- Department of Integrative Medicine for Longevity, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hiroaki Takayama
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
- Department of System Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
- Life Sciences Division, Engineering and Technology Department, Kanazawa University, Kanazawa, Japan
| | - Xingyu Yao
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Halimulati Abuduwaili
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Ryota Tanida
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Yasumasa Taniguchi
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Hein Ko Oo
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Guzel Gafiyatullina
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Shuichi Kaneko
- Department of System Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Seiichi Matsugo
- Institute of Science and Engineering, Faculty of Natural System, Kanazawa University, Kanazawa, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
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Bano N, Patel P, Chakrabarty D, Bag SK. Genome-wide identification, phylogeny, and expression analysis of the bHLH gene family in tobacco ( Nicotiana tabacum). PHYSIOLOGY AND MOLECULAR BIOLOGY OF PLANTS : AN INTERNATIONAL JOURNAL OF FUNCTIONAL PLANT BIOLOGY 2021; 27:1747-1764. [PMID: 34539114 PMCID: PMC8405835 DOI: 10.1007/s12298-021-01042-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/24/2021] [Accepted: 07/27/2021] [Indexed: 05/05/2023]
Abstract
UNLABELLED The basic helix-loop-helix (bHLH) is the second-largest TF family in plants that play important roles in plant growth, development, and stress responses. In this study, a total of 100 bHLHs were identified using Hidden Markov Model profiles in the Nicotiana tabacum genome, clustered into 15 major groups (I-XV) based on their conserved domains and phylogenetic relationships. Group VIII genes were found to be the most abundant, with 27 NtbHLH members. The expansion of NtbHLHs in the genome was due to segmental and tandem duplication. The purifying selection was found to have an important role in the evolution of NtHLHs. Subsequent qRT-PCR validation of five selected genes from transcriptome data revealed that NtbHLH3.1, NtbHLH3.2, NtbHLH24, NtbHLH50, and NtbHLH59.2 have higher expressions at 12 and 24 h in comparison to 0 h (control) of chilling stress. The validated results demonstrated that NtbHLH3.2 and NtbHLH24 genes have 3 and fivefold higher expression at 12 h and 2 and threefold higher expression at 24 h than control plant, shows high sensitivity towards chilling stress. Moreover, the co-expression of positively correlated genes of NtbHLH3.2 and NtbHLH24 confirmed their functional significance in chilling stress response. Therefore, suggesting the importance of NtbHLH3.2 and NtbHLH24 genes in exerting control over the chilling stress responses in tobacco. SUPPLEMENTARY INFORMATION The online version contains supplementary material available at 10.1007/s12298-021-01042-x.
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Affiliation(s)
- Nasreen Bano
- Molecular Biology and Biotechnology Division, CSIR-National Botanical Research Institute (CSIR-NBRI), Rana Pratap Marg, Lucknow, 226001 India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
| | - Preeti Patel
- Molecular Biology and Biotechnology Division, CSIR-National Botanical Research Institute (CSIR-NBRI), Rana Pratap Marg, Lucknow, 226001 India
| | - Debasis Chakrabarty
- Molecular Biology and Biotechnology Division, CSIR-National Botanical Research Institute (CSIR-NBRI), Rana Pratap Marg, Lucknow, 226001 India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
| | - Sumit Kumar Bag
- Molecular Biology and Biotechnology Division, CSIR-National Botanical Research Institute (CSIR-NBRI), Rana Pratap Marg, Lucknow, 226001 India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
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Integrated regulatory network reveals novel candidate regulators in the development of negative energy balance in cattle. Animal 2017; 12:1196-1207. [PMID: 29282162 DOI: 10.1017/s1751731117003524] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Negative energy balance (NEB) is an altered metabolic state in modern high-yielding dairy cows. This metabolic state occurs in the early postpartum period when energy demands for milk production and maintenance exceed that of energy intake. Negative energy balance or poor adaptation to this metabolic state has important effects on the liver and can lead to metabolic disorders and reduced fertility. The roles of regulatory factors, including transcription factors (TFs) and micro RNAs (miRNAs) have often been separately studied for evaluating of NEB. However, adaptive response to NEB is controlled by complex gene networks and still not fully understood. In this study, we aimed to discover the integrated gene regulatory networks involved in NEB development in liver tissue. We downloaded data sets including mRNA and miRNA expression profiles related to three and four cows with severe and moderate NEB, respectively. Our method integrated two independent types of information: module inference network by TFs, miRNAs and mRNA expression profiles (RNA-seq data) and computational target predictions. In total, 176 modules were predicted by using gene expression data and 64 miRNAs and 63 TFs were assigned to these modules. By using our integrated computational approach, we identified 13 TF-module and 19 miRNA-module interactions. Most of these modules were associated with liver metabolic processes as well as immune and stress responses, which might play crucial roles in NEB development. Literature survey results also showed that several regulators and gene targets have already been characterized as important factors in liver metabolic processes. These results provided novel insights into regulatory mechanisms at the TF and miRNA levels during NEB. In addition, the method described in this study seems to be applicable to construct integrated regulatory networks for different diseases or disorders.
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Kim YS, Kim M, Choi MY, Lee DH, Roh GS, Kim HJ, Kang SS, Cho GJ, Park KH, Kim SJ, Yoo JM, Choi WS. Aralia elata (Miq) Seem Extract Decreases O-GlcNAc Transferase Expression and Retinal Cell Death in Diabetic Mice. J Med Food 2017; 20:989-1001. [DOI: 10.1089/jmf.2016.3891] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
- Yoon Sook Kim
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Minjun Kim
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Mee Young Choi
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Dong Hoon Lee
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Gu Seob Roh
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Hyun Joon Kim
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Sang Soo Kang
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Gyeong Jae Cho
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Ki Hun Park
- Division of Applied Life Science, Institute of Agriculture Life Science, Graduate School of Gyeongsang National University, Jinju, South Korea
| | - Seong-Jae Kim
- Department of Ophthalmology, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Ji-Myong Yoo
- Department of Ophthalmology, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Wan Sung Choi
- Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
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Bidwell AJ. Chronic Fructose Ingestion as a Major Health Concern: Is a Sedentary Lifestyle Making It Worse? A Review. Nutrients 2017; 9:nu9060549. [PMID: 28555043 PMCID: PMC5490528 DOI: 10.3390/nu9060549] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 05/17/2017] [Accepted: 05/25/2017] [Indexed: 12/13/2022] Open
Abstract
Obesity contributes to metabolic abnormalities such as insulin resistance, dyslipidemia, hypertension, and glucose intolerance, all of which are risk factors associated with metabolic syndrome. The growing prevelance of metabolic syndrome seems to be an end result of our current lifestyle which promotes high caloric, high-fat foods and minimal physical activity, resulting in a state of positive energy balance. Increased adiposity and physical inactivity may represent the beginning of the appearance of these risk factors. Understanding the metabolic and cardiovascular disturbances associated with diet and exercise habits is a crucial step towards reducing the risk factors for metabolic syndrome. Although considerable research has been conducted linking chronic fructose ingestion to the increased prevalence of obesity and metabolic syndrome risk factors, these studies have mainly been performed on animals, and/or in a post-absorptive state. Further, the magnitude of the effect of fructose may depend on other aspects of the diet, including the total amount of carbohydrates and fats in the diet and the overall consumption of meals. Therefore, the overall aim of this review paper is to examine the effects of a diet high in fructose on postprandial lipidemia, inflammatory markers and glucose tolerance, all risk factors for diabetes and cardiovascular disease. Moreover, an objective is to investigate whether increased physical activity can alter such effects.
