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Du F, Wang G, Dai Q, Huang J, Li J, Liu C, Du K, Tian H, Deng Q, Xie L, Zhao X, Zhang Q, Yang L, Li Y, Wu Z, Zhang Z. Targeting novel regulated cell death: disulfidptosis in cancer immunotherapy with immune checkpoint inhibitors. Biomark Res 2025; 13:35. [PMID: 40012016 DOI: 10.1186/s40364-025-00748-4] [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: 01/07/2025] [Accepted: 02/11/2025] [Indexed: 02/28/2025] Open
Abstract
The battle against cancer has evolved over centuries, from the early stages of surgical resection to contemporary treatments including chemotherapy, radiation, targeted therapies, and immunotherapies. Despite significant advances in cancer treatment over recent decades, these therapies remain limited by various challenges. Immune checkpoint inhibitors (ICIs), a cornerstone of tumor immunotherapy, have emerged as one of the most promising advancements in cancer treatment. Although ICIs, such as CTLA-4 and PD-1/PD-L1 inhibitors, have demonstrated clinical efficacy, their therapeutic impact remains suboptimal due to patient-specific variability and tumor immune resistance. Cell death is a fundamental process for maintaining tissue homeostasis and function. Recent research highlights that the combination of induced regulatory cell death (RCD) and ICIs can substantially enhance anti-tumor responses across multiple cancer types. In cells exhibiting high levels of recombinant solute carrier family 7 member 11 (SLC7A11) protein, glucose deprivation triggers a programmed cell death (PCD) pathway characterized by disulfide bond formation and REDOX (reduction-oxidation) reactions, termed "disulfidptosis." Studies suggest that disulfidptosis plays a critical role in the therapeutic efficacy of SLC7A11high cancers. Therefore, to investigate the potential synergy between disulfidptosis and ICIs, this study will explore the mechanisms of both processes in tumor progression, with the goal of enhancing the anti-tumor immune response of ICIs by targeting the intracellular disulfidptosis pathway.
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Affiliation(s)
- Fei Du
- Department of Pharmacy, The Fourth Affiliated Hospital Of Southwest Medical University, Meishan, 620000, Sichuan, China.
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, China.
| | - Guojun Wang
- Department of Pharmacy, The Fourth Affiliated Hospital Of Southwest Medical University, Meishan, 620000, Sichuan, China
| | - Qian Dai
- Department of Pharmacy, The Fourth Affiliated Hospital Of Southwest Medical University, Meishan, 620000, Sichuan, China
| | - Jiang Huang
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, China
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Junxin Li
- Department of pharmacy, Zigong Fourth People's Hospital, Zigong, 643000, China
| | - Congxing Liu
- Department of Pharmacy, Chengfei Hospital, Chengdu, 610000, China
| | - Ke Du
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, China
- Department of Pediatrics, Luzhou Maternal and Child Health Hospital, Luzhou Second People's Hospital, Luzhou, 646000, Sichuan, China
| | - Hua Tian
- School of Nursing, Chongqing College of Humanities, Science & Technology, Chongqing, 401520, China
| | - Qiwei Deng
- Heruida Pharmaceutical Co.,ltd, Haikou, Hainan, 570100, China
| | - Longxiang Xie
- The TCM Hospital of Longquanyi District, Chengdu, 610100, Sichuan, China
| | - Xin Zhao
- Department of Pharmacy, The Fourth Affiliated Hospital Of Southwest Medical University, Meishan, 620000, Sichuan, China
| | - Qimin Zhang
- Department of Pharmacy, The Fourth Affiliated Hospital Of Southwest Medical University, Meishan, 620000, Sichuan, China
| | - Lan Yang
- Department of Pharmacy, The Fourth Affiliated Hospital Of Southwest Medical University, Meishan, 620000, Sichuan, China
| | - Yaling Li
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Zhigui Wu
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Zhuo Zhang
- Department of Pharmacy, The Fourth Affiliated Hospital Of Southwest Medical University, Meishan, 620000, Sichuan, China.
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, China.
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Ye J, Wang JG, Liu RQ, Shi Q, Wang WX. Association between intra-pancreatic fat deposition and diseases of the exocrine pancreas: A narrative review. World J Gastroenterol 2025; 31:101180. [PMID: 39811515 PMCID: PMC11684206 DOI: 10.3748/wjg.v31.i2.101180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/26/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024] Open
Abstract
Intrapancreatic fat deposition (IPFD) has garnered increasing attention in recent years. The prevalence of IPFD is relatively high and associated with factors such as obesity, age, and sex. However, the pathophysiological mechanisms underlying IPFD remain unclear, with several potential contributing factors, including oxidative stress, alterations in the gut microbiota, and hormonal imbalances. IPFD was found to be highly correlated with the occurrence and prognosis of exocrine pancreatic diseases. Although imaging techniques remain the primary diagnostic approach for IPFD, an expanding array of biomarkers and clinical scoring systems have been identified for screening purposes. Currently, effective treatments for IPFD are not available; however, existing medications, such as glucagon-like peptide-1 receptor agonists, and new therapeutic approaches explored in animal models have shown considerable potential for managing this disease. This paper reviews the pathogenesis of IPFD, its association with exocrine pancreatic diseases, and recent advancements in its diagnosis and treatment, emphasizing the significant clinical relevance of IPFD.
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Affiliation(s)
- Jing Ye
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Jian-Guo Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Rong-Qiang Liu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Qiao Shi
- Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wei-Xing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
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Fernandes-da-Silva A, Santana-Oliveira DA, Oliveira ASD, Ferreira TAM, Monteiro NC, Silva-Veiga FM, Martins FF, Cummins CL, Romeiro LAS, Souza-Mello V. LDT409 (pan-PPAR partial agonist) mitigates metabolic dysfunction-associated steatotic liver disease in high-fructose-fed mice. Mol Cell Endocrinol 2024; 594:112380. [PMID: 39332468 DOI: 10.1016/j.mce.2024.112380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 09/23/2024] [Accepted: 09/25/2024] [Indexed: 09/29/2024]
Abstract
AIM This study sought to evaluate the effects of LDT409, a pan-PPAR partial agonist obtained from the main industrial waste from cashew nut processing, on hepatic remodeling, highlighting energy metabolism and endoplasmic reticulum (ER) stress in high-fructose-fed mice. METHODS Male C57BL/6 mice received a control diet (C) or a high-fructose diet (HFRU) for ten weeks. Then, a five-week treatment started: C, C-LDT409, HFRU, and HFRU-LDT409. The LDT409 (40 mg/kg of body weight) was mixed with the diets. RESULTS The HFRU diet caused insulin resistance and endoplasmic reticulum (ER) stress. High Pparg and decreased Ppara expression increased steatosis and pro-fibrogenic gene expression in livers of HFRU-fed mice. Suppressed lipogenic factors, orchestrated by PPAR-gamma, and mitigated ER stress concomitant with the increase in beta-oxidation driven by PPAR-alpha mediated the LDT409 beneficial effects. CONCLUSIONS LDT409 may represent a potential low-cost approach to treat metabolic dysfunction-associated steatotic liver disease, which does not currently have a specific treatment.
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Affiliation(s)
- Aline Fernandes-da-Silva
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Daiana Araujo Santana-Oliveira
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Andressa S de Oliveira
- Graduate Program in Pharmaceutical Sciences, Department of Pharmacy, Health Sciences Faculty, University of Brasília, Brasília, DF, Brazil; Laboratory of Development of Therapeutic Innovations (LDT), Center for Tropical Medicine, Faculty of Medicine, University of Brasília, Brasília, DF, Brazil
| | - Thaís A M Ferreira
- Graduate Program in Pharmaceutical Sciences, Department of Pharmacy, Health Sciences Faculty, University of Brasília, Brasília, DF, Brazil; Laboratory of Development of Therapeutic Innovations (LDT), Center for Tropical Medicine, Faculty of Medicine, University of Brasília, Brasília, DF, Brazil
| | - Natália Cipriano Monteiro
- Graduate Program in Pharmaceutical Sciences, Department of Pharmacy, Health Sciences Faculty, University of Brasília, Brasília, DF, Brazil; Laboratory of Development of Therapeutic Innovations (LDT), Center for Tropical Medicine, Faculty of Medicine, University of Brasília, Brasília, DF, Brazil
| | - Flávia Maria Silva-Veiga
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fabiane Ferreira Martins
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Carolyn L Cummins
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada
| | - Luiz Antonio Soares Romeiro
- Graduate Program in Pharmaceutical Sciences, Department of Pharmacy, Health Sciences Faculty, University of Brasília, Brasília, DF, Brazil; Laboratory of Development of Therapeutic Innovations (LDT), Center for Tropical Medicine, Faculty of Medicine, University of Brasília, Brasília, DF, Brazil
| | - Vanessa Souza-Mello
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
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Jia RB, Gao S, Huang Z, Li ZR, Wang H, Wu J, Zhou C, Zhao M. The potential auxiliary effects of Sargassum fusiform polysaccharides on sitagliptin in the treatment of diabetes mellitus. Int J Biol Macromol 2024; 281:136154. [PMID: 39357709 DOI: 10.1016/j.ijbiomac.2024.136154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 09/05/2024] [Accepted: 09/28/2024] [Indexed: 10/04/2024]
Abstract
This work aimed to evaluate the potential positive effects of Sargassum fusiform polysaccharides (SFP) as add-on adjuncts to sitagliptin (SIT) in treating diabetes in rats. The results showed that both SIT and SIT co-administrated with SFP (SIT+SFP) could improve hyperglycemia, glucose tolerance, insulin resistance and hyperlipidemia, and SIT+SFP exhibited better effects in alleviating the levels of blood glucose, glucose tolerance, insulin resistance index, cholesterol, and low-density lipoprotein cholesterol compared to SIT administration. Intestinal flora analysis showed that SIT+SFP treatment significantly restored the beneficial composition of gut flora as compared with SIT administration, such as the increase of Lactobacillus, Romboutsia, Blautia, Bifidobacterium, Bacteroides, Ruminococcaceae_UCG_014 and Ruminococcus_1, and the decrease of Helicobacter, Escherichia-Shigella and Pseudomonas. The fecal metabolite analysis demonstrated that the fecal bile acid and short-chain fatty acid levels in the SIT+SFP group significantly increased compared to SIT treatment. Additionally, mRNA expression results confirmed that the hypoglycemic effects of SIT+SFP were better than those of SIT, which might be attributed to the regulation of blood glucose absorption, inhibition of gluconeogenesis and regulation of cholesterol metabolism. These results suggested that SFP could be used as an auxiliary substance for SIT in treating diabetes mellitus.
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Affiliation(s)
- Rui-Bo Jia
- College of Food Science and Technology, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Province Engineering Laboratory for Marine Biological Products, Guangdong Provincial Engineering Technology Research Center of Seafood, Guangdong Provincial Engineering Technology Research Center of Prefabricated Seafood Processing and Quality Control, Zhanjiang 524088, China; School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China
| | - Shang Gao
- College of Food Science and Technology, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Province Engineering Laboratory for Marine Biological Products, Guangdong Provincial Engineering Technology Research Center of Seafood, Guangdong Provincial Engineering Technology Research Center of Prefabricated Seafood Processing and Quality Control, Zhanjiang 524088, China
| | - Zirui Huang
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Zhao-Rong Li
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China.
| | - Haozheng Wang
- College of Food Science and Technology, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Province Engineering Laboratory for Marine Biological Products, Guangdong Provincial Engineering Technology Research Center of Seafood, Guangdong Provincial Engineering Technology Research Center of Prefabricated Seafood Processing and Quality Control, Zhanjiang 524088, China
| | - Juan Wu
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China
| | - Chunxia Zhou
- College of Food Science and Technology, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Province Engineering Laboratory for Marine Biological Products, Guangdong Provincial Engineering Technology Research Center of Seafood, Guangdong Provincial Engineering Technology Research Center of Prefabricated Seafood Processing and Quality Control, Zhanjiang 524088, China
| | - Mouming Zhao
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China.
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Su F, Koeberle A. Regulation and targeting of SREBP-1 in hepatocellular carcinoma. Cancer Metastasis Rev 2024; 43:673-708. [PMID: 38036934 PMCID: PMC11156753 DOI: 10.1007/s10555-023-10156-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 11/10/2023] [Indexed: 12/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is an increasing burden on global public health and is associated with enhanced lipogenesis, fatty acid uptake, and lipid metabolic reprogramming. De novo lipogenesis is under the control of the transcription factor sterol regulatory element-binding protein 1 (SREBP-1) and essentially contributes to HCC progression. Here, we summarize the current knowledge on the regulation of SREBP-1 isoforms in HCC based on cellular, animal, and clinical data. Specifically, we (i) address the overarching mechanisms for regulating SREBP-1 transcription, proteolytic processing, nuclear stability, and transactivation and (ii) critically discuss their impact on HCC, taking into account (iii) insights from pharmacological approaches. Emphasis is placed on cross-talk with the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt)-mechanistic target of rapamycin (mTOR) axis, AMP-activated protein kinase (AMPK), protein kinase A (PKA), and other kinases that directly phosphorylate SREBP-1; transcription factors, such as liver X receptor (LXR), peroxisome proliferator-activated receptors (PPARs), proliferator-activated receptor γ co-activator 1 (PGC-1), signal transducers and activators of transcription (STATs), and Myc; epigenetic mechanisms; post-translational modifications of SREBP-1; and SREBP-1-regulatory metabolites such as oxysterols and polyunsaturated fatty acids. By carefully scrutinizing the role of SREBP-1 in HCC development, progression, metastasis, and therapy resistance, we shed light on the potential of SREBP-1-targeting strategies in HCC prevention and treatment.
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Affiliation(s)
- Fengting Su
- Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020, Innsbruck, Austria
| | - Andreas Koeberle
- Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020, Innsbruck, Austria.
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Nanda D, Venkatraman AC, Kalaivanan K. A cross talk study on sitagliptin mediated reclamation on TGF β signalling, DPP 4, miR-29a and miR-24 expression in PCOS rats fed with high fat-high fructose diet. Tissue Cell 2024; 88:102375. [PMID: 38604038 DOI: 10.1016/j.tice.2024.102375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 04/04/2024] [Accepted: 04/04/2024] [Indexed: 04/13/2024]
Abstract
Polycystic Ovary Syndrome (PCOS) is a multifactorial reproductive, endocrine and metabolic disturbance which is very commonly observed in females of reproductive age group. The disease is still incurable however the use of synthetic drugs in combination with lifestyle is recommended. Accordingly, the present study was conducted to investigate the possible beneficial effects of sitagliptin on PCOS induced rats on control diet (CD)/high fat- high fructose diet (HFFD). PCOS was induced by giving testosterone propionate (TP) for 28 days to both the CD/HFFD rats and treated with STG i.p. for last 15 days. At the end of the experiment lipid profile, inflammatory markers, expression of NF-κB-p65, miR-24 and miR-29a, fibrotic and apoptotic proteins from ovary tissue were examined. Moreover, lipid accumulation and fibrosis of ovary tissue was further confirmed using Sudan III and Masson's trichrome stain. STG treated rats exerted a significant decrease in levels of cholesterol, TG, LDL-C, VLDL-C, IL-6 and TNF-α and increased HDL-C level, miR-24 and miR-29a expression. STG treated groups expressed significantly decreased expression of NF-κB-p65, TGF-β1, p-Smad 2 and p-Smad 3 followed by no significant changes in the expression of BAX, caspase-9, caspase-3 and Bcl-2 in all the PCOS induced groups. Among all the CD/ HFFD fed groups, rats on HFFD showed more devastating effect which suggests that diet plays a major role in genesis of PCOS. In conclusion, current results reflect the potential impact of STG against dyslipidaemia, inflammation and fibrosis in PCOS rats via regulating dyslipidaemia and fibrosis via DPP 4 mediated miR-29a expression.
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Affiliation(s)
- Dipti Nanda
- Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, India.
| | | | - Kalpana Kalaivanan
- Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, India
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Petrov MS. The Pharmacological Landscape for Fatty Change of the Pancreas. Drugs 2024; 84:375-384. [PMID: 38573485 PMCID: PMC11101365 DOI: 10.1007/s40265-024-02022-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/07/2024] [Indexed: 04/05/2024]
Abstract
The quest for medications to reduce intra-pancreatic fat deposition is now quarter a century old. While no specific medication has been approved for the treatment of fatty change of the pancreas, drug repurposing shows promise in reducing the burden of the most common disorder of the pancreas. This leading article outlines the 12 classes of medications that have been investigated to date with a view to reducing intra-pancreatic fat deposition. Information is presented hierarchically-from preclinical studies to retrospective findings in humans to prospective interventional studies to randomised controlled trials. This lays the grounds for shepherding the most propitious drugs into medical practice through well-designed basic science studies and adequately powered randomised controlled trials.
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Affiliation(s)
- Maxim S Petrov
- School of Medicine, University of Auckland, Auckland, New Zealand.
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Lin X, Qu J, Yin L, Wang R, Wang X. Aerobic exercise-induced decrease of chemerin improved glucose and lipid metabolism and fatty liver of diabetes mice through key metabolism enzymes and proteins. Biochim Biophys Acta Mol Cell Biol Lipids 2023; 1868:159409. [PMID: 37871796 DOI: 10.1016/j.bbalip.2023.159409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 10/18/2023] [Accepted: 10/20/2023] [Indexed: 10/25/2023]
Abstract
Our previous studies have implicated an important role of adipokine chemerin in exercise-induced improvements of glycolipid metabolism and fatty liver in diabetes rat, but the underlying mechanisms remain unknown. This study first used an exogenous chemerin supplement to clarify the roles of decreased chemerin in exercised diabetes mice and possible mechanisms of glucose and lipid metabolism key enzymes and proteins [such as adipose triglyceride lipase (ATGL), lipoprotein lipase (LPL), phosphoenolpyruvate carboxykinase (PEPCK), and glucose transporter 4 (GLUT4)]. In addition, two kinds of adipose-specific chemerin knockout mice were generated to demonstrate the regulation of chemerin on glucose and lipid metabolism enzymes and proteins. We found that in diabetes mice, exercise-induced improvements of glucose and lipid metabolism and fatty liver, and exercise-induced increases of ATGL, LPL, and GLUT4 in liver, gastrocnemius and fat were reversed by exogenous chemerin. Furthermore, in chemerin knockdown mice, chemerin(-/-)∙adiponectin mice had lower body fat mass, improved blood glucose and lipid, and no fatty liver; while chemerin(-/-)∙fabp4 mice had hyperlipemia and unchanged body fat mass. Peroxisome proliferator-activated receptor γ (PPARγ), ATGL, LPL, GLUT4 and PEPCK in the liver and gastrocnemius had improve changes in chemerin(-/-)·adiponectin mice while deteriorated alterations in chemerin(-/-)·fabp4 mice, although PPARγ, ATGL, LPL, and GLUT4 increased in the fat of two kinds of chemerin(-/-) mice. CONCLUSIONS: Decreased chemerin exerts an important role in exercise-induced improvements of glucose and lipid metabolism and fatty liver in diabetes mice, which was likely to be through PPARγ mediating elevations of ATGL, LPL and GLUT4 in peripheral metabolic organs.
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Affiliation(s)
- Xiaojing Lin
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China
| | - Jing Qu
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China
| | - Lijun Yin
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China
| | - Ru Wang
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China.
| | - Xiaohui Wang
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China.
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Souza-Tavares H, Miranda CS, Vasques-Monteiro IML, Sandoval C, Santana-Oliveira DA, Silva-Veiga FM, Fernandes-da-Silva A, Souza-Mello V. Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas. World J Gastroenterol 2023; 29:4136-4155. [PMID: 37475842 PMCID: PMC10354577 DOI: 10.3748/wjg.v29.i26.4136] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/26/2023] [Accepted: 06/13/2023] [Indexed: 07/10/2023] Open
Abstract
The world is experiencing reflections of the intersection of two pandemics: Obesity and coronavirus disease 2019. The prevalence of obesity has tripled since 1975 worldwide, representing substantial public health costs due to its comorbidities. The adipose tissue is the initial site of obesity impairments. During excessive energy intake, it undergoes hyperplasia and hypertrophy until overt inflammation and insulin resistance turn adipocytes into dysfunctional cells that send lipotoxic signals to other organs. The pancreas is one of the organs most affected by obesity. Once lipotoxicity becomes chronic, there is an increase in insulin secretion by pancreatic beta cells, a surrogate for type 2 diabetes mellitus (T2DM). These alterations threaten the survival of the pancreatic islets, which tend to become dysfunctional, reaching exhaustion in the long term. As for the liver, lipotoxicity favors lipogenesis and impairs beta-oxidation, resulting in hepatic steatosis. This silent disease affects around 30% of the worldwide population and can evolve into end-stage liver disease. Although therapy for hepatic steatosis remains to be defined, peroxisome proliferator-activated receptors (PPARs) activation copes with T2DM management. Peroxisome PPARs are transcription factors found at the intersection of several metabolic pathways, leading to insulin resistance relief, improved thermogenesis, and expressive hepatic steatosis mitigation by increasing mitochondrial beta-oxidation. This review aimed to update the potential of PPAR agonists as targets to treat metabolic diseases, focusing on adipose tissue plasticity and hepatic and pancreatic remodeling.
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Affiliation(s)
| | | | | | - Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Osorno 5310431, Chile
- Departamento de Ciencias Preclínicas, Universidad de la Frontera, Temuco 4780000, Chile
| | | | | | | | - Vanessa Souza-Mello
- Department of Anatomy, Rio de Janeiro State University, Rio de Janeiro 20551030, Brazil
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Bernardini F, Nusca A, Coletti F, La Porta Y, Piscione M, Vespasiano F, Mangiacapra F, Ricottini E, Melfi R, Cavallari I, Ussia GP, Grigioni F. Incretins-Based Therapies and Their Cardiovascular Effects: New Game-Changers for the Management of Patients with Diabetes and Cardiovascular Disease. Pharmaceutics 2023; 15:1858. [PMID: 37514043 PMCID: PMC10386670 DOI: 10.3390/pharmaceutics15071858] [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: 05/31/2023] [Revised: 06/26/2023] [Accepted: 06/27/2023] [Indexed: 07/30/2023] Open
Abstract
Atherosclerosis is the leading cause of death worldwide, especially in patients with type 2 diabetes mellitus (T2D). GLP-1 receptor agonists and DPP-4 inhibitors were demonstrated to play a markedly protective role for the cardiovascular system beyond their glycemic control. Several cardiovascular outcome trials (CVOT) reported the association between using these agents and a significant reduction in cardiovascular events in patients with T2D and a high cardiovascular risk profile. Moreover, recent evidence highlights a favorable benefit/risk profile in myocardial infarction and percutaneous coronary revascularization settings. These clinical effects result from their actions on multiple molecular mechanisms involving the immune system, platelets, and endothelial and vascular smooth muscle cells. This comprehensive review specifically concentrates on these cellular and molecular processes mediating the cardiovascular effects of incretins-like molecules, aiming to improve clinicians' knowledge and stimulate a more extensive use of these drugs in clinical practice as helpful cardiovascular preventive strategies.
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Affiliation(s)
- Federico Bernardini
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Annunziata Nusca
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Federica Coletti
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Ylenia La Porta
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Mariagrazia Piscione
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Francesca Vespasiano
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Fabio Mangiacapra
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Elisabetta Ricottini
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Rosetta Melfi
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Ilaria Cavallari
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Gian Paolo Ussia
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Francesco Grigioni
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
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Rashmi P, Urmila A, Likhit A, Subhash B, Shailendra G. Rodent models for diabetes. 3 Biotech 2023; 13:80. [PMID: 36778766 PMCID: PMC9908807 DOI: 10.1007/s13205-023-03488-0] [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: 11/28/2022] [Accepted: 01/19/2023] [Indexed: 02/11/2023] Open
Abstract
Diabetes mellitus (DM) is associated with many health complications and is potentially a morbid condition. As prevalence increases at an alarming rate around the world, research into new antidiabetic compounds with different mechanisms is the top priority. Therefore, the preclinical experimental induction of DM is imperative for advancing knowledge, understanding pathogenesis, and developing new drugs. Efforts have been made to examine recent literature on the various induction methods of Type I and Type II DM. The review summarizes the different in vivo models of DM induced by chemical, surgical, and genetic (immunological) manipulations and the use of pathogens such as viruses. For good preclinical assessment, the animal model must exhibit face, predictive, and construct validity. Among all reported models, chemically induced DM with streptozotocin was found to be the most preferred model. However, the purpose of the research and the outcomes to be achieved should be taken into account. This review was aimed at bringing together models, benefits, limitations, species, and strains. It will help the researcher to understand the pathophysiology of DM and to choose appropriate animal models.
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Affiliation(s)
- Patil Rashmi
- Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Paud Road, Erandwane, Pune, 411038 India
| | - Aswar Urmila
- Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Paud Road, Erandwane, Pune, 411038 India
| | - Akotkar Likhit
- Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Paud Road, Erandwane, Pune, 411038 India
| | - Bodhankar Subhash
- Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Paud Road, Erandwane, Pune, 411038 India
| | - Gurav Shailendra
- Department of Pharmacognosy, Goa College of Pharmacy, Goa University, Panaji, Goa India
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Patel R, Parmar N, Palit SP, Rathwa N, Begum R. A novel combination of sitagliptin and melatonin ameliorates T2D manifestations: studies on experimental diabetic models. J Endocrinol Invest 2023:10.1007/s40618-023-02014-6. [PMID: 36692817 DOI: 10.1007/s40618-023-02014-6] [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: 09/05/2022] [Accepted: 01/16/2023] [Indexed: 01/25/2023]
Abstract
INTRODUCTION Type 2 diabetes (T2D) is an endocrine disorder characterized by hyperglycemia, insulin resistance, dysregulated glucose and lipid metabolism, reduced pancreatic β-cell function and mass, and a reduced incretin effect. Circadian rhythm disruption is associated with increased T2D risk. We have investigated the therapeutic potential of a combination of melatonin (M) and sitagliptin (S), a dipeptidyl peptidase IV (DPP-IV) inhibitor, in the amelioration of T2D manifestations in high-fat diet (HFD) induced T2D mouse model and also on β-cell proliferation under gluco-lipotoxicity stress in vitro. METHODS For in vivo study, mice were fed with HFD for 25 weeks to induce T2D and were treated with monotherapies and S + M for four weeks. For the in vitro study, primary mouse islets were exposed to normal glucose and high glucose + palmitate to induce gluco-lipotoxic stress. RESULTS Our results suggest that monotherapies and S + M improve metabolic parameters and glyco-lipid metabolism in the liver and adipose tissue, respectively, and improve mitochondrial function in the skeletal muscle. Moreover, it increases peripheral insulin sensitivity. Our in vitro and in vivo studies suggest that β-cell mass was preserved in all the drug-treated groups. CONCLUSION The combination treatment is superior to monotherapies in the management of T2D.