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Affiliation(s)
- Amy J Bidwell
- Department of Health Promotion and Wellness, State University of New York at Oswego, 105G Park Hall, Oswego, NY 13027, USA.
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Abstract
According to the standard model of G protein-coupled receptor (GPCR) signaling, GPCRs are localized to the cell membrane where they respond to extracellular signals. Stimulation of GPCRs leads to the activation of heterotrimeric G proteins and their intracellular signaling pathways. However, this model fails to accommodate GPCRs, G proteins, and their downstream effectors that are found on the nuclear membrane or in the nucleus. Evidence from isolated nuclei indicates the presence of GPCRs on the nuclear membrane that can activate similar G protein-dependent signaling pathways in the nucleus as at the cell surface. These pathways also include activation of cyclic adenosine monophosphate, calcium and nitric oxide synthase signaling in cardiomyocytes. In addition, a number of distinct heterotrimeric and monomeric G proteins have been found in the nucleus of various cell types. This review will focus on understanding the function of nuclear G proteins with a focus on cardiac signaling where applicable.
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Sakamoto Y, Yamamoto K, Hatakeyama Y, Tsuduki T. Effects of Fatty Acid Quality and Quantity in the Japanese Diet on the Suppression of Lipid Accumulation. J Oleo Sci 2016; 65:61-73. [DOI: 10.5650/jos.ess15150] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Yu Sakamoto
- Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University
| | - Kazushi Yamamoto
- Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University
| | - Yu Hatakeyama
- Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University
| | - Tsuyoshi Tsuduki
- Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University
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Wu W, Tang S, Shi J, Yin W, Cao S, Bu R, Zhu D, Bi Y. Metformin attenuates palmitic acid-induced insulin resistance in L6 cells through the AMP-activated protein kinase/sterol regulatory element-binding protein-1c pathway. Int J Mol Med 2015; 35:1734-40. [PMID: 25891779 DOI: 10.3892/ijmm.2015.2187] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Accepted: 04/09/2015] [Indexed: 11/05/2022] Open
Abstract
AMP-activated protein kinase (AMPK) is an important effector of metformin action on glucose uptake in skeletal muscle cells. We recently reported that metformin improved insulin receptor substrate-1 (IRS-1)-associated insulin signaling by downregulating sterol regulatory element-binding protein-1c (SREBP-1c) expression. In this study, we investigated whether AMPK activation and SREBP-1c inhibition contribute to the beneficial effects of metformin on IRS-1-associated insulin signaling in L6 myotubes. L6 muscle cells were incubated with palmitic acid (PA) to induce insulin resistance and then treated with metformin and/or the AMPK inhibitor, compound C. AMPK, SREBP-1c, IRS-1 and Akt protein expression levels were determined by western blot analysis. The effects of metformin on SREBP-1c gene transcription were determined by a luciferase reporter assay. Glucose uptake was evaluated using the 2-NBDG method. In the PA-treated L6 cells, metformin treatment enhanced AMPK phosphorylation, reduced SREBP-1c expression and increased IRS-1 and Akt protein expression, whereas treatment with compound C blocked the effects of metformin on SREBP-1c expression and the IRS-1 and Akt levels. Moreover, metformin suppressed SREBP-1c promoter activity and promoted glucose uptake through AMPK. The results from this study demonstrate that metformin ameliorates PA-induced insulin resistance through the activation of AMPK and the suppression of SREBP-1c in skeletal muscle cells.
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Affiliation(s)
- Wenjun Wu
- Department of Endocrinology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Sunyinyan Tang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, P.R. China
| | - Junfeng Shi
- Department of Oncology, Nanjing First Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Wenwen Yin
- Department of Endocrinology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Shu Cao
- Department of Endocrinology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Ruifang Bu
- Department of Endocrinology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, P.R. China
| | - Dalong Zhu
- Department of Endocrinology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Yan Bi
- Department of Endocrinology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
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Yoon HJ, Cha BS. Pathogenesis and therapeutic approaches for non-alcoholic fatty liver disease. World J Hepatol 2014; 6:800-811. [PMID: 25429318 PMCID: PMC4243154 DOI: 10.4254/wjh.v6.i11.800] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 08/27/2014] [Accepted: 10/16/2014] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease affects approximately one-third of the population worldwide, and its incidence continues to increase with the increasing prevalence of other metabolic disorders such as type 2 diabetes. As non-alcoholic fatty liver disease can progress to liver cirrhosis, its treatment is attracting greater attention. The pathogenesis of non-alcoholic fatty liver disease is closely associated with insulin resistance and dyslipidemia, especially hypertriglyceridemia. Increased serum levels of free fatty acid and glucose can cause oxidative stress in the liver and peripheral tissue, leading to ectopic fat accumulation, especially in the liver. In this review, we summarize the mechanism underlying the progression of hepatic steatosis to steatohepatitis and cirrhosis. We also discuss established drugs that are already being used to treat non-alcoholic fatty liver disease, in addition to newly discovered agents, with respect to their mechanisms of drug action, focusing mainly on hepatic insulin resistance. As well, we review clinical data that demonstrate the efficacy of these drugs, together with improvements in biochemical or histological parameters.
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12
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Increasing prevalence of diabetes mellitus in association with fatty liver in a Japanese population. J Gastroenterol 2014; 49:1406-13. [PMID: 24170184 DOI: 10.1007/s00535-013-0902-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2013] [Accepted: 10/12/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND The prevalence of diabetes mellitus (DM) has been increasing. The present study was carried out to examine the relationship between this increase and fatty liver. METHODS Japanese participants who underwent regular health examinations in 1991, 1996, 2001, 2006, and 2011 were enrolled. Fatty liver was diagnosed using ultrasonography. DM was defined as requiring the use of medication for DM, having a fasting blood glucose level ≥ 126 mg/dl, or hemoglobin A1c level ≥ 6.5 %. RESULTS Logistic regression analysis on data from 11,235 participants (6,882 men and 4,271 women) in 2011 revealed that the association between fatty liver and DM was independent of age, body composition, and other confounders [odds ratio (OR) 1.97, 95 % confidence interval (95 % CI) 1.66-2.32 in men, and OR, 3.12; 95 % CI, 2.29-4.26 in women]. In 2006, 5,318 participants did not have DM and were able to be followed up in 2011. Fatty liver in 2006 was an independent predictor of DM in 2011 [OR 1.73 (95 % CI 1.20-2.50) in men, 4.13 (2.16-8.10) in women]. The prevalence of DM increased significantly during the 20-year period examined among both men (6.0, 8.9, 10.0, 10.8, 12.0 %, P < 0.001) and women (3.3, 4.5, 4.2, 4.1, 5.1 %, P = 0.004), accompanied with an increased prevalence of fatty liver among both men (10.8, 26.3, 33.8, 36.7, and 38.0 %, P < 0.001) and women (6.5, 16.7, 22.2, 21.3, and 20.8 %, P < 0.001). CONCLUSION Fatty liver independently predicts both present and future DM. Fatty liver may play an important role in the recent increases in the prevalence of DM.
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Alwahsh SM, Xu M, Schultze FC, Wilting J, Mihm S, Raddatz D, Ramadori G. Combination of alcohol and fructose exacerbates metabolic imbalance in terms of hepatic damage, dyslipidemia, and insulin resistance in rats. PLoS One 2014; 9:e104220. [PMID: 25101998 PMCID: PMC4125190 DOI: 10.1371/journal.pone.0104220] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Accepted: 07/11/2014] [Indexed: 12/13/2022] Open
Abstract
Although both alcohol and fructose are particularly steatogenic, their long-term effect in the development of a metabolic syndrome has not been studied in vivo. Consumption of fructose generally leads to obesity, whereas ethanol can induce liver damage in the absence of overweight. Here, Sprague-Dawley rats were fed ad libitum for 28 days on five diets: chow (control), liquid Lieber-DeCarli (LDC) diet, LDC +30%J of ethanol (L-Et) or fructose (L-Fr), and LDC combined with 30%J ethanol and 30%J fructose (L-EF). Body weight (BW) and liver weight (LW) were measured. Blood and liver samples were harvested and subjected to biochemical tests, histopathological examinations, and RT-PCR. Alcohol-containing diets substantially reduced the food intake and BW (≤3rd week), whereas fructose-fed animals had higher LW than controls (P<0.05). Additionally, leukocytes, plasma AST and leptin levels were the highest in the fructose-administered rats. Compared to the chow and LDC diets, the L-EF diet significantly elevated blood glucose, insulin, and total-cholesterol levels (also vs. the L-Et group). The albumin and Quick-test levels were the lowest, whereas ALT activity was the highest in the L-EF group. Moreover, the L-EF diet aggravated plasma triglyceride and reduced HDL-cholesterol levels more than 2.7-fold compared to the sum of the effects of the L-Et and L-Fr diets. The decreased hepatic insulin clearance in the L-EF group vs. control and LDC groups was reflected by a significantly decreased C-peptide:insulin ratio. All diets except the control caused hepatosteatosis, as evidenced by Nile red and H&E staining. Hepatic transcription of insulin receptor substrate-1/2 was mainly suppressed by the L-Fr and L-EF diets. The L-EF diet did not enhance the mitochondrial β-oxidation of fatty acids (Cpt1α and Ppar-α expressions) compared to the L-Et or L-Fr diet. Together, our data provide evidence for the coaction of ethanol and fructose with a high-fat-diet on dyslipidemia and insulin resistance-accompanied liver damage.
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Affiliation(s)
- Salamah Mohammad Alwahsh
- Department Gastroenterology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany
- * E-mail:
| | - Min Xu
- Department of General, Visceral, and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany
| | - Frank Christian Schultze
- Department Gastroenterology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany
| | - Jörg Wilting
- Institute of Anatomy and Cell Biology, University Medical Center Goettingen, Goettingen, Germany
| | - Sabine Mihm
- Department Gastroenterology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany
| | - Dirk Raddatz
- Department Gastroenterology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany
| | - Giuliano Ramadori
- Department Gastroenterology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany
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14
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Effect of acute beer ingestion on the liver: studies in female mice. Eur J Nutr 2014; 54:465-74. [DOI: 10.1007/s00394-014-0730-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Accepted: 06/03/2014] [Indexed: 12/20/2022]
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15
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Bi Y, Wu W, Shi J, Liang H, Yin W, Chen Y, Tang S, Cao S, Cai M, Shen S, Gao Q, Weng J, Zhu D. Role for sterol regulatory element binding protein-1c activation in mediating skeletal muscle insulin resistance via repression of rat insulin receptor substrate-1 transcription. Diabetologia 2014; 57:592-602. [PMID: 24362725 DOI: 10.1007/s00125-013-3136-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Accepted: 11/15/2013] [Indexed: 12/19/2022]
Abstract
AIMS/HYPOTHESIS Sterol regulatory element binding protein-1c (SREBP-1c) is a master regulator of fatty acid synthase and controls lipogenesis. IRS-1 is the key insulin signalling mediator in skeletal muscle. In the present study, we investigated the role of SREBP-1c in the regulation of IRS-1 in skeletal muscle cells. METHODS L6 muscle cells were treated with palmitic acid (PA) or metformin. Adenovirus vectors expressing Srebp-1c (also known as Srebf1) and small interfering RNA (siRNA) against Srebp-1c were transfected into the L6 cells. Protein-DNA interactions were assessed by luciferase reporter analysis, electrophoretic mobility shift assay and chromatin immunoprecipitation assay. RESULTS We found that both gene and protein expression of SREBP-1c was increased in contrast to IRS-1 expression in PA-treated L6 cells. SREBP-1c overproduction decreased Irs-1 mRNA and IRS-1 protein expression in a dose-dependent manner, and suppressed the resultant insulin signalling, whereas SERBP-1c knockdown by Serbp-1c siRNA blocked the downregulation of IRS-1 induced by PA. Protein-DNA interaction studies demonstrated that SREBP-1c was able to bind to the rat Irs-1 promoter region, thereby repressing its gene transcription. Of particular importance, we found that metformin treatment downregulated Srebp-1c promoter activity, decreased the specific binding of SREBP-1c to Irs-1 promoter and upregulated Irs-1 promoter activity in PA-cultured L6 cells. CONCLUSIONS/INTERPRETATION Our data indicate for the first time that SREBP-1c activation participates in skeletal muscle insulin resistance through a direct effect of suppressing Irs-1 transcription. These findings imply that SREBP-1c could serve as an attractive therapeutic target for insulin resistance.