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Affiliation(s)
- R Patel
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India
| | - N Parmar
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India
| | - S P Palit
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India
| | - N Rathwa
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India
| | - R Begum
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India.
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Qi JH, Chen PY, Cai DY, Wang Y, Wei YL, He SP, Zhou W. Exploring novel targets of sitagliptin for type 2 diabetes mellitus: Network pharmacology, molecular docking, molecular dynamics simulation, and SPR approaches. Front Endocrinol (Lausanne) 2023; 13:1096655. [PMID: 36699034 PMCID: PMC9868454 DOI: 10.3389/fendo.2022.1096655] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 12/19/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Diabetes has become a serious global public health problem. With the increasing prevalence of type 2 diabetes mellitus (T2DM), the incidence of complications of T2DM is also on the rise. Sitagliptin, as a targeted drug of DPP4, has good therapeutic effect for T2DM. It is well known that sitagliptin can specifically inhibit the activity of DPP4 to promote insulin secretion, inhibit islet β cell apoptosis and reduce blood glucose levels, while other pharmacological mechanisms are still unclear, such as improving insulin resistance, anti-inflammatory, anti-oxidative stress, and anti-fibrosis. The aim of this study was to explore novel targets and potential signaling pathways of sitagliptin for T2DM. METHODS Firstly, network pharmacology was applied to find the novel target most closely related to DPP4. Semi-flexible molecular docking was performed to confirm the binding ability between sitagliptin and the novel target, and molecular dynamics simulation (MD) was carried to verify the stability of the complex formed by sitagliptin and the novel target. Furthermore, surface-plasmon resonance (SPR) was used to explored the affinity and kinetic characteristics of sitagliptin with the novel target. Finally, the molecular mechanism of sitagliptin for T2DM was predicted by the enrichment analysis of GO function and KEGG pathway. RESULTS In this study, we found the cell surface receptor-angiotensin-converting enzyme 2 (ACE2) most closely related to DPP4. Then, we confirmed that sitagliptin had strong binding ability with ACE2 from a static perspective, and the stability of sitagliptin-ACE2 complex had better stability and longer binding time than BAR708-ACE2 in simulated aqueous solution within 50 ns. Significantly, we have demonstrated a strong affinity between sitagliptin and ACE2 on SPR biosensor, and their kinetic characteristics were "fast binding/fast dissociation". The guiding significance of clinical administration: low dose can reach saturation, but repeated administration was needed. Finally, there was certain relationship between COVID-19 and T2DM, and ACE2/Ang-(1-7)/Mas receptor (MasR) axis may be the important pathway of sitagliptin targeting ACE2 for T2DM. CONCLUSION This study used different methods to prove that ACE2 may be another novel target of sitagliptin for T2DM, which extended the application of ACE2 in improving diabetes mellitus.
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Affiliation(s)
| | | | | | | | | | | | - Wei Zhou
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China
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14
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Carrillo-Tripp M, Reyes Y, Delgado-Coello B, Mas-Oliva J, Gutiérrez-Vidal R. Peptide Helix-Y 12 as Potential Effector for Peroxisome Proliferator-Activated Receptors. PPAR Res 2023; 2023:8047378. [PMID: 37096195 PMCID: PMC10122583 DOI: 10.1155/2023/8047378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 03/29/2023] [Accepted: 04/03/2023] [Indexed: 04/26/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of lipids and glucose metabolism, and immune response. Therefore, they have been considered pharmacological targets for treating metabolic diseases, such as dyslipidemia, atherosclerosis, and non-alcoholic fatty liver disease. However, the available synthetic ligands of PPARs have mild to significant side effects, generating the necessity to identify new molecules that are selective PPAR ligands with specific biological responses. This study aimed to evaluate some components of the atheroprotective and hepatoprotective HB-ATV-8 nanoparticles [the amphipathic peptide Helix-Y12, thermozeaxanthin, thermozeaxanthin-13, thermozeaxanthin-15, and a set of glycolipids], as possible ligands of PPARs through blind molecular docking. According to the change in free energy upon protein-ligand binding, ∆G b, thermozeaxanthins show a more favorable interaction with PPARs, followed by Helix-Y12. Moreover, Helix-Y12 interacts with most parts of the Y-shaped ligand-binding domain (LBD), surrounding helix 3 of PPARs, and reaching helix 12 of PPARα and PPARγ. As previously reported for other ligands, Tyr314 and Tyr464 of PPARα interact with Helix-Y12 through hydrogen bonds. Several PPARα's amino acids are involved in the ligand binding by hydrophobic interactions. Furthermore, we identified additional PPARs' amino acids interacting with Helix-Y12 through hydrogen bonds still not reported for known ligands. Our results show that, from the studied ligand set, the Helix-Y12 peptide and Tzeaxs have the most significant probability of binding to the PPARs' LBD, suggesting novel ligands for PPARs.
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Affiliation(s)
- Mauricio Carrillo-Tripp
- Biomolecular Diversity Laboratory, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Unidad Monterrey, Vía del Conocimiento 201, PIIT, C.P. 66600, Apodaca, Nuevo León, Mexico
| | - Yair Reyes
- Metabolic Diseases Laboratory, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Unidad Monterrey, Vía del Conocimiento 201, PIIT, C.P. 66600, Apodaca, Nuevo León, Mexico
- Universidad Politécnica de Puebla, Tercer Carril del Ejido, Serrano s/n, Cuanalá, C.P. 7264, Puebla, Mexico
| | - Blanca Delgado-Coello
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, C.P. 04510, CDMX, Mexico
| | - Jaime Mas-Oliva
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, C.P. 04510, CDMX, Mexico
| | - Roxana Gutiérrez-Vidal
- Metabolic Diseases Laboratory, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Unidad Monterrey, Vía del Conocimiento 201, PIIT, C.P. 66600, Apodaca, Nuevo León, Mexico
- Programa de Investigadoras e Investigadores por México, Conacyt, CDMX, Mexico
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Wu QL, Zeng SX, Peng JY, Yuan Y, Zhu Z, Xie ZC, Huang ZH, Huang JS, Lai JM, Chen JA, Lin MH. Advances in metformin for the treatment of non-alcoholic fatty liver disease in children. Expert Rev Gastroenterol Hepatol 2022; 16:863-877. [PMID: 36039840 DOI: 10.1080/17474124.2022.2118112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
INTRODUCTION The increased economic and social burdens for NAFLD worldwide make treating such a disease a significant public health issue. Metformin, a kind of insulin sensitizer generally used to treat type 2 diabetes, has been recently found to have efficacy on children's NAFLD in various areas such as glucolipid metabolism, intestinal bacterial metabolism, oxidative stress, and anti-inflammatory response. This article aims to provide an overview of the possible mechanisms of NAFLD in children and the potential therapeutic application of metformin. AREAS COVERED The Cochrane Library, PubMed, Scopus, and EMBASE database was systematically searched on 12 April 2022, using the keywords metformin; non-alcoholic fatty liver disease; and children to identify similar studies. An additional search for recently published research was performed in June 2020. EXPERT OPINION Although metformin has been proved to have an excellent therapeutic effect on children's NAFLD; we can still explore its potential impacts and mechanisms from different angles, such as combined medication. At the same time, we should also pay attention to its side effects.
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Affiliation(s)
- Qian-Long Wu
- Guangzhou Medical University, Guangzhou, Guangdong province, China
| | - Shu-Xin Zeng
- Guangzhou Medical University, Guangzhou, Guangdong province, China
| | | | | | | | - Zi-Chun Xie
- Guangzhou Medical University, Guangzhou, Guangdong province, China
| | - Ze-Hong Huang
- Guangzhou Medical University, Guangzhou, Guangdong province, China
| | - Jia-Shuan Huang
- Guangzhou Medical University, Guangzhou, Guangdong province, China
| | - Jian-Mei Lai
- Guangzhou Medical University, Guangzhou, Guangdong province, China
| | - Jin-An Chen
- Guangzhou Medical University, Guangzhou, Guangdong province, China
| | - Min-Hua Lin
- Guangzhou Medical University, Guangzhou, Guangdong province, China
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16
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Baumann A, Burger K, Brandt A, Staltner R, Jung F, Rajcic D, Lorenzo Pisarello MJ, Bergheim I. GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease. Metabolism 2022; 133:155233. [PMID: 35654114 DOI: 10.1016/j.metabol.2022.155233] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 05/20/2022] [Accepted: 05/26/2022] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Insulin resistance is among the key risk factors for the development of non-alcoholic fatty liver disease (NAFLD). Recently, it has been reported that GW9662, shown to be a potent peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, may improve insulin sensitivity in settings of type 2 diabetes. Here, we determined the effects of GW9662 on the development of NAFLD and molecular mechanisms involved. METHODS Female C57BL/6J mice were pair-fed either a liquid control diet (C) or a fat-, fructose- and cholesterol-rich diet (FFC) for 8 weeks while either being treated with GW9662 (1 mg/kg body weight; C+GW9662 and FFC+GW9662) or vehicle (C and FFC) i.p. three times weekly. Indices of liver damage and inflammation, parameters of glucose metabolism and portal endotoxin levels were determined. Lipopolysaccharide (LPS)-challenged J774A.1 cells were treated with 10 μM GW9662. RESULTS Despite similar caloric intake the development of NAFLD and insulin resistance were significantly attenuated in FFC+GW9662-treated mice when compared to FFC-fed animals. Bacterial endotoxin levels in portal plasma were almost similarly increased in both FFC-fed groups while expressions of toll-like receptor 4 (Tlr4), myeloid differentiation primary response 88 (Myd88) and interleukin 1 beta (Il1b) as well as nitrite (NO2-) concentration in liver were significantly higher in FFC-fed mice than in FFC+GW9662-treated animals. In J774A.1 cells, treatment with GW9662 significantly attenuated LPS-induced expression of Il1b, interleukin 6 (Il6) and inducible nitric oxide synthase (iNos) as well as NO2- formation. CONCLUSION In summary, our data suggest that the PPARγ antagonist GW9662 attenuates the development of a diet-induced NAFLD and that this is associated with a protection against the activation of the TLR4 signaling cascade.
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Affiliation(s)
- Anja Baumann
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Katharina Burger
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Annette Brandt
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Raphaela Staltner
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Finn Jung
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Dragana Rajcic
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | | | - Ina Bergheim
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria.
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Schmitz K, Turnwald EM, Kretschmer T, Janoschek R, Bae-Gartz I, Voßbrecher K, Kammerer MD, Köninger A, Gellhaus A, Handwerk M, Wohlfarth M, Gründemann D, Hucklenbruch-Rother E, Dötsch J, Appel S. Metformin Prevents Key Mechanisms of Obesity-Related Complications in Visceral White Adipose Tissue of Obese Pregnant Mice. Nutrients 2022; 14:nu14112288. [PMID: 35684088 PMCID: PMC9182976 DOI: 10.3390/nu14112288] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 12/13/2022] Open
Abstract
With the gaining prevalence of obesity, related risks during pregnancy are rising. Inflammation and oxidative stress are considered key mechanisms arising in white adipose tissue (WAT) sparking obesity-associated complications and diseases. The established anti-diabetic drug metformin reduces both on a systemic level, but only little is known about such effects on WAT. Because inhibiting these mechanisms in WAT might prevent obesity-related adverse effects, we investigated metformin treatment during pregnancy using a mouse model of diet-induced maternal obesity. After mating, obese mice were randomised to metformin administration. On gestational day G15.5, phenotypic data were collected and perigonadal WAT (pgWAT) morphology and proteome were examined. Metformin treatment reduced weight gain and visceral fat accumulation. We detected downregulation of perilipin-1 as a correlate and observed indications of recovering respiratory capacity and adipocyte metabolism under metformin treatment. By regulating four newly discovered potential adipokines (alpha-1 antitrypsin, Apoa4, Lrg1 and Selenbp1), metformin could mediate anti-diabetic, anti-inflammatory and oxidative stress-modulating effects on local and systemic levels. Our study provides an insight into obesity-specific proteome alterations and shows novel modulating effects of metformin in pgWAT of obese dams. Accordingly, metformin therapy appears suitable to prevent some of obesity’s key mechanisms in WAT.