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Affiliation(s)
- Yan Bi
- Department of Endocrinology, Drum Tower hospital affiliated to Nanjing University Medical School, No321 Zhongshan Road, Nanjing, 210008, People's Republic of China,
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16
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Martina JA, Diab HI, Li H, Puertollano R. Novel roles for the MiTF/TFE family of transcription factors in organelle biogenesis, nutrient sensing, and energy homeostasis. Cell Mol Life Sci 2014; 71:2483-97. [PMID: 24477476 DOI: 10.1007/s00018-014-1565-8] [Citation(s) in RCA: 122] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 01/14/2014] [Accepted: 01/14/2014] [Indexed: 01/22/2023]
Abstract
The MiTF/TFE family of basic helix-loop-helix leucine zipper transcription factors includes MITF, TFEB, TFE3, and TFEC. The involvement of some family members in the development and proliferation of specific cell types, such as mast cells, osteoclasts, and melanocytes, is well established. Notably, recent evidence suggests that the MiTF/TFE family plays a critical role in organelle biogenesis, nutrient sensing, and energy metabolism. The MiTF/TFE family is also implicated in human disease. Mutations or aberrant expression of most MiTF/TFE family members has been linked to different types of cancer. At the same time, they have recently emerged as novel and very promising targets for the treatment of neurological and lysosomal diseases. The characterization of this fascinating family of transcription factors is greatly expanding our understanding of how cells synchronize environmental signals, such as nutrient availability, with gene expression, energy production, and cellular homeostasis.
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Affiliation(s)
- José A Martina
- Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, 9000 Rockville Pike, Bldg. 50/3537, Bethesda, MD, 20892, USA
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Abstract
ASC-2 (activating signal co-integrator-2, also known as AIB3 and NCoA6) is a transcriptional co-activator and regulates insulin secretion and β-cell survival. The present study was performed to elucidate the role of ASC-2 in the regulation of insulin sensitivity. Although islet cells from 10-week-old ASC-2+/- mice secreted less insulin than wild-type islets, there was no significant difference in glucose tolerance between ASC-2+/- and wild-type mice. However, ASC-2+/- mice did show increased insulin sensitivity compared with wild-type mice in insulin tolerance tests. Consistently, the levels of phosphorylated Akt were higher in ASC-2+/- hepatocytes than in wild-type hepatocytes after insulin treatment. Moreover, decreases in phosphoenol pyruvate carboxykinase mRNA in refed mice were more prominent in ASC-2+/- livers than in wild-type livers. Interestingly, the expression levels of SOCS1 (suppressor of cytokine signalling 1) and SOCS3, well-known insulin signalling inhibitors, were decreased in ASC-2+/- hepatocytes and increased in ASC-2-overexpressing hepatocytes. Furthermore, ASC-2 was recruited to the promoter region of SOCS1 and potentiated the transcription by SREBP-1c (sterol-regulatory-element-binding protein-1c). This transcription-activating function of ASC-2 was diminished by mutations of SREBP-1c-binding sites in the SOCS1 promoter. Taken together, these results suggest that ASC-2 negatively affects hepatic insulin sensitivity, at least in part, through induction of the insulin signalling inhibitors SOCS1 and SOCS3.
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Balaji V, Selvaraj J, Sathish S, Mayilvanan C, Balasubramanian K. Molecular Mechanism Underlying the Antidiabetic Effects of a Siddha Polyherbal Preparation in the Liver of Type 2 Diabetic Adult Male Rats. J Evid Based Complementary Altern Med 2012. [DOI: 10.1177/2156587212460047] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
A siddha polyherbal preparation consisting of 5 medicinal plants, namely, Asparagus racemosus, Emblica officinalis, Salacia oblonga, Syzygium aromaticum, and Tinospora cordifolia, in equal ratio, was formulated to examine the molecular mechanism by which it exhibits antidiabetic effects in the liver of high-fat and fructose-induced type 2 diabetic rats. The polyherbal preparation treated type 2 diabetic rats showed an increase in insulin receptor, Akt, and glucose transporter2 mRNA levels compared with diabetic rats. Insulin receptor, insulin receptor substrate-2, Akt, phosphorylated Akt substrate of 160kDaThreonine642, α-Actinin-4, β-arrestin-2, and glucose transporter2 proteins were also markedly decreased in diabetic rats, whereas the polyherbal preparation treatment significantly improved the expression of these proteins more than that of metformin-treated diabetic rats. The expression pattern of insulin signaling molecules analyzed in the present study signifies the therapeutic efficacy of the siddha polyherbal preparation.
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Abstract
Intake of carbohydrates above the dietary guidelines to support performance of physical activity is common but may be unnecessary and counterproductive. Sports nutrition guidelines have not been designed to incorporate characteristics that may make high carbohydrate consumption a source of metabolic stress that may increase oxidative stress, inflammation, and lipogenesis. This metabolic stress is linked to the physiology underlying the development of insulin resistance, type 2 diabetes mellitus, and cardiovascular diseases. This review describes research-based evidence to aid in bridging the gap between dietary guidelines for overall health and those to support physical activity. Characteristics that increase the likelihood of metabolic stress resulting from carbohydrate intake include overweight and obesity, central/visceral adiposity, older age, sedentary lifestyle, and caloric state. Carbohydrate-based foods that provide the most health benefits are whole grains, beans and legumes, fruits, and vegetables. Carbohydrate-based foods that most readily elicit metabolic stress are those with added sugars and refined grains or that have a high glycemic index. A checklist that incorporates both the number of these characteristics and prevailing guidelines for nutrition and physical activity is presented. This may be useful in determining whether additional carbohydrates are needed to support the physical activity level of the individual.