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Affiliation(s)
- Katrin Schmitz
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Eva-Maria Turnwald
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Tobias Kretschmer
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
- UFZ-Helmholtz Centre for Environmental Research, Department Environmental Immunology, Permoserstraße 15, 04318 Leipzig, Germany
| | - Ruth Janoschek
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Inga Bae-Gartz
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Kathrin Voßbrecher
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Merlin D. Kammerer
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Angela Köninger
- Department of Obstetrics and Gynecology, University of Regensburg, St. Hedwigs Clinic of the Order of St. John, Steinmetzstrasse 1-3, 93049 Regensburg, Germany;
| | - Alexandra Gellhaus
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany;
| | - Marion Handwerk
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Maria Wohlfarth
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Dirk Gründemann
- Department of Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Gleueler Straße 24, 50931 Cologne, Germany;
| | - Eva Hucklenbruch-Rother
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Jörg Dötsch
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Sarah Appel
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
- Correspondence: ; Tel.: +49-221-478-96890
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18
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Progressive brown adipocyte dysfunction: whitening and impaired nonshivering thermogenesis as long-term obesity complications. J Nutr Biochem 2022; 105:109002. [PMID: 35346828 DOI: 10.1016/j.jnutbio.2022.109002] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 11/23/2021] [Accepted: 02/22/2022] [Indexed: 12/12/2022]
Abstract
Chronic obesity damages the cytoarchitecture of brown adipose tissue (BAT), leading to whitening of brown adipocytes and impaired thermogenesis, characterizing BAT dysfunction. Understanding the pathways of whitening progression can bring new targets to counter obesity. This study aimed to evaluate the chronic effect (12, 16, and 20 weeks) of a high-fat diet (50% energy as fat) upon energy expenditure, thermogenic markers, and pathways involved in BAT whitening in C57BL/6J mice. Sixty adult male mice comprised six nutritional groups, where the letters refer to the diet type (control, C or high-fat, HF), and the numbers refer to the period (in weeks) of diet administration: C12, HF12, C16, HF16, C20, and HF20. After sacrifice, biochemical, molecular, and stereological analyses addressed the outcomes. The HF groups had overweight, oral glucose intolerance, and hyperleptinemia, resulting in progressive whitening of BAT and decreased numerical density of nuclei per area of tissue compared to age-matched control groups. In addition, the whitening maximization was related to altered batokines gene expression, decreased nonshivering thermogenesis, and body temperature, resulting in low energy expenditure. The HF20 group showed enlarged adipocytes with stable and dysfunctional lipid droplets, followed by inflammation and ER stress. In conclusion, chronic HF diet intake caused time-dependent maximization of whitening with defective nonshivering thermogenesis. Long-term BAT dysfunction includes down-regulated vascularization markers, upregulated inflammasome activation, and ER stress markers.
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19
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Huber G, Ogrodnik M, Wenzel J, Stölting I, Huber L, Will O, Peschke E, Matschl U, Hövener JB, Schwaninger M, Jurk D, Raasch W. Telmisartan prevents high-fat diet-induced neurovascular impairments and reduces anxiety-like behavior. J Cereb Blood Flow Metab 2021; 41:2356-2369. [PMID: 33730932 PMCID: PMC8393307 DOI: 10.1177/0271678x211003497] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Angiotensin II receptor blockers (telmisartan) prevent rodents from diet-induced obesity and improve their metabolic status. Hyperglycemia and obesity are associated with reduced cerebral blood flow and neurovascular uncoupling which may lead to behavioral deficits. We wanted to know whether a treatment with telmisartan prevents these changes in obesity.We put young mice on high-fat diet and simultaneously treated them with telmisartan. At the end of treatment, we performed laser speckle imaging and magnetic resonance imaging to assess the effect on neurovascular coupling and cerebral blood flow. Different behavioral tests were used to investigate cognitive function.Mice developed diet-induced obesity and after 16, not 8 weeks of high-fat diet, however, the response to whisker pad stimulation was about 30% lower in obese compared to lean mice. Simultaneous telmisartan treatment increased the response again by 10% compared to obese mice. Moreover, telmisartan treatment normalized high-fat diet-induced reduction of cerebral blood flow and prevented a diet-induced anxiety-like behavior. In addition to that, telmisartan affects cellular senescence and string vessel formation in obesity.We conclude, that telmisartan protects against neurovascular unit impairments in a diet-induced obesity setting and may play a role in preventing obesity related cognitive deficits in Alzheimer's disease.
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Affiliation(s)
- Gianna Huber
- Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.,CBBM (Centre for Brain, Behavior and Metabolism), University of Lübeck, Lübeck, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany
| | - Mikolaj Ogrodnik
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester MN, USA.,Ludwig Boltzmann Research Group Senescence and Healing of Wounds at LBI Trauma, Vienna, Austria
| | - Jan Wenzel
- Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.,CBBM (Centre for Brain, Behavior and Metabolism), University of Lübeck, Lübeck, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany
| | - Ines Stölting
- Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.,CBBM (Centre for Brain, Behavior and Metabolism), University of Lübeck, Lübeck, Germany
| | - Lukas Huber
- Section Biomedical Imaging, MOIN CC, Department of Radiology and Neuroradiology, UKSH, Kiel University, Kiel, Germany
| | - Olga Will
- Section Biomedical Imaging, MOIN CC, Department of Radiology and Neuroradiology, UKSH, Kiel University, Kiel, Germany
| | - Eva Peschke
- Section Biomedical Imaging, MOIN CC, Department of Radiology and Neuroradiology, UKSH, Kiel University, Kiel, Germany
| | - Urte Matschl
- Department Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Jan-Bernd Hövener
- Section Biomedical Imaging, MOIN CC, Department of Radiology and Neuroradiology, UKSH, Kiel University, Kiel, Germany
| | - Markus Schwaninger
- Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.,CBBM (Centre for Brain, Behavior and Metabolism), University of Lübeck, Lübeck, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany
| | - Diana Jurk
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester MN, USA
| | - Walter Raasch
- Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.,CBBM (Centre for Brain, Behavior and Metabolism), University of Lübeck, Lübeck, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany
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20
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Impaired Leptin Signalling in Obesity: Is Leptin a New Thermolipokine? Int J Mol Sci 2021; 22:ijms22126445. [PMID: 34208585 PMCID: PMC8235268 DOI: 10.3390/ijms22126445] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 06/03/2021] [Accepted: 06/10/2021] [Indexed: 12/17/2022] Open
Abstract
Leptin is a principal adipose-derived hormone mostly implicated in the regulation of energy balance through the activation of anorexigenic neuronal pathways. Comprehensive studies have established that the maintenance of certain concentrations of circulating leptin is essential to avoid an imbalance in nutrient intake. Indeed, genetic modifications of the leptin/leptin receptor axis and the obesogenic environment may induce changes in leptin levels or action in a manner that accelerates metabolic dysfunctions, resulting in a hyperphagic status and adipose tissue expansion. As a result, a vicious cycle begins wherein hyperleptinaemia and leptin resistance occur, in turn leading to increased food intake and fat enlargement, which is followed by leptin overproduction. In addition, in the context of obesity, a defective thermoregulatory response is associated with impaired leptin signalling overall within the ventromedial nucleus of the hypothalamus. These recent findings highlight the role of leptin in the regulation of adaptive thermogenesis, thus suggesting leptin to be potentially considered as a new thermolipokine. This review provides new insight into the link between obesity, hyperleptinaemia, leptin resistance and leptin deficiency, focusing on the ability to restore leptin sensitiveness by way of enhanced thermogenic responses and highlighting novel anti-obesity therapeutic strategies.
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21
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Gubergrits NB, Byelyayeva NV, Mozhyna TL. Parallels between non-alcoholic fatty liver disease and non-alcoholic fatty pancreatic disease: looking for points of contact or regard through the lens of metabolic syndrome. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2020; 183:80-101. [DOI: 10.31146/1682-8658-ecg-183-11-80-101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The aim. The aim of our study was to analyze the available data from literature sources concerning the issues of etiology, pathogenesis, clinic, diagnosis and features of treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic fatty pancreatic disease (NAFPD).Materials and methods. We conducted a retrospective analysis of foreign literature sources that contain up-to-date information about the state of the problem of NAFLD and NAFPD.Results. NAFLD and NAFPD develop against the background of metabolic syndrome (MS), systemic insulin resistance, oxidative stress, changes in lipid metabolism. The natural course of NAFPD is associated with high risk of MS progression, occurrence of NAFLD, arterial hypertension, type 2 diabetes mellitus, exocrine pancreatic insufficiency, acute and chronic pancreatitis, pancreas cancer. Correction of the components of MS can reduce the severity of NAFLD and NAFPD; enzyme replacement therapy can improve the function of β-cells in pancreas steatosis.Conclusion. The alternatives of the pharmacological treatment of NAFLD and NAFPD continue to be actively explored. We emphasize the need of including medications containing pancreatic enzymes in the treatment of NAFLD.
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22
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Santos FO, Correia BRO, Marinho TS, Barbosa-da-Silva S, Mandarim-de-Lacerda CA, Souza-Mello V. Anti-steatotic linagliptin pleiotropic effects encompasses suppression of de novo lipogenesis and ER stress in high-fat-fed mice. Mol Cell Endocrinol 2020; 509:110804. [PMID: 32259637 DOI: 10.1016/j.mce.2020.110804] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 03/30/2020] [Accepted: 03/30/2020] [Indexed: 12/30/2022]
Abstract
AIM To investigate the effects of linagliptin treatment on hepatic energy metabolism and ER stress in high-fat-fed C57BL/6 mice. METHODS Forty male C57BL/6 mice, three months of age, received a control diet (C, 10% of lipids as energy, n = 20) or high-fat diet (HF, 50% of lipids as energy, n = 20) for 10 weeks. The groups were randomly subdivided into four groups to receive linagliptin, for five weeks, at a dose of 30 mg/kg/day added to the diets: C, C-L, HF, and HF-L groups. RESULTS The HF group showed higher body mass, total and hepatic cholesterol levels and total and hepatic triacylglycerol levels than the C group, all of which were significantly diminished by linagliptin in the HF-L group. The HF group had higher hepatic steatosis than the C group, whereas linagliptin markedly reduced the hepatic steatosis (less 52%, P < 0.001). The expression of Sirt1 and Pgc1a was more significant in the HF-L group than in the HF group. Linagliptin also elicited enhanced GLP-1 concentrations and a reduction in the expression of the lipogenic genes Fas and Srebp1c. Besides, HF-L showed a reduction in the genes related to endoplasmic reticulum stress Chop, Atf4, and Gadd45 coupled with reduced apoptotic nuclei immunostaining. CONCLUSION Linagliptin caused a marked reduction in hepatic steatosis as a secondary effect of its glucose-lowering property. NAFLD countering involved reduced lipogenesis, increased beta-oxidation, and relief in endoplasmic reticulum stress, leading to reduced apoptosis and better preservation of the hepatic structure. Therefore, linagliptin may be used, preferably in diabetic patients, to avoid the progression of hepatic steatosis.
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Affiliation(s)
- F O Santos
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - B R O Correia
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - T S Marinho
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Sandra Barbosa-da-Silva
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Carlos A Mandarim-de-Lacerda
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vanessa Souza-Mello
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
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23
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Sinha RA, Rajak S, Singh BK, Yen PM. Hepatic Lipid Catabolism via PPARα-Lysosomal Crosstalk. Int J Mol Sci 2020; 21:2391. [PMID: 32244266 PMCID: PMC7170715 DOI: 10.3390/ijms21072391] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/01/2020] [Accepted: 03/02/2020] [Indexed: 12/13/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which belong to the nuclear hormone receptor superfamily. They regulate key aspects of energy metabolism within cells. Recently, PPARα has been implicated in the regulation of autophagy-lysosomal function, which plays a key role in cellular energy metabolism. PPARα transcriptionally upregulates several genes involved in the autophagy-lysosomal degradative pathway that participates in lipolysis of triglycerides within the hepatocytes. Interestingly, a reciprocal regulation of PPARα nuclear action by autophagy-lysosomal activity also exists with implications in lipid metabolism. This review succinctly discusses the unique relationship between PPARα nuclear action and lysosomal activity and explores its impact on hepatic lipid homeostasis under pathological conditions such as non-alcoholic fatty liver disease (NAFLD).
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Affiliation(s)
- Rohit A. Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India;
| | - Sangam Rajak
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India;
| | - Brijesh K. Singh
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169587, Singapore (P.M.Y.)
| | - Paul M. Yen
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169587, Singapore (P.M.Y.)
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24
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Marinho TDS, Borges CC, Aguila MB, Mandarim-de-Lacerda CA. Intermittent fasting benefits on alpha- and beta-cell arrangement in diet-induced obese mice pancreatic islet. J Diabetes Complications 2020; 34:107497. [PMID: 31866258 DOI: 10.1016/j.jdiacomp.2019.107497] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/21/2019] [Accepted: 11/21/2019] [Indexed: 12/21/2022]
Abstract
AIMS There is a pancreatic islet adaptation in obese subjects, resulting in insulin resistance and diabetes type 2. We studied the effect of intermittent fasting (IntF) on the islet structure of diet-induced obese (DIO) mice. METHODS Three-month-old male mice fed a control diet (C, 10% Kcal fat) or a high-fat diet (HF, 50% Kcal fat) for two months (n = 20 each group). Then, half of each group did IntF (alternating 24 h fed/24 h fast), continuing in their diets four more weeks: C, C-IntF, HF, HF-IntF. Islets were prepared to microscopy or isolated for molecular analysis. RESULTS HF group (vs. C group) showed hyperglycemia, hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, glucose intolerance, insulin resistance, and islet hypertrophy with a consequent higher both the alpha-cell and beta-cell masses. In the HF group (vs. C), there was low PDX1 (pancreatic and duodenal homeobox 1), and IntF did not alter PDX1. There was a low p-AKT/AKT ratio (protein kinase B), and IntF enhanced it. Also, tumor suppressor p53 was increased, and IntF decreased it. IL (interleukin) -6 was higher in the HF group (vs. C), and HF-IntF (vs. C-IntF). Any significant change in NFkB was seen among groups. CONCLUSIONS IntF improves pancreatic islet structure in DIO mice, even with continued HF diet intake, primarily considering on the alpha- and beta-cell masses regulation, then improving insulin signaling and decreasing cell apoptosis. Future research should explore whether the shortening of the IntF extend could maintain the benefits observed in the long term.
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Affiliation(s)
- Thatiany de Souza Marinho
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Celina Carvalho Borges
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcia Barbosa Aguila
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Carlos Alberto Mandarim-de-Lacerda
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
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25
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d'Angelo M, Castelli V, Tupone MG, Catanesi M, Antonosante A, Dominguez-Benot R, Ippoliti R, Cimini AM, Benedetti E. Lifestyle and Food Habits Impact on Chronic Diseases: Roles of PPARs. Int J Mol Sci 2019; 20:ijms20215422. [PMID: 31683535 PMCID: PMC6862628 DOI: 10.3390/ijms20215422] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 10/28/2019] [Accepted: 10/29/2019] [Indexed: 02/07/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exert important functions in mediating the pleiotropic effects of diverse exogenous factors such as physical exercise and food components. Particularly, PPARs act as transcription factors that control the expression of genes implicated in lipid and glucose metabolism, and cellular proliferation and differentiation. In this review, we aim to summarize the recent advancements reported on the effects of lifestyle and food habits on PPAR transcriptional activity in chronic disease.
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Affiliation(s)
- Michele d'Angelo
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Vanessa Castelli
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Maria Grazia Tupone
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Mariano Catanesi
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Andrea Antonosante
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Reyes Dominguez-Benot
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Rodolfo Ippoliti
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Anna Maria Cimini
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
- Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA.
| | - Elisabetta Benedetti
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
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Pinte L, Balaban DV, Băicuş C, Jinga M. Non-alcoholic fatty pancreas disease - practices for clinicians. ROMANIAN JOURNAL OF INTERNAL MEDICINE = REVUE ROUMAINE DE MEDECINE INTERNE 2019; 57:209-219. [PMID: 30901317 DOI: 10.2478/rjim-2019-0005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Indexed: 02/07/2023]
Abstract
Obesity is a growing health burden worldwide, increasing the risk for several diseases featuring the metabolic syndrome - type 2 diabetes mellitus, dyslipidemia, non-alcoholic fatty liver disease and cardiovascular diseases. With the increasing epidemic of obesity, a new pathologic condition has emerged as a component of the metabolic syndrome - that of non-alcoholic fatty pancreas disease (NAFPD). Similar to non-alcoholic fatty liver disease (NAFLD), NAFPD comprises a wide spectrum of disease - from deposition of fat in the pancreas - fatty pancreas, to pancreatic inflammation and possibly pancreatic fibrosis. In contrast with NAFLD, diagnostic evaluation of NAFPD is less standardized, consisting mostly in imaging methods. Also the natural evolution of NAFPD and its association with pancreatic cancer is much less studied. Not least, the clinical consequences of NAFPD remain largely presumptions and knowledge about its metabolic impact is limited. This review will cover epidemiology, pathogenesis, diagnostic evaluation tools and treatment options for NAFPD, with focus on practices for clinicians.
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Affiliation(s)
- Larisa Pinte
- "Colentina" Clinical Hospital, Bucharest, Romania
| | - Daniel Vasile Balaban
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
- "Dr. Carol Davila" Central Military Emergency University Hospital, Bucharest, Romania
| | - Cristian Băicuş
- "Colentina" Clinical Hospital, Bucharest, Romania
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - Mariana Jinga
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
- "Dr. Carol Davila" Central Military Emergency University Hospital, Bucharest, Romania
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27
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de Oliveira Correia BR, Rachid TL, de Oliveira Glauser JS, Martins FF, Mandarim-de-Lacerda CA, Souza-Mello V. High dose of linagliptin induces thermogenic beige adipocytes in the subcutaneous white adipose tissue in diet-induced obese C57BL/6 mice. Endocrine 2019; 65:252-262. [PMID: 31161561 DOI: 10.1007/s12020-019-01969-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 05/24/2019] [Indexed: 02/07/2023]
Abstract
PURPOSE To verify whether the treatment with linagliptin induces the browning of the subcutaneous WAT (sWAT) and thermogenesis in murine diet-induced obesity (DIO) model. METHODS Forty animals were randomly assigned to receive a control diet (C, 10% lipids as energy) or a high-fat diet (HF, 50% lipids as energy) for 10 weeks. Each group was re-divided to begin the 5-week treatment, totalizing four experimental groups: C, C-L (C plus linagliptin, 30 mg/kg body mass; BM), HF, and HF-L (HF plus linagliptin, 30 mg/kg BM). The drug was mixed with diet. RESULTS HF animals showed overweight, glucose intolerance, and a greater cross-sectional area of adipocytes. The treatment with linagliptin was able to normalize the BM, restore the glucose tolerance and the cross-sectional area of adipocytes. These observations comply with the observation of UCP1-positive multilocular adipocytes in the sWAT of treated animals. Both treated groups (C-L and HF-L) showed high expression of thermogenic and type 2 cytokines genes, which agree with the enhanced body temperature and the lower respiratory exchange ratio, implying enhanced thermogenesis with the use of lipids as fuel. CONCLUSIONS The reduced BM, the enhanced body temperature, and the presence of positive UCP1 beige cells in the sWAT point to the activation of the browning cascade on the sWAT of linagliptin-treated mice, and hence, linagliptin could induce the thermogenic pathway as a pleiotropic effect that can have translational potential.
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Affiliation(s)
- Byanca Ramos de Oliveira Correia
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Tamiris Lima Rachid
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Jade Sancha de Oliveira Glauser
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fabiane Ferreira Martins
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Carlos Alberto Mandarim-de-Lacerda
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vanessa Souza-Mello
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
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28
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Wewer Albrechtsen NJ, Mark PD, Terzic D, Hansen LH, Andersen UØ, Hartmann B, Carr RD, Gustafsson F, Deacon CF, Holst JJ, Goetze JP, Plomgaard P. Sacubitril/valsartan augments postprandial plasma concentrations of active GLP-1 when combined with sitagliptin in men. J Clin Endocrinol Metab 2019; 104:3868-3876. [PMID: 31074791 DOI: 10.1210/jc.2019-00515] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 05/01/2019] [Indexed: 12/25/2022]
Abstract
CONTEXT Combined inhibition of neprilysin and dipeptidyl peptidase 4 (DPP-4) has been shown to augment plasma concentrations of glucagon-like peptide-1(GLP-1) in animal models, but whether this occurs in humans is unknown. OBJECTIVE To investigate the effects of inhibition of neprilysin by sacubitril/valsartan alone or in combination with a DPP-4 inhibitor (sitagliptin) on plasma concentrations of GLP-1 in healthy men. DESIGN Two open-labeled crossover studies were performed in human subjects. SETTING General community. PARTICIPANTS Nine and 10 healthy young males were included in study 1 and study 2, respectively. INTERVENTION Study participants received a standardized meal (34% carbohydrates, 45% fat, 21% protein, total caloric content of 2106kJ) combined with a prior dose of either sacubitril/valsartan (194/206mg) or control in study 1, and in study 2, with a prior dose of sitagliptin (2x100mg, given ∼10 hours apart) either alone or with sacubitril/valsartan (194/206mg). MAIN OUTCOME MEASURES Plasma concentrations of total and intact GLP-1. RESULTS Sacubitril/valsartan increased postprandial plasma concentrations of total GLP-1 by 67% (tAUC0-240min: 3929±344 vs. 2348±181 min × pmol/L P=0.0023), and increased concentrations of intact GLP-1 plasma concentrations more than sitagliptin alone (tAUC0-240min: 1021±114 vs. 660±80 min × pmol/L, P=0.01). Plasma concentrations of glucose, insulin, and GIP were not significantly (P>0.10) changed upon sacubitril/valsartan treatment. CONCLUSIONS Sacubitril/valsartan combined with a DPP-4 inhibitor lead to markedly higher concentrations of intact GLP-1 than DPP-4 inhibition alone, supporting a role for both neprilysin and DPP-4 in the metabolism of GLP-1 in humans, a finding which may have therapeutic implications.
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Affiliation(s)
- Nicolai J Wewer Albrechtsen
- Department of Clinical Biochemistry, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Peter D Mark
- Department of Clinical Biochemistry, University of Copenhagen, Copenhagen, Denmark
| | - Dijana Terzic
- Department of Clinical Biochemistry, University of Copenhagen, Copenhagen, Denmark
| | - Lasse H Hansen
- Department of Clinical Biochemistry, University of Copenhagen, Copenhagen, Denmark
| | - Ulrik Ø Andersen
- Department of Clinical Biochemistry, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Richard D Carr
- MSD, Copenhagen, Denmark
- University College London, London, UK
| | - Finn Gustafsson
- Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Carolyn F Deacon
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens P Goetze
- Department of Clinical Biochemistry, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Peter Plomgaard
- Department of Clinical Biochemistry, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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29
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Graus-Nunes F, Santos FDO, Marinho TDS, Miranda CS, Barbosa-da-Silva S, Souza-Mello V. Beneficial effects of losartan or telmisartan on the local hepatic renin-angiotensin system to counter obesity in an experimental model. World J Hepatol 2019; 11:359-369. [PMID: 31114640 PMCID: PMC6504859 DOI: 10.4254/wjh.v11.i4.359] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 02/23/2019] [Accepted: 03/16/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Obesity has been associated with hepatic overexpression of the renin-angiotensin system (RAS). AIM To evaluate the action of two angiotensin II (ANGII) receptor blockers (losartan or telmisartan) on the modulation of local hepatic RAS and the resulting metabolic effects in a diet-induced obesity murine model. METHODS Twenty C57BL/6 mice were randomly divided into two nutritional groups for 10 wk: control group (C, n = 5, 10% of energy as fat) or high-fat group (HF, n = 15, 50% of energy as fat). After treatment started, the HF group was randomly divided into three groups: untreated HF group (n = 5), HF treated with losartan (HFL, n = 5) and HF treated with telmisartan (HFT, n = 5). The treatments lasted for 5 wk, and the dose was 10 mg/kg body mass. RESULTS HF diet induced body mass gain (+28%, P < 0.0001), insulin resistance (+69%, P = 0.0079), high hepatic triacylglycerol (+127%, P = 0.0004), and overexpression of intrahepatic angiotensin-converting enzyme (ACE) 1/ ANGII type 1 receptor (AT1r) (+569.02% and +141.40%, respectively, P < 0.0001). The HFL and HFT groups showed higher ACE2/rMAS gene expression compared to the HF group (ACE2: +465.57%, P = 0.0002 for HFL and +345.17%, P = 0.0049 for HFT; rMAS: +711.39%, P < 0.0001 for HFL and +539.75%, P < 0.0001 for HFT), followed by reduced insulin/glucose ratio (-30% for HFL and -33% for HFT, P = 0.0181), hepatic triacylglycerol levels (-28%, P = 0.0381 for HFL; and -45%, P = 0.0010 for HFT, and Plin2 expression. CONCLUSION Modulation of the intrahepatic RAS, with favored involvement of the ACE2/rMAS axis over the ACE1/AT1r axis after losartan or telmisartan treatments, caused hepatic and metabolic beneficial effects as demonstrated by reduced hepatic triacylglycerol levels coupled with reduced PLIN 2 expression and improved glycemic control.
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Affiliation(s)
- Francielle Graus-Nunes
- Laboratório de Morfometria, Metabolismo e Doenças Cardiovasculares, Departamento de Anatomia, Instituto de Biologia Roberto Alcântara Gomes, Rio de Janeiro 20551-030, Brazil
| | - Felipe de Oliveira Santos
- Laboratório de Morfometria, Metabolismo e Doenças Cardiovasculares, Departamento de Anatomia, Instituto de Biologia Roberto Alcântara Gomes, Rio de Janeiro 20551-030, Brazil
| | - Thatiany de Souza Marinho
- Laboratório de Morfometria, Metabolismo e Doenças Cardiovasculares, Departamento de Anatomia, Instituto de Biologia Roberto Alcântara Gomes, Rio de Janeiro 20551-030, Brazil
| | - Carolline Santos Miranda
- Laboratório de Morfometria, Metabolismo e Doenças Cardiovasculares, Departamento de Anatomia, Instituto de Biologia Roberto Alcântara Gomes, Rio de Janeiro 20551-030, Brazil
| | - Sandra Barbosa-da-Silva
- Laboratório de Morfometria, Metabolismo e Doenças Cardiovasculares, Departamento de Anatomia, Instituto de Biologia Roberto Alcântara Gomes, Rio de Janeiro 20551-030, Brazil
| | - Vanessa Souza-Mello
- Laboratório de Morfometria, Metabolismo e Doenças Cardiovasculares, Departamento de Anatomia, Instituto de Biologia Roberto Alcântara Gomes, Rio de Janeiro 20551-030, Brazil.