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Affiliation(s)
- Mary P. Miles
- Department of Health and Human Development, Montana State University, Bozeman, Montana
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20
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Amemiya-Kudo M, Oka J, Takeuchi Y, Okazaki H, Yamamoto T, Yahagi N, Matsuzaka K, Okazaki S, Osuga JI, Yamada N, Murase T, Shimano H. Suppression of the pancreatic duodenal homeodomain transcription factor-1 (Pdx-1) promoter by sterol regulatory element-binding protein-1c (SREBP-1c). J Biol Chem 2011; 286:27902-14. [PMID: 21652712 DOI: 10.1074/jbc.m110.186221] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Overexpression of sterol regulatory element-binding protein-1c (SREBP-1c) in β cells causes impaired insulin secretion and β cell dysfunction associated with diminished pancreatic duodenal homeodomain transcription factor-1 (PDX-1) expression in vitro and in vivo. To identify the molecular mechanism responsible for this effect, the mouse Pdx-1 gene promoter (2.7 kb) was analyzed in β cell and non-β cell lines. Despite no apparent sterol regulatory element-binding protein-binding sites, the Pdx-1 promoter was suppressed by SREBP-1c in β cells in a dose-dependent manner. PDX-1 activated its own promoter. The E-box (-104/-99 bp) in the proximal region, occupied by ubiquitously expressed upstream stimulatory factors (USFs), was crucial for the PDX-1-positive autoregulatory loop through direct PDX-1·USF binding. This positive feedback activation was a prerequisite for SREBP-1c suppression of the promoter in non-β cells. SREBP-1c and PDX-1 directly interact through basic helix-loop-helix and homeobox domains, respectively. This robust SREBP-1c·PDX-1 complex interferes with PDX-1·USF formation and inhibits the recruitment of PDX-1 coactivators. SREBP-1c also inhibits PDX-1 binding to the previously described PDX-1-binding site (-2721/-2646 bp) in the distal enhancer region of the Pdx-1 promoter. Endogenous up-regulation of SREBP-1c in INS-1 cells through the activation of liver X receptor and retinoid X receptor by 9-cis-retinoic acid and 22-hydroxycholesterol inhibited PDX-1 mRNA and protein expression. Conversely, SREBP-1c RNAi restored Pdx-1 mRNA and protein levels. Through these multiple mechanisms, SREBP-1c, when induced in a lipotoxic state, repressed PDX-1 expression contributing to the inhibition of insulin expression and β cell dysfunction.
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Affiliation(s)
- Michiyo Amemiya-Kudo
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo 105-8470, Japan.
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Tanabe K, Liu Y, Hasan SD, Martinez SC, Cras-Méneur C, Welling CM, Bernal-Mizrachi E, Tanizawa Y, Rhodes CJ, Zmuda E, Hai T, Abumrad NA, Permutt MA. Glucose and fatty acids synergize to promote B-cell apoptosis through activation of glycogen synthase kinase 3β independent of JNK activation. PLoS One 2011; 6:e18146. [PMID: 21541314 PMCID: PMC3082528 DOI: 10.1371/journal.pone.0018146] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2010] [Accepted: 02/27/2011] [Indexed: 01/09/2023] Open
Abstract
Background The combination of elevated glucose and free-fatty acids (FFA), prevalent in diabetes, has been suggested to be a major contributor to pancreatic β-cell death. This study examines the synergistic effects of glucose and FFA on β-cell apoptosis and the molecular mechanisms involved. Mouse insulinoma cells and primary islets were treated with palmitate at increasing glucose and effects on apoptosis, endoplasmic reticulum (ER) stress and insulin receptor substrate (IRS) signaling were examined. Principal Findings Increasing glucose (5–25 mM) with palmitate (400 µM) had synergistic effects on apoptosis. Jun NH2-terminal kinase (JNK) activation peaked at the lowest glucose concentration, in contrast to a progressive reduction in IRS2 protein and impairment of insulin receptor substrate signaling. A synergistic effect was observed on activation of ER stress markers, along with recruitment of SREBP1 to the nucleus. These findings were confirmed in primary islets. The above effects associated with an increase in glycogen synthase kinase 3β (Gsk3β) activity and were reversed along with apoptosis by an adenovirus expressing a kinase dead Gsk3β. Conclusions/Significance Glucose in the presence of FFA results in synergistic effects on ER stress, impaired insulin receptor substrate signaling and Gsk3β activation. The data support the importance of controlling both hyperglycemia and hyperlipidemia in the management of Type 2 diabetes, and identify pancreatic islet β-cell Gsk3β as a potential therapeutic target.
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Affiliation(s)
- Katsuya Tanabe
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Yang Liu
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Syed D. Hasan
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Sara C. Martinez
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Corentin Cras-Méneur
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Cris M. Welling
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Ernesto Bernal-Mizrachi
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Yukio Tanizawa
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics Department of Bio-Signal Analysis, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Christopher J. Rhodes
- Department of Medicine, Kovler Diabetes Center, University of Chicago, Chicago, Illinois, United States of America
| | - Erik Zmuda
- Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, Ohio State University, Columbus, Ohio, United States of America
| | - Tsonwin Hai
- Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, Ohio State University, Columbus, Ohio, United States of America
| | - Nada A. Abumrad
- Division of Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - M. Alan Permutt
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, United States of America
- * E-mail:
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Izuchi R, Nakai Y, Takahashi H, Ushiama S, Okada S, Misaka T, Abe K. Hepatic gene expression of the insulin signaling pathway is altered by administration of persimmon peel extract: a DNA microarray study using type 2 diabetic Goto-Kakizaki rats. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2011; 59:3320-3329. [PMID: 21370910 DOI: 10.1021/jf102422z] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Persimmon (Diospyros kaki) is a very popular fruit in East Asian countries, but its peels are not consumed despite the fact that they contain many antioxidants such as carotenoids and polyphenols. We prepared a fat-soluble extract from persimmon peel (PP) and fed type 2 diabetic Goto-Kakizaki (GK) rats an AIN-93G rodent diet supplemented with persimmon peel extract (PP diet) for 12 weeks. Compared with the control AIN-93G diet, the PP diet significantly reduced plasma glutamic-pyruvate transaminase activity, with accumulation of β-cryptoxanthin in the liver. DNA microarray analysis revealed that the PP diet altered hepatic gene expression profiles. In particular, expression of insulin signaling pathway-related genes was significantly enriched in differentially expressed gene sets. Moreover, Western blotting analysis showed an increase in insulin receptor beta tyrosine phosphorylation in rats fed the PP diet. These data suggest that the PP diet improves insulin resistance in GK rats.
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Affiliation(s)
- Ryoichi Izuchi
- Toyo Institute of Food Technology, Kawanishi-shi, Hyogo, Japan.