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Green CJ, Marjot T, Tomlinson JW, Hodson L. Of mice and men: Is there a future for metformin in the treatment of hepatic steatosis? Diabetes Obes Metab 2019; 21:749-760. [PMID: 30456918 DOI: 10.1111/dom.13592] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 11/06/2018] [Accepted: 11/15/2018] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver diseases, of which the first stage is steatosis. It is one of the most common liver diseases in developed countries and there is a clear association between type 2 diabetes (T2DM) and NAFLD. It is estimated that 70% of people with T2DM have NAFLD and yet there is currently no licensed pharmacological agent to treat it. Whilst lifestyle modification may ameliorate liver fat, it is often difficult to achieve or sustain; thus, there is great interest in pharmacological treatments for NAFLD. Metformin is the first-line medication in the management of T2DM and evidence from animal and human studies has suggested that it may be useful in reducing liver fat via inhibition of lipogenesis and increased fatty acid oxidation. Findings from the majority of studies undertaken in rodent models clearly suggest that metformin may be a powerful therapeutic agent specifically to reduce liver fat accumulation; data from human studies are less convincing. In the present review we discuss the evidence for the specific effects of metformin treatment on liver fat accumulation in animal and human studies, as well as the underlying proposed mechanisms, to try and understand and reconcile the difference in findings between rodent and human work in this area.
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Affiliation(s)
- Charlotte J Green
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
| | - Thomas Marjot
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
| | - Jeremy W Tomlinson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK
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Abstract
Nonalcoholic fatty liver disease and hypertension are closely related but there has been little genetic evidence to link them. In this issue, Musso et al. provide evidence that a common variant in AGTR1 (A1166C) is associated with both incident hypertension and nonalcoholic fatty liver disease, as well as nonalcoholic steatohepatitis, fibrosis, dyslipidemia, and insulin resistance. AGTR1 is strongly expressed in adipose, liver, and arteries. The mechanism of this gain-of-function variant is unclear but may include adipose or endothelial dysfunction and immune activation. Despite previous unsuccessful clinical trials of angiotensin receptor blockers in nonalcoholic steatohepatitis, individuals with the rs5186A>C variant may have greater benefit from this therapy.
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Khalaf HM, Ibrahim MA, Amin EF, Abdel-tawab Ibrahim S, Abdel-Wahab S, Fouad YM. Allopurinol potentiates the hepatoprotective effect of metformin and vitamin E in fructose-induced fatty liver in rats. Clin Exp Hepatol 2019; 5:65-74. [PMID: 30915409 PMCID: PMC6431087 DOI: 10.5114/ceh.2019.83159] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 10/14/2018] [Indexed: 02/07/2023] Open
Abstract
AIM OF THE STUDY Non-alcoholic fatty liver disease (NAFLD) is a challenging health problem. Hyperuricemia is a key player in the pathogenesis of NAFLD. This study investigated the effect of allopurinol (uric acid synthesis inhibitor) in combination with metformin and vitamin E in prevention of fructose induced-fatty liver in rats. MATERIAL AND METHODS Rats were divided into 7 groups: control group, fructose group (model group of NAFLD), allopurinol-treated group, metformin-treated group, vitamin E-treated group, metformin plus vitamin E-treated group and a combination group (received allopurinol plus metformin plus vitamin E). Development of NAFLD was assessed biochemically by serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as well as by histopathological examination. Oxidative stress parameters [reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA)], and the inflammatory mediators tumor necrosis factor α (TNF-α) and inducible nitric oxide synthase (iNOS) were assessed, along with serum levels of uric acid and triglyceride (TG). RESULTS Combination of allopurinol plus metformin plus vitamin E significantly attenuated fatty changes compared to their respective monotherapy. Interestingly, though all treated groups showed significant attenuation in the oxidative stress markers, TNF-α level and iNOS immunostaining in hepatic tissue, along with a significant decrease in the levels of uric acid and TG, the combination group showed a further significant decrease in the serum level of uric acid and iNOS immunostaining compared to other treated regimens. CONCLUSIONS Allopurinol synergistically increases the protective effect of metformin and vitamin E in treatment of NAFLD, namely via reduction of uric acid synthesis and iNOS expression.
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Affiliation(s)
| | | | | | | | - Soha Abdel-Wahab
- Department of Histology, Faculty of Medicine, Minia University, Egypt
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Concurrent exercise improves insulin resistance and nonalcoholic fatty liver disease by upregulating PPAR-γ and genes involved in the beta-oxidation of fatty acids in ApoE-KO mice fed a high-fat diet. Lipids Health Dis 2019; 18:6. [PMID: 30611282 PMCID: PMC6320624 DOI: 10.1186/s12944-018-0933-z] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Accepted: 11/27/2018] [Indexed: 12/16/2022] Open
Abstract
Objective To emphasize the mechanism of concurrent exercise effect on lipid disorders in insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD). Materials and methods Twenty male ApoE knockout mice were randomly divided into two groups: HFD group (n = 10) fed a high fat diet, and HFDE group (n = 10) with high-fat diet intervention for 12 weeks and swimming exercise. Other ten healthy male C57BL/6 J mice were fed a normal diet, and included as control group. Retro-orbital blood samples were collected for biochemical analysis. Oil red O staining of liver tissues was performed to confirm the exercise effect. Western blotting was performed to evaluate the expressions of PPAR-γ, CPT-1, MCAD. Results The levels of TG, TC, LDL, FFA, FIN, FPG and Homa-IRI in the HFD group were significantly higher than ND group, while these were markedly decreased in the HFDE group compared with HFD group. The Oil Red O staining of liver samples further confirmed the exercise effect on the change of lipid deposition in the liver. Western blotting showed increased expressions of PPAR-γ, CPT-1, MCAD induced by high fat diet were significantly downregulated by exercise. Conclusion A concurrent 12-week exercise protocol alleviated the lipid metabolism disorders of IR and NAFLD, probably via PPAR-γ/CPT-1/MCAD signaling.
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Choudhary NS, Kumar N, Duseja A. Peroxisome Proliferator-Activated Receptors and Their Agonists in Nonalcoholic Fatty Liver Disease. J Clin Exp Hepatol 2019; 9:731-739. [PMID: 31889755 PMCID: PMC6926194 DOI: 10.1016/j.jceh.2019.06.004] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 06/23/2019] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. In addition to the liver-related morbidity and mortality, NAFLD is now also associated with various extrahepatic diseases. Pathogenesis of NAFLD is multifactorial with limited pharmacotherapy options for the treatment of patients with NAFLD. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in the transcriptional regulation of lipid metabolism, glucose homeostasis, energy balance, inflammation, and atherosclerosis. PPAR agonists are attractive options for treatment of NAFLD as they can act at multiple targets involved in the pathogenesis of NAFLD. We reviewed the available literature on the pathophysiological role of PPARs and use of PPAR agonists in the treatment of NAFLD. Original studies and review articles available on PubMed regarding the role of PPARs in the pathogenesis and utility of PPAR agonists in the treatment of NAFLD were included in this review article. ClinicalTrials.gov and Clinical Trials Registry-India sites were searched for ongoing studies on saroglitazar. The available literature suggests that PPARs play an important role in the pathogenesis of NAFLD. Use of PPAR gamma agonists is associated with histological improvement in NAFLD. Dual PPAR agonists with no or minimal PPAR gamma activity are being explored in the treatment of NAFLD. Because of the pathophysiological role of PPARs in NAFLD, PPAR agonists are attractive options for the treatment of patients with NAFLD. Dual PPAR agonists without significant gamma activity appear promising for the treatment of NAFLD.
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Affiliation(s)
- Narendra S. Choudhary
- Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, Gurugram, India
| | | | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India,Address for correspondence: Dr. Ajay Duseja MD, DM, FAMS, FAASLD, FACG, FSGEI Professor, Department of Hepatology, Sector 12, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
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Li X, Wang Z, Klaunig JE. Modulation of xenobiotic nuclear receptors in high-fat diet induced non-alcoholic fatty liver disease. Toxicology 2018; 410:199-213. [DOI: 10.1016/j.tox.2018.08.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 08/06/2018] [Accepted: 08/13/2018] [Indexed: 02/07/2023]
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36
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The potential role of vascular alterations and subsequent impaired liver blood flow and hepatic hypoxia in the pathophysiology of non-alcoholic steatohepatitis. Med Hypotheses 2018; 122:188-197. [PMID: 30593409 DOI: 10.1016/j.mehy.2018.11.014] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 11/21/2018] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disease ranging from steatosis to steatohepatitis (NASH) and fibrosis, but the underlying pathophysiological mechanisms remain largely unknown. As there is currently no approved pharmacological therapy and the prevalence of NAFLD keeps increasing, understanding of its pathophysiology is crucial. We hypothesise that vascular alterations in early NAFLD play a role in the progression of the disease by inducing an increased intrahepatic vascular resistance and consequently relative hypoxia in the liver. Evidence of the detrimental effects of hypoxia in NAFLD has already been observed in liver surgery, where the outcomes of steatotic livers after ischaemia-reperfusion are worse than in healthy livers, and in obstructive sleep apnoea, which is an independent risk factor of NAFLD. Moreover, early histological damage in NAFLD is situated in the pericentral zone, which is also the first zone to be affected by a decreased oxygen tension because of the unique hepatic vacsular anatomy that causes the pericentral oxygen tension to be the lowest. Angiogenesis is also a characteristic of NAFLD, driven by hypoxia-induced mechanisms, as demonstrated in both animal models and in humans with NAFLD. Relative hypoxia is most probably induced by impaired blood flow to the liver, caused by increased intrahepatic vascular resistance. An increased intrahepatic vascular resistance early in the development of disease has been convincingly demonstrated in several animal models of NAFLD, whereas an increased portal pressure, a consequence of increased intrahepatic vascular resistance, has been proven in patients with NAFLD. Animal studies demonstrated a decreased intrahepatic effect of vasodilators and an increased reactivity to vasoconstrictors that results in an increased intrahepatic vascular resistance, thus the presence of a functional component. Pharmacological products that target vasoregulation can hence improve the intrahepatic vascular resistance and this might prevent or reverse progression of NAFLD, representing an important therapeutic option to study. Some of the drugs currently under evaluation in clinical trials for NASH have interesting properties related to the hepatic vasculature. Some other interesting drugs have been tested in animal models but further study in patients with NAFLD is warranted. In summary, in this paper we summarise the evidence that leads to the hypothesis that an increased intrahepatic vascular resistance and subsequent parenchymal hypoxia in early NAFLD is an important pathophysiological driving mechanism for the progression of the disease.
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Telmisartan prevents diet-induced obesity and preserves leptin transport across the blood-brain barrier in high-fat diet-fed mice. Pflugers Arch 2018; 470:1673-1689. [PMID: 29978352 DOI: 10.1007/s00424-018-2178-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 06/20/2018] [Accepted: 06/27/2018] [Indexed: 12/14/2022]
Abstract
Obesity is a global health problem and treatment options are still insufficient. When chronically treated with the angiotensin II receptor blocker telmisartan (TEL), rodents do not develop diet-induced obesity (DIO). However, the underlying mechanism for this is still unclear. Here we investigated whether TEL prevents leptin resistance by enhancing leptin uptake across the blood-brain barrier (BBB). To address this question, we fed C57BL/6 mice a high-fat diet (HFD) and treated them daily with TEL by oral gavage. In addition to broadly characterizing the metabolism of leptin, we determined leptin uptake into the brain by measuring BBB transport of radioactively labeled leptin after long-term and short-term TEL treatment. Additionally, we assessed BBB integrity in response to angiotensin II in vitro and in vivo. We found that HFD markedly increased body weight, energy intake, and leptin concentration but that this effect was abolished under TEL treatment. Furthermore, glucose control and, most importantly, leptin uptake across the BBB were impaired in mice on HFD, but, again, both were preserved under TEL treatment. BBB integrity was not impaired due to angiotensin II or blocking of angiotensin II receptors. However, TEL did not exhibit an acute effect on leptin uptake across the BBB. Our results confirm that TEL prevents DIO and show that TEL preserves leptin transport and thereby prevents leptin resistance. We conclude that the preservation of leptin sensitivity is, however, more a consequence than the cause of TEL preventing body weight gain.
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Grasselli E, Canesi L, Portincasa P, Voci A, Vergani L, Demori I. Models of non-Alcoholic Fatty Liver Disease and Potential Translational Value: the Effects of 3,5-L-diiodothyronine. Ann Hepatol 2018; 16:707-719. [PMID: 28809727 DOI: 10.5604/01.3001.0010.2713] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in industrialized countries and is associated with increased risk of cardiovascular, hepatic and metabolic diseases. Molecular mechanisms on the root of the disrupted lipid homeostasis in NAFLD and potential therapeutic strategies can benefit of in vivo and in vitro experimental models of fatty liver. Here, we describe the high fat diet (HFD)-fed rat in vivo model, and two in vitro models, the primary cultured rat fatty hepatocytes or the FaO rat hepatoma fatty cells, mimicking human NAFLD. Liver steatosis was invariably associated with increased number/size of lipid droplets (LDs) and modulation of expression of genes coding for key genes of lipid metabolism such as peroxisome proliferator-activated receptors (Ppars) and perilipins (Plins). In these models, we tested the anti-steatotic effects of 3,5-L-diiodothyronine (T2), a metabolite of thyroid hormones. T2 markedly reduced triglyceride content and LD size acting on mRNA expression of both Ppars and Plins. T2 also stimulated mitochondrial oxidative metabolism of fatty acids. We conclude that in vivo and especially in vitro models of NAFLD are valuable tools to screen a large number of compounds counteracting the deleterious effect of liver steatosis. Because of the high and negative impact of liver steatosis on human health, ongoing experimental studies from our group are unravelling the ultimate translational value of such cellular models of NAFLD.
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Affiliation(s)
- Elena Grasselli
- University of Genoa, Genoa, Italy Department of Earth, Environmental and Life Sciences-DISTAV
| | - Laura Canesi
- University of Genoa, Genoa, Italy Department of Earth, Environmental and Life Sciences-DISTAV
| | - Piero Portincasa
- University of Bari Medical School, Bari, Italy Department of Biomedical Sciences and Human Oncology Clinica Medica "A. Murri"
| | - Adriana Voci
- University of Genoa, Genoa, Italy Department of Earth, Environmental and Life Sciences-DISTAV
| | - Laura Vergani
- University of Genoa, Genoa, Italy Department of Earth, Environmental and Life Sciences-DISTAV
| | - Ilaria Demori
- University of Genoa, Genoa, Italy Department of Earth, Environmental and Life Sciences-DISTAV
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Bulatova N, Kasabri V, Qotineh A, Al-Athami T, Yousef AM, AbuRuz S, Momani M, Zayed A. Effect of metformin combined with lifestyle modification versus lifestyle modification alone on proinflammatory-oxidative status in drug-naïve pre-diabetic and diabetic patients: A randomized controlled study. Diabetes Metab Syndr 2018; 12:257-267. [PMID: 29221717 DOI: 10.1016/j.dsx.2017.11.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 11/22/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND Targeting biomarkers of oxidative-proinflammatory stress may result in improvement of modifiable metabolic syndrome, pre-diabetes and diabetes risk factors and subsequent risk reduction. METHODS 64 newly diagnosed antihyperglycemic treatment-naïve prediabetic and type 2 diabetes mellitus (T2DM) patients were randomly assigned using block design to either metformin combined with therapeutic lifestyle changes (TLC) or TLC alone. Body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), fasting lipid profile, plasma oxidative status and tumor necrosis factor (TNF)-α were measured at baseline, after 3 months and after 6 months from baseline. RESULTS Except for HbA1c, baseline values did not differ significantly between the two groups. The post 3-months relative reductions in BMI (P=0.014) and HbA1c (P=0.037) in metformin combined with TLC intervention were significantly greater than those in TLC alone group. TNFα plasma levels were decreased significantly vs. baseline by metformin combined with TLC intervention (-22.90±46.76%, P=0.01). Conversely, TLC alone basically worsened proinflammatory status (42.40±40.82 %), P<0.001. Metformin with TLC treatment effected a therapeutic decrement of the oxidative stress (-15.44±35.32%, P=0.029 vs. baseline) unlike TLC alone (61.49±122.66%, P=0.01 vs. baseline). Both interventions' effects were sustained in the 6-month follow up periods. CONCLUSION In both intervention groups, the relative changes in plasma TNFα were significantly correlated (P<0.01) with systolic blood pressure and the relative changes in oxidative stress were markedly correlated (P<0.05) with total cholesterol.
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Affiliation(s)
- Nailya Bulatova
- School of Pharmacy, The University of Jordan, Queen Rania Street, Amman 11942, Jordan
| | - Violet Kasabri
- School of Pharmacy, The University of Jordan, Queen Rania Street, Amman 11942, Jordan.
| | - Amenah Qotineh
- School of Pharmacy, The University of Jordan, Queen Rania Street, Amman 11942, Jordan
| | - Taiba Al-Athami
- School of Pharmacy, The University of Jordan, Queen Rania Street, Amman 11942, Jordan
| | - Al-Motassem Yousef
- School of Pharmacy, The University of Jordan, Queen Rania Street, Amman 11942, Jordan
| | - Salah AbuRuz
- School of Pharmacy, The University of Jordan, Queen Rania Street, Amman 11942, Jordan; College of Pharmacy, Al Ain University of Science and Technology, AL Ain, Abu Dhabi, United Arab Emirates
| | - Munther Momani
- School of Medicine, The University of Jordan, Queen Rania Street, Amman 11942, Jordan
| | - Aymen Zayed
- School of Medicine, The University of Jordan, Queen Rania Street, Amman 11942, Jordan
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Borém LMA, Neto JFR, Brandi IV, Lelis DF, Santos SHS. The role of the angiotensin II type I receptor blocker telmisartan in the treatment of non-alcoholic fatty liver disease: a brief review. Hypertens Res 2018; 41:394-405. [PMID: 29636553 PMCID: PMC7091617 DOI: 10.1038/s41440-018-0040-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 10/31/2017] [Accepted: 11/17/2017] [Indexed: 01/18/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently considered an important component of metabolic syndrome (MetS). The spectrum of NAFLD includes conditions that range from simple hepatic steatosis to non-alcoholic steatohepatitis. NAFLD is correlated with liver-related death and is predicted to be the most frequent indication for liver transplantation by 2030. Insulin resistance is directly correlated to the central mechanisms of hepatic steatosis in NAFLD patients, which is strongly correlated to the imbalance of the renin–angiotensin system, that is involved in lipid and glucose metabolism. Among the emerging treatment approaches for NAFLD is the anti-hypertensive agent telmisartan, which has positive effects on liver, lipid, and glucose metabolism, especially through its action on the renin–angiotensin system, by blocking the ACE/AngII/AT1 axis and increasing ACE2/Ang(1–7)/Mas axis activation. However, treatment with this drug is only recommended for patients with an established indication for anti-hypertensive therapy. Thus, there is an increased need for large randomized controlled trials with the aim of elucidating the effects of telmisartan on liver disease, especially NAFLD. From this perspective, the present review aims to provide a brief examination of the pathogenesis of NAFLD/NASH and the role of telmisartan on preventing liver disorders and thus to improve the discussion on potential therapies.
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Affiliation(s)
- Luciana M A Borém
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brazil.,Medicine Department, Faculdades Integradas Pitágoras, Montes Claros, Minas Gerais, Brazil
| | - João F R Neto
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brazil
| | - Igor V Brandi
- Institute of Agricultural Sciences, Food Engineering College, Universidade Federal de Minas Gerais (UFMG), Montes Claros, Minas Gerais, Brazil
| | - Deborah F Lelis
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brazil
| | - Sergio H S Santos
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brazil. .,Institute of Agricultural Sciences, Food Engineering College, Universidade Federal de Minas Gerais (UFMG), Montes Claros, Minas Gerais, Brazil.
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41
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Qing Z, Xiao-Hui W, Xi-Mei W, Chao-Chun Z. Vitamin C deficiency aggravates tumor necrosis factor α-induced insulin resistance. Eur J Pharmacol 2018; 829:1-11. [PMID: 29625084 DOI: 10.1016/j.ejphar.2018.03.044] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 03/26/2018] [Accepted: 03/29/2018] [Indexed: 02/06/2023]
Abstract
Chronic low-grade inflammation plays a major role in the development of insulin resistance. The potential role and underlying mechanism of vitamin C, an antioxidant and anti-inflammatory agent, was investigated in tumor necrosis factor-α (TNF-α)-induced insulin resistance. Gulonolactone oxidase knockout (Gulo-/-) mice genetically unable to synthesize vitamin C were used to induce insulin resistance by continuously pumping small doses of TNF-α for seven days, and human liver hepatocellular carcinoma cells (HepG2 cells) were used to induce insulin resistance by treatment with TNF-α. Vitamin C deficiency aggravated TNF-α-induced insulin resistance in Gulo-/- mice, resulting in worse glucose tolerance test (GTT) results, higher fasting plasma insulin level, and the inactivation of the protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β) pathway in the liver. Vitamin C deficiency also worsened liver lipid accumulation and inflammation in TNF-α-treated Gulo-/- mice. In HepG2 cells, vitamin C reversed the TNF-α-induced reduction of glucose uptake and glycogen synthesis, which were mediated by increasing GLUT2 levels and the activation of the insulin receptor substrate (IRS-1)/AKT/GSK3β pathway. Furthermore, vitamin C inhibited the TNF-α-induced activation of not only the mitogen-activated protein kinase (MAPKs), but also nuclear factor-kappa B (NF-κB) signaling. Taken together, vitamin C is essential for preventing and improving insulin resistance, and the supplementing with vitamin C may be an effective therapeutic intervention for metabolic disorders.
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Affiliation(s)
- Zhou Qing
- Department of Endocrinology of the affiliated Children's Hospital, Zhejiang University School of Medicine, China
| | - Wu Xiao-Hui
- Department of Endocrinology of the affiliated Children's Hospital, Zhejiang University School of Medicine, China
| | - Wu Xi-Mei
- Department of Pharmacology, Zhejiang University School of Medicine, China
| | - Zou Chao-Chun
- Department of Endocrinology of the affiliated Children's Hospital, Zhejiang University School of Medicine, China.
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Short-term treatment with metformin reduces hepatic lipid accumulation but induces liver inflammation in obese mice. Inflammopharmacology 2018; 26:1103-1115. [PMID: 29450671 DOI: 10.1007/s10787-018-0443-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 01/12/2018] [Indexed: 12/11/2022]
Abstract
The study aimed to evaluate the metabolic and inflammatory effects of short-term treatments (10 days) with metformin (MET) on the NAFLD caused by a high-fat diet (HFD) in C57BL/6 mice. After the treatment, histological liver slices were obtained, hepatocytes and macrophages were extracted and cultured with phosphate buffered saline, LPS (2.5 µg/mL) and MET (1 µM) for 24 h. Cytokine levels were determined by ELISA. NAFLD caused by the HFD was partially reduced by MET. The lipid accumulation induced by the HFD was not associated with liver inflammation; however, MET seemed to promote pro-inflammatory effects in liver, since it increased hepatic concentration of IL-1β, TNF-α, IL-6, MCP-1 and IFN-γ. Similarly, MET increased the concentration of IL-1β, IL-6 in hepatocyte cultures. However, in macrophages culture, MET lowered levels of IL-1β, IL-6 and TNF-α stimulated by LPS. Overall, MET reduced liver NAFLD but promoted hepatocyte increase in pro-inflammatory cytokines, thus, leading to liver inflammation.
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Metformin potentiates cognitive and antidepressant effects of fluoxetine in rats exposed to chronic restraint stress and high fat diet: potential involvement of hippocampal c-Jun repression. Naunyn Schmiedebergs Arch Pharmacol 2018; 391:407-422. [PMID: 29379991 DOI: 10.1007/s00210-018-1466-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Accepted: 01/09/2018] [Indexed: 12/15/2022]
Abstract
Several hypotheses link high fat diet (HFD) with the pathophysiology of depression and its response to antidepressants. This study aimed to determine the effect of metformin (MET) on the cognitive and antidepressant activity of fluoxetine (FLU) through its effect on c-Jun expression. Behavioral, cognitive function, biochemical, and histopathological studies were performed in non-HFD- and HFD-fed rats exposed to chronic restraint stress (CRS). Stressed group showed cognitive impairment, depressive-like symptoms, disturbed glucose homeostasis and lipid profile, reduced adiponectin level, brain-derived neurotrophic factor (BDNF) expression, and increased corticosterone and c-Jun. All these were aggravated by HFD. MET, FLU and their combination produced significant improvement in lipid profile with significant increase in adiponectin and BDNF expression. Corticosterone, body weight and insulin resistance showed significant decrease in the treated groups. Moreover, there was a significant decrease in hippocampal c Jun expression. There was a significant preferable effect toward the combination. Conclusion, MET may decrease the refractoriness to FLU and improves the cognition in individuals who are fed on HFD.