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23
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Shao S, Liu Z, Yang Y, Zhang M, Yu X. SREBP-1c, Pdx-1, and GLP-1R involved in palmitate-EPA regulated glucose-stimulated insulin secretion in INS-1 cells. J Cell Biochem 2011; 111:634-42. [PMID: 20589757 DOI: 10.1002/jcb.22750] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Impairment of glucose-stimulated insulin secretion (GSIS) caused by glucolipotoxicity is an essential feature in type 2 diabetes mellitus (T2DM). Palmitate and eicosapentaenoate (EPA), because of their lipotoxicity and protection effect, were found to impair or restore the GSIS in beta cells. Furthermore, palmitate was found to up-regulate the expression level of sterol regulatory element-binding protein (SREBP)-1c and down-regulate the levels of pancreatic and duodenal homeobox (Pdx)-1 and glucagon-like peptide (GLP)-1 receptor (GLP-1R) in INS-1 cells. To investigate the underlying mechanism, the lentiviral system was used to knock-down or over-express SREBP-1c and Pdx-1, respectively. It was found that palmitate failed to suppress the expression of Pdx-1 and GLP-1R in SREBP-1c-deficient INS-1 cells. Moreover, down-regulation of Pdx-1 could cause the low expression of GLP-1R with/without palmitate treatment. Additionally, either SREBP-1c down-regulation or Pdx-1 over-expression could partially alleviate palmitate-induced GSIS impairment. These results suggested that sequent SREBP-1c-Pdx-1-GLP-1R signal pathway was involved in the palmitate-caused GSIS impairment in beta cells.
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Affiliation(s)
- Shiying Shao
- Division of Endocrinology, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Wuhan 430030, PR China
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Tong X, Muchnik M, Chen Z, Patel M, Wu N, Joshi S, Rui L, Lazar MA, Yin L. Transcriptional repressor E4-binding protein 4 (E4BP4) regulates metabolic hormone fibroblast growth factor 21 (FGF21) during circadian cycles and feeding. J Biol Chem 2010; 285:36401-9. [PMID: 20851878 DOI: 10.1074/jbc.m110.172866] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Fibroblast growth factor 21 (FGF21) is a potent antidiabetic and triglyceride-lowering hormone whose hepatic expression is highly responsive to food intake. FGF21 induction in the adaptive response to fasting has been well studied, but the molecular mechanism responsible for feeding-induced repression remains unknown. In this study, we demonstrate a novel link between FGF21 and a key circadian output protein, E4BP4. Expression of Fgf21 displays a circadian rhythm, which peaks during the fasting phase and is anti-phase to E4bp4, which is elevated during feeding periods. E4BP4 strongly suppresses Fgf21 transcription by binding to a D-box element in the distal promoter region. Depletion of E4BP4 in synchronized Hepa1c1c-7 liver cells augments the amplitude of Fgf21 expression, and overexpression of E4BP4 represses FGF21 secretion from primary mouse hepatocytes. Mimicking feeding effects, insulin significantly increases E4BP4 expression and binding to the Fgf21 promoter through AKT activation. Thus, E4BP4 is a novel insulin-responsive repressor of FGF21 expression during circadian cycles and feeding.
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Affiliation(s)
- Xin Tong
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
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25
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Kanuri G, Spruss A, Wagnerberger S, Bischoff SC, Bergheim I. Role of tumor necrosis factor α (TNFα) in the onset of fructose-induced nonalcoholic fatty liver disease in mice. J Nutr Biochem 2010; 22:527-34. [PMID: 20801629 DOI: 10.1016/j.jnutbio.2010.04.007] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2009] [Revised: 02/11/2010] [Accepted: 04/14/2010] [Indexed: 12/22/2022]
Abstract
Tumor necrosis factor α (TNFα) is known to be involved in dysregulation of hepatic lipid metabolism and insulin signaling. However, whether TNFα also plays a casual role in the onset of fructose-induced nonalcoholic fatty liver disease (NAFLD) has not yet been determined. Therefore, wild-type and TNFα receptor 1 (TNFR1)-/- mice were fed with either 30% fructose solution or plain tap water. Hepatic triglycerides, markers of inflammation and ATP concentration as well as plasma ALT levels were determined. Hepatic PAI-1, SREBP-1, FAS mRNA expression was assessed by real-time RT-PCR. Furthermore, lipid peroxidation and indices of insulin resistance were determined in liver tissue and plasma. In comparison to water controls, chronic intake of 30% fructose solution caused a significant ∼5-fold increase in triglyceride accumulation and neutrophil infiltration in livers of wild-type mice and a ∼8-fold increase in plasma ALT levels. In TNFR1-/- mice, hepatic steatosis was attenuated and neutrophil infiltration in the liver as well as plasma ALT levels was similar to water controls. The protective effect of the TNFR1 deletion against the onset of fructose-induced steatosis was associated with increased phospho AMPK and Akt levels, decreased SREBP-1 and FAS expression in the liver and decreased RBP4 plasma levels, whereas hepatic lipid peroxidation, iNOS protein and ATP levels were similar between wild-type and TNFR1-/- mice fed fructose. Taken together, these data suggest that TNFα plays a casual role in the onset of fructose-induced liver damage as well as insulin resistance in mice through signaling cascades downstream of TNFR1.
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Affiliation(s)
- Giridhar Kanuri
- Department of Nutritional Medicine (180 a), University of Hohenheim, 70599 Stuttgart, Germany.
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Tirosh O, Artan A, Aharoni-Simon M, Ramadori G, Madar Z. Impaired liver glucose production in a murine model of steatosis and endotoxemia: protection by inducible nitric oxide synthase. Antioxid Redox Signal 2010; 13:13-26. [PMID: 19951063 DOI: 10.1089/ars.2009.2789] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This study hypothesized that upregulation of inducible nitric oxide synthase (iNOS) would preserve the metabolic status of the liver under conditions of steatosis and acute inflammation. Wild-type C57BL/6J and C57BL/6 iNOS-knockout (-/-) mice were fed a choline-deficient ethionine-supplemented diet (CDE). Mice were also injected with 5 mg/kg lipopolysaccharide (LPS) to induce endotoxemia. Consumption of the CDE diet led to steatosis of the liver and decreased expression of the gluconeogenic genes compared with controls. LPS treatment exacerbated these effects because of inhibition of PGC-1alpha expression, which resulted in hypoglycemia. In steatotic livers, LPS-induced iNOS expression was enhanced. Comparison between wild-type and iNOS-knockout mice under these conditions demonstrated a protective role of iNOS against fatal hypoglycemia. Nitric oxide (NO) signaling effects were confirmed by treatment of hepatocytes in culture with an NO donor, which resulted in increased expression of PGC-1alpha and gluconeogenic genes. In conclusion, iNOS was found to act as a protective protein and provides a possible mechanism by which the liver preserves glucose homeostasis under stress.