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Differential actions of PPAR-α and PPAR-β/δ on beige adipocyte formation: A study in the subcutaneous white adipose tissue of obese male mice. PLoS One 2018; 13:e0191365. [PMID: 29351550 PMCID: PMC5774787 DOI: 10.1371/journal.pone.0191365] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 01/03/2018] [Indexed: 12/18/2022] Open
Abstract
Background and aims Obesity compromises adipocyte physiology. PPARs are essential to adipocyte plasticity, but its isolated role in the browning phenomenon is not clear. This study aimed to examine whether activation of PPAR-α or PPAR-β/δ could induce beige cell depots in the subcutaneous white adipose tissue of diet-induced obese mice. Material and methods Sixty animals were randomly assigned to receive a control diet (C, 10% lipids) or a high-fat diet (HF, 50% lipids) for ten weeks. Then each group was re-divided to begin the treatments that lasted 4 weeks, totalizing six groups: C, C-α (C plus PPAR-α agonist, 2.5 mg/kg BM), C-β (C plus PPAR-β/δ agonist, 1 mg/kg BM), HF, HF-α (HF plus PPAR-α agonist), HF-β (HF plus PPAR-β/δ agonist). Results HF animals presented with overweight, glucose intolerance and subcutaneous white adipocyte hypertrophy. Both treatments significantly attenuated these parameters. Browning, verified by UCP1 positive beige cells and enhanced body temperature, was just observed in PPAR-α treated groups. PPAR-α agonism also elicited an enhanced gene expression of the thermogenesis effector UCP1, the beige-selective gene TMEM26 and the PRDM16, an essential gene for brown-like phenotype maintenance in the beige adipocytes when compared to their counterparts. The enhanced CIDEA and the reduced UCP1 gene levels might justify the white phenotype predominance after the treatment with the PPAR-β/δ agonist. Conclusions This work provides evidence that the PPAR-β/δ agonist ameliorated metabolic disorders through enhanced beta-oxidation and better tolerance to glucose, whereas the PPAR-α agonism was confirmed as a promising therapeutic target for treating metabolic diseases via beige cell induction and enhanced thermogenesis.
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β-ecdysterone from Cyanotis arachnoidea exerts hypoglycemic effects through activating IRS-1/Akt/GLUT4 and IRS-1/Akt/GLUT2 signal pathways in KK-Ay mice. J Funct Foods 2017. [DOI: 10.1016/j.jff.2017.09.061] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
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Drygalski K, Berk K, Charytoniuk T, Iłowska N, Łukaszuk B, Chabowski A, Konstantynowicz-Nowicka K. Does the enterolactone (ENL) affect fatty acid transporters and lipid metabolism in liver? Nutr Metab (Lond) 2017; 14:69. [PMID: 29158770 PMCID: PMC5683590 DOI: 10.1186/s12986-017-0223-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Accepted: 10/23/2017] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND NAFLD as a result of inappropriate diet and obesity, may progress to sever conditions such as: type 2 diabetes mellitus or steatohepatitis, and has recently become a prevalent topic of numerous investigations. Due to its dangerous aftermaths, finding new substances, such as polyphenols and their derivatives, which might reduce liver steatosis is the main target of research into NAFLD treatment. Hence, the aim of the present study was to evaluate the effect(s) of enterolactone (ENL), a metabolite of secoisolariciresinol (SECO), on lipid metabolism together with changes in the expression of fatty acid transporters in fatty liver. METHODS The experiments were conducted on HepG2 cells incubated with either ENL and/or palmitic acid during 16 h exposure. The expression of selected fatty acid transport proteins: FATP2, FATP5, CD36, FABPpm, ABCA1, MTP, ACBP and L-FABP, as well as the proteins directly involved in lipogenesis (FAS), oxidation pathway (CPT 1), and lipid metabolism (PPARα, LXR, SREBP1c, pAMPK) was estimated by Western Blot. Intra and extracellular lipid contents were assessed by Gas-Liquid Chromatography. The data was analyzed with two-way analysis of variance (ANOVA), and results were considered to be statistically significant at p ≤ 0.05. RESULTS ENL stimulated extracellular efflux of free fatty acids (FFA) and triacylglicerols (TAG) to the medium, while, it had no influence on FATP-family mediated intracellular fatty acid uptake. Moreover, ENL decreased the expression of CPT 1, pAMPK, PPARα, increased SREBP1c and had no effect on LXR, and FAS content. CONCLUSIONS The findings of our study demonstrate that ENL had opposite effect on liver steatosis in comparison with other polyphenols what suggests that it may be an inactive metabolite. ENL did not affect significantly the intracellular accumulation of FFA, DAG and TAG, yet it promoted their extracellular efflux. Furthermore, it inhibited ß-oxydation and intracellular lipid metabolism what may contribute to the progression of NAFLD.
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Affiliation(s)
- Krzysztof Drygalski
- Department of Physiology, Medical University of Bialystok, Białystok, Poland
| | - Klaudia Berk
- Department of Physiology, Medical University of Bialystok, Białystok, Poland
| | - Tomasz Charytoniuk
- Department of Physiology, Medical University of Bialystok, Białystok, Poland
| | - Nicoletta Iłowska
- Department of Physiology, Medical University of Bialystok, Białystok, Poland
| | - Bartłomiej Łukaszuk
- Department of Physiology, Medical University of Bialystok, Białystok, Poland
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, Białystok, Poland
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Bornstein S, Moschetta M, Kawano Y, Sacco A, Huynh D, Brooks D, Manier S, Fairfield H, Falank C, Roccaro AM, Nagano K, Baron R, Bouxein M, Vary C, Ghobrial IM, Rosen CJ, Reagan MR. Metformin Affects Cortical Bone Mass and Marrow Adiposity in Diet-Induced Obesity in Male Mice. Endocrinology 2017; 158:3369-3385. [PMID: 28977604 PMCID: PMC5659683 DOI: 10.1210/en.2017-00299] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 07/21/2017] [Indexed: 01/15/2023]
Abstract
Obesity during maturation can affect the growing skeleton directly and indirectly, although these effects and the mechanisms behind them are not fully understood. Our objective was to determine how a high-fat diet with or without metformin treatment affects skeletal development. We also sought to characterize changes that occur in white adipose tissue, circulating metabolites, lipids, and gut microbiota. A diet-induced obesity C57BL/6J mouse model was used to test the effects of obesity and metformin on bone using bone histomorphometry and microcomputed tomography. Bone marrow adipose tissue was quantified with osmium tetroxide microcomputed tomography and histology. Dual-energy x-ray absorptiometry was used to analyze body composition. Hematoxylin and eosin staining was used to assess changes in white adipose depots, mass spectrometry was used for circulating lipids and protein metabolite analysis, and ribosomal RNA sequencing was used for gut microbiome analysis. Mice fed a high fat-diet since wean displayed increased medullary areas and decreased osteoblast numbers in the long bones; this phenotype was partially normalized by metformin. Marrow and inguinal adipose expansion was also noted in obese mice, and this was partially normalized by metformin. A drug-by-diet interaction was noted for circulating lipid molecules, protein metabolites, and gut microbiome taxonomical units. Obesity was not detrimental to trabecular bone in growing mice, but bone marrow medullary expansion was observed, likely resulting from inhibition of osteoblastogenesis, and this was partially reversed by metformin treatment.
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Affiliation(s)
- Sheila Bornstein
- Maine Medical Center Research Institute, Scarborough, Maine 04074
| | | | - Yawara Kawano
- Dana-Farber Cancer Institute, Boston, Massachusetts 02115
| | - Antonio Sacco
- Dana-Farber Cancer Institute, Boston, Massachusetts 02115
- Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Progettazione Ricerca Clinica e Studi di Fase I, Laboratorio Centro Ricerca oncoEmatologica AIL, Brescia, BS, Italy
| | - Daisy Huynh
- Dana-Farber Cancer Institute, Boston, Massachusetts 02115
| | - Daniel Brooks
- Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115
- Center for Skeletal Research, Massachusetts General Hospital, Boston, Massachusetts 02114
| | - Salomon Manier
- Dana-Farber Cancer Institute, Boston, Massachusetts 02115
| | - Heather Fairfield
- Maine Medical Center Research Institute, Scarborough, Maine 04074
- University of Maine Graduate School of Biomedical Science and Engineering, Orono, Maine 04469
- Tufts University School of Medicine, Boston, Massachusetts 02111
| | - Carolyne Falank
- Maine Medical Center Research Institute, Scarborough, Maine 04074
- University of Maine Graduate School of Biomedical Science and Engineering, Orono, Maine 04469
- Tufts University School of Medicine, Boston, Massachusetts 02111
| | - Aldo M. Roccaro
- Dana-Farber Cancer Institute, Boston, Massachusetts 02115
- Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Progettazione Ricerca Clinica e Studi di Fase I, Laboratorio Centro Ricerca oncoEmatologica AIL, Brescia, BS, Italy
| | - Kenichi Nagano
- Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Harvard Medical School, Boston, Massachusetts 02115
| | - Roland Baron
- Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Harvard Medical School, Boston, Massachusetts 02115
| | - Mary Bouxein
- Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115
- Center for Skeletal Research, Massachusetts General Hospital, Boston, Massachusetts 02114
| | - Calvin Vary
- Maine Medical Center Research Institute, Scarborough, Maine 04074
- University of Maine Graduate School of Biomedical Science and Engineering, Orono, Maine 04469
- Tufts University School of Medicine, Boston, Massachusetts 02111
| | | | - Clifford J. Rosen
- Maine Medical Center Research Institute, Scarborough, Maine 04074
- University of Maine Graduate School of Biomedical Science and Engineering, Orono, Maine 04469
- Tufts University School of Medicine, Boston, Massachusetts 02111
| | - Michaela R. Reagan
- Maine Medical Center Research Institute, Scarborough, Maine 04074
- Dana-Farber Cancer Institute, Boston, Massachusetts 02115
- University of Maine Graduate School of Biomedical Science and Engineering, Orono, Maine 04469
- Tufts University School of Medicine, Boston, Massachusetts 02111
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Veiga FMS, Graus-Nunes F, Rachid TL, Barreto AB, Mandarim-de-Lacerda CA, Souza-Mello V. Anti-obesogenic effects of WY14643 (PPAR -alpha agonist): Hepatic mitochondrial enhancement and suppressed lipogenic pathway in diet-induced obese mice. Biochimie 2017; 140:106-116. [DOI: 10.1016/j.biochi.2017.07.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 07/10/2017] [Indexed: 02/07/2023]
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Marinho TDS, Kawasaki A, Bryntesson M, Souza-Mello V, Barbosa-da-Silva S, Aguila MB, Mandarim-de-Lacerda CA. Rosuvastatin limits the activation of hepatic stellate cells in diet-induced obese mice. Hepatol Res 2017; 47:928-940. [PMID: 27653239 DOI: 10.1111/hepr.12821] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 09/07/2016] [Accepted: 09/19/2016] [Indexed: 12/14/2022]
Abstract
AIM The aim of this study was to investigate the effects of rosuvastatin in a model of diet-induced obesity and non-alcoholic fatty liver disease, with attention to the activation of hepatic stellate cells (HSCs). METHOD Male C57BL/6 mice received a control diet (C; 10% energy as lipids) or a high-fat diet (HF; 50% energy as lipids) for 12 weeks, followed by 7 weeks of treatment. Group CR received control diet + rosuvastatin; group HFR received high-fat diet + rosuvastatin. RESULTS The HF group showed higher insulin, total cholesterol, triacylglycerol, and leptin levels than the C group, all of which were significantly diminished by rosuvastatin in the HFR group. The HF group had greater steatosis and activated HSCs than the C group, whereas rosuvastatin diminished the steatosis (less 21%, P < 0.001) and significantly inhibited the activation of the HSCs in the HFR group compared to the HF group. The sterol regulatory element-binding protein-1 and the peroxisome proliferator-activated receptor (PPAR)-γ protein expressions were increased in HF animals and reduced after treatment in the HFR group. By contrast, low PPAR-α and carnitine palmitoyltransferase-1 expressions were found in the HF group, and were restored by rosuvastatin treatment in the HFR group. CONCLUSION Rosuvastatin mitigated hepatic steatosis by modulating PPAR balance, favoring PPAR-α over PPAR-γ downstream effects. The effects were accompanied by a diminishing of insulin resistance, the anti-inflammatory adipokine profile, and HSC activation, avoiding non-alcoholic fatty liver disease progression and non-alcoholic steatohepatitis onset in this model.
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Affiliation(s)
- Thatiany de Souza Marinho
- Laboratory of Morphometry, Metabolism, and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Adriana Kawasaki
- Laboratory of Morphometry, Metabolism, and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Vanessa Souza-Mello
- Laboratory of Morphometry, Metabolism, and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Sandra Barbosa-da-Silva
- Laboratory of Morphometry, Metabolism, and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcia B Aguila
- Laboratory of Morphometry, Metabolism, and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Carlos A Mandarim-de-Lacerda
- Laboratory of Morphometry, Metabolism, and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
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Caputo T, Gilardi F, Desvergne B. From chronic overnutrition to metaflammation and insulin resistance: adipose tissue and liver contributions. FEBS Lett 2017; 591:3061-3088. [DOI: 10.1002/1873-3468.12742] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 06/28/2017] [Accepted: 07/02/2017] [Indexed: 12/16/2022]
Affiliation(s)
- Tiziana Caputo
- Center for Integrative Genomics; Lausanne Faculty of Biology and Medicine; University of Lausanne; Switzerland
| | - Federica Gilardi
- Center for Integrative Genomics; Lausanne Faculty of Biology and Medicine; University of Lausanne; Switzerland
| | - Béatrice Desvergne
- Center for Integrative Genomics; Lausanne Faculty of Biology and Medicine; University of Lausanne; Switzerland
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