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Affiliation(s)
- Oren Tirosh
- The School of Nutritional Sciences, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot, Israel.
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In utero exposure to di-(2-ethylhexyl) phthalate affects liver morphology and metabolism in post-natal CD-1 mice. Reprod Toxicol 2010; 29:427-32. [PMID: 20307648 DOI: 10.1016/j.reprotox.2010.03.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2009] [Revised: 02/19/2010] [Accepted: 03/13/2010] [Indexed: 12/12/2022]
Abstract
The plasticizer di-(2-ethylhexyl)phthalate (DEHP) affects reproductive development, glycogen and lipid metabolism. Whereas liver is a main DEHP target in adult rodents, the potential impact on metabolic programming is unknown. Effects of in utero DEHP exposure on liver development were investigated upon treatment of pregnant CD-1 mice on gestational days (GD)11-19. F1 mice were examined at post-natal days 21 (weaning) and 35 (start of puberty): parameters included liver histopathological, immunocytochemical and alpha-fetoprotein (AFP) gene expression analyses. In utero DEHP exposure altered post-natal liver development in weanling mice causing significant, dose-related (i) increased hepatosteatosis, (ii) decreased glycogen storage, (iii) increased beta-catenin intracytoplasmic localization (females only). At puberty, significantly decreased glycogen storage was still present in males. A treatment-induced phenotype was identified with lack of glycogen accumulation and intracytoplasmic localization of beta-catenin which was associated with increased AFP gene expression. Our findings suggested that DEHP alters post-natal liver development delaying the programming of glycogen metabolism.
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The Mechanisms of Insulin Action. Endocrinology 2010. [DOI: 10.1016/b978-1-4160-5583-9.00034-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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29
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Fan Y, Menon RK, Cohen P, Hwang D, Clemens T, DiGirolamo DJ, Kopchick JJ, Le Roith D, Trucco M, Sperling MA. Liver-specific deletion of the growth hormone receptor reveals essential role of growth hormone signaling in hepatic lipid metabolism. J Biol Chem 2009; 284:19937-44. [PMID: 19460757 DOI: 10.1074/jbc.m109.014308] [Citation(s) in RCA: 202] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Growth hormone (GH) plays a pivotal role in growth and metabolism, with growth promotion mostly attributed to generation of insulin-like growth factor I (IGF-I) in liver or at local sites of GH action, whereas the metabolic effects of GH are considered to be intrinsic to GH itself. To distinguish the effects of GH from those of IGF-I, we developed a Cre-lox-mediated model of tissue-specific deletion of the growth hormone receptor (GHR). Near total deletion of the GHR in liver (GHRLD) had no effect on total body or bone linear growth despite a >90% suppression of circulating IGF-I; however, total bone density was significantly reduced. Circulating GH was increased 4-fold, and GHRLD displayed insulin resistance, glucose intolerance, and increased circulating free fatty acids. Livers displayed marked steatosis, the result of increased triglyceride synthesis and decreased efflux; reconstitution of hepatic GHR signaling via adenoviral expression of GHR restored triglyceride output to normal, whereas IGF-I infusion did not correct steatosis despite restoration of circulating GH to normal. Thus, with near total absence of circulating IGF-I, GH action at the growth plate, directly and via locally generated IGF-I, can regulate bone growth, but at the expense of diabetogenic, lipolytic, and hepatosteatotic consequences. Our results indicate that IGF-I is essential for bone mineral density, whereas hepatic GH signaling is essential to regulate intrahepatic lipid metabolism. We propose that circulating IGF-I serves to amplify the growth-promoting effects of GH, while simultaneously dampening the catabolic effects of GH.
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Affiliation(s)
- Yong Fan
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA
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Abstract
Sterol regulatory element-binding proteins (SREBPs) have been established as physiological regulators of lipid synthesis. The molecular mechanisms by which cellular sterol balance and nutritional states regulate SREBP activities are the current research focus of this field. Meanwhile, it has been shown that overnutrition or disturbed energy balance causes accumulation of tissue lipids, leading to metabolic disorders, often referred to as 'lipotoxicity'. In this overview, I discuss the pathological aspects of SREBPs, which contribute to lipotoxicity in a wide variety of organs, including hepatic insulin resistance in hepatosteatosis, impaired insulin secretion in pancreatic beta-cells, diabetic nephropathy, cardiac arrythmiasis, and obesity.
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Affiliation(s)
- Hitoshi Shimano
- Department of Internal Medicine (Endocrinoglogy and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan.
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Xie X, Liao H, Dang H, Pang W, Guan Y, Wang X, Shyy JYJ, Zhu Y, Sladek FM. Down-regulation of hepatic HNF4alpha gene expression during hyperinsulinemia via SREBPs. Mol Endocrinol 2009; 23:434-43. [PMID: 19179483 DOI: 10.1210/me.2007-0531] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mutations in the coding region of hepatocyte nuclear factor 4alpha (HNF4alpha), and its upstream promoter (P2) that drives expression in the pancreas, are known to lead to maturity-onset diabetes of the young 1 (MODY1). HNF4alpha also controls gluconeogenesis and lipid metabolism in the liver, where the proximal promoter (P1) predominates. However, very little is known about the role of hepatic HNF4alpha in diabetes. Here, we examine the expression of hepatic HNF4alpha in two diabetic mouse models, db/db mice (type 2, insulin resistant) and streptozotocin-treated mice (type 1, insulin deficient). We found that the level of HNF4alpha protein and mRNA was decreased in the liver of db/db mice but increased in streptozotocin-treated mice. Because insulin increases the activity of sterol regulatory element-binding proteins (SREBP)-1c and -2, we also examined the effect of SREBPs on hepatic HNF4alpha gene expression and found that, like insulin, ectopic expression of SREBPs decreases the level of hepatic HNF4alpha protein and mRNA both in vitro in primary hepatocytes and in vivo in the liver of C57BL/6 mice. Finally, we use gel shift, chromatin immunoprecipitation, small interfering RNA, and reporter gene analysis to show that SREBP2 binds the human HNF4alpha P1 promoter and negatively regulates its expression. These data indicate that hyperinsulinemia down-regulates HNF4alpha in the liver through the up-regulation of SREBPs, thereby establishing a link between these two critical transcription factor pathways that regulate lipid and glucose metabolism in the liver. These findings also provide new insights into diabetes-associated complications such as fatty liver disease.
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Affiliation(s)
- Xuefen Xie
- Department of Physiology and Pathophysiology, Peking University, Health Sciences Center, Beijing 100083, China
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Bibliography. Current world literature. Lipid metabolism. Curr Opin Lipidol 2008; 19:314-21. [PMID: 18460925 DOI: 10.1097/mol.0b013e328303e27e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med 2008; 14:222-31. [PMID: 18235842 DOI: 10.2119/2007-00119.tilg] [Citation(s) in RCA: 503] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2007] [Accepted: 01/18/2008] [Indexed: 12/18/2022] Open
Abstract
Insulin resistance (IR) plays a key role in the pathophysiology of obesity-related diseases such as type 2 diabetes and nonalcoholic fatty liver disease. It has been demonstrated that IR is associated with a state of chronic low-grade inflammation, and several mediators released from various cell types, including immune cells and adipocytes, have been identified as being involved in the development of IR. Among those are several pro-inflammatory cytokines such as tumor necrosis factor-alpha(TNF-alpha), interleukin (IL)-1, IL-6, and various adipocytokines. Furthermore, several transcription factors and kinases such as c-Jun N-terminal kinase (JNK) and inhibitor of kappa B kinase-beta (IKKbeta), a kinase located proximal of nuclear factor-kappaB (NF-kappaB), participate in this process. Hepatocyte-specific overexpression of NF-kappaB is associated with IR and can mimic all features of fatty liver disease. Whereas the evidence for an important role of many pro-inflammatory pathways in IR in in vitro and animal studies is overwhelming, data from interventional studies in humans to prove this concept are still minor. As a complex network of inflammatory cytokines, adipocytokines, transcription factors, receptor molecules, and acute-phase reactants are involved in the development of IR, new therapeutic approaches in IR-related diseases will be based on a better understanding of their complex interactions.
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Affiliation(s)
- Herbert Tilg
- Department of Gastroenterology and Hepatology, Innsbruck Medical University, Innsbruck, Austria.
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Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. MOLECULAR MEDICINE (CAMBRIDGE, MASS.) 2008. [PMID: 18235842 DOI: 10.2119/2007-00119] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Insulin resistance (IR) plays a key role in the pathophysiology of obesity-related diseases such as type 2 diabetes and nonalcoholic fatty liver disease. It has been demonstrated that IR is associated with a state of chronic low-grade inflammation, and several mediators released from various cell types, including immune cells and adipocytes, have been identified as being involved in the development of IR. Among those are several pro-inflammatory cytokines such as tumor necrosis factor-alpha(TNF-alpha), interleukin (IL)-1, IL-6, and various adipocytokines. Furthermore, several transcription factors and kinases such as c-Jun N-terminal kinase (JNK) and inhibitor of kappa B kinase-beta (IKKbeta), a kinase located proximal of nuclear factor-kappaB (NF-kappaB), participate in this process. Hepatocyte-specific overexpression of NF-kappaB is associated with IR and can mimic all features of fatty liver disease. Whereas the evidence for an important role of many pro-inflammatory pathways in IR in in vitro and animal studies is overwhelming, data from interventional studies in humans to prove this concept are still minor. As a complex network of inflammatory cytokines, adipocytokines, transcription factors, receptor molecules, and acute-phase reactants are involved in the development of IR, new therapeutic approaches in IR-related diseases will be based on a better understanding of their complex interactions.
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Affiliation(s)
- Herbert Tilg
- Department of Gastroenterology and Hepatology, Innsbruck Medical University, Innsbruck, Austria.
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Shimano H. [Ageing and metabolic syndrome]. Nihon Ronen Igakkai Zasshi 2008; 45:299-301. [PMID: 18622114 DOI: 10.3143/geriatrics.45.299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
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Okuyama H, Hashimoto M, Ito M, Tokudome S, Shimano H, Itakura H. [Diverse physiological and pharmacological functions of fatty acids]. Nihon Yakurigaku Zasshi 2008; 131:259-267. [PMID: 18408336 DOI: 10.1254/fpj.131.259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
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Chapman MJ, Sposito AC. Hypertension and dyslipidaemia in obesity and insulin resistance: Pathophysiology, impact on atherosclerotic disease and pharmacotherapy. Pharmacol Ther 2008; 117:354-73. [DOI: 10.1016/j.pharmthera.2007.10.004] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2007] [Accepted: 10/01/2007] [Indexed: 01/12/2023]
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Shimano H, Amemiya-Kudo M, Takahashi A, Kato T, Ishikawa M, Yamada N. Sterol regulatory element-binding protein-1c and pancreatic beta-cell dysfunction. Diabetes Obes Metab 2007; 9 Suppl 2:133-9. [PMID: 17919187 DOI: 10.1111/j.1463-1326.2007.00779.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
It has long been known that excess intracellular fatty acids cause impaired insulin secretion, referred to as beta-cell lipotoxicity. Sterol regulatory element-binding protein (SREBP)-1c is a transcription factor that controls hepatic fatty acid synthesis. Activation of SREBP-1c by overnutrition also inhibits insulin receptor substrate-2 (IRS-2) and induces insulin resistance in the liver. As SREBP-1c is also expressed in beta cells, we hypothesized that activation of SREBP-1c could be a part of the mechanism by which saturated fatty acids induce beta-cell lipotoxicity. We found that nuclear SREBP-1c has a negative impact on both glucose- and potassium-stimulated insulin secretion as determined in islets from beta-cell-specific SREBP-1c transgenic mice as well as SREBP-1c knockout mice. This effect of SREBP-1c involves multiple functional pathways required for insulin secretion from beta cells: (i) decreased ATP caused by energy consumption through lipogenesis and uncoupling protein-2 (UCP-2) activation; (ii) repressed IRS-2 and pancreas duodenum homeobox 1 (PDX1) expression, leading to impaired beta-cell mass; and (iii) impaired post-ATP membrane voltage-dependent steps of the insulin secretion pathway caused by upregulated granuphilin and other ion channel proteins. Saturated fatty acids, such as palmitic acid (PA), impair insulin secretion through SREBP-1c activation, whereas polyunsaturated fatty acids including eicosapentaenoic acid (EPA) restore PA-suppressed insulin secretion through suppression of SREBP-1c. These data implicate a therapeutic potential of EPA against insulin secretion defects caused by lipotoxicity.
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Affiliation(s)
- H Shimano
- Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
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