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Modder M, Tomas A, Afkir S, Pronk ACM, Streefland TCM, Lalai RA, van Eenige R, Rensen PCN, Jones B, Kooijman S. Oppositely biased glucagon-like peptide-1 receptor agonism does not differentially affect lipid metabolism in APOE*3-Leiden CETP mice. Diabetes Obes Metab 2025; 27:3477-3489. [PMID: 40176480 PMCID: PMC12046449 DOI: 10.1111/dom.16374] [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: 01/16/2025] [Revised: 03/21/2025] [Accepted: 03/21/2025] [Indexed: 04/04/2025]
Abstract
AIMS [D3,G40,K41.C16 diacid]exendin-4 (acyl-ExD3) and [F1,G40,K41.C16 diacid]exendin-4 (acyl-ExF1) are oppositely biased glucagon-like peptide-1 (GLP-1) receptor agonists that preferentially promote β-arrestin recruitment or G protein-induced signalling, respectively. The latter is more favourable in glycaemic control and induces a steeper reduction in body weight in diet-induced obese mice. Here, we compared the effects of G protein-biased agonist acyl-ExF1 to those of β-arrestin-biased agonist acyl-ExD3 on lipid metabolism in hyperlipidaemic mice. MATERIALS AND METHODS APOE*3-Leiden.CETP mice were treated with saline, acyl-ExD3 or acyl-ExF1 via intraperitoneal injections for 6 weeks or intracerebroventricular infusion for 18 days. Body weight and composition were monitored at regular intervals, as were plasma glucose, triglyceride and cholesterol levels. At endpoint, mice were injected with very low-density lipoprotein (VLDL)-like particles containing glycerol tri[3H]oleate to study triglyceride-derived fatty acid uptake by peripheral tissues including brown and white adipose tissue (BAT and WAT). RESULTS Upon peripheral treatment, body weight gain was prevented and plasma glucose levels were reduced by acyl-ExF1, but circulating lipids were not affected by either acyl-ExF1 or acyl-ExD3. In contrast, central administration of either agonist strongly reduced plasma triglyceride and cholesterol levels, but did not affect glucose levels. Acyl-ExD3 and acyl-ExF1 increased [3H]oleate uptake by adipose tissue, reaching statistical significance for the uptake by BAT and WAT, respectively, compared to vehicle treatment. CONCLUSION The oppositely biased GLP-1 receptor agonists acyl-ExD3 and acyl-ExF1 do not differentially affect lipid metabolism in APOE*3-Leiden.CETP mice, while effects on glucose homeostasis and prevention of body weight gain are more pronounced upon peripheral acyl-ExF1 treatment.
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Affiliation(s)
- Melanie Modder
- Division of Endocrinology, Department of MedicineLeiden University Medical CenterLeidenThe Netherlands
- Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Alejandra Tomas
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and ReproductionImperial College LondonLondonUK
| | - Salwa Afkir
- Division of Endocrinology, Department of MedicineLeiden University Medical CenterLeidenThe Netherlands
- Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Amanda C. M. Pronk
- Division of Endocrinology, Department of MedicineLeiden University Medical CenterLeidenThe Netherlands
- Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Trea C. M. Streefland
- Division of Endocrinology, Department of MedicineLeiden University Medical CenterLeidenThe Netherlands
- Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Reshma A. Lalai
- Division of Endocrinology, Department of MedicineLeiden University Medical CenterLeidenThe Netherlands
- Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Robin van Eenige
- Division of Endocrinology, Department of MedicineLeiden University Medical CenterLeidenThe Netherlands
- Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Patrick C. N. Rensen
- Division of Endocrinology, Department of MedicineLeiden University Medical CenterLeidenThe Netherlands
- Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Ben Jones
- Section of Endocrinology and Investigative Medicine, Department of Metabolism, Digestion and ReproductionImperial College LondonLondonUK
| | - Sander Kooijman
- Division of Endocrinology, Department of MedicineLeiden University Medical CenterLeidenThe Netherlands
- Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
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Zafer M, Tavaglione F, Romero-Gómez M, Loomba R. Review Article: GLP-1 Receptor Agonists and Glucagon/GIP/GLP-1 Receptor Dual or Triple Agonists-Mechanism of Action and Emerging Therapeutic Landscape in MASLD. Aliment Pharmacol Ther 2025; 61:1872-1888. [PMID: 40364529 DOI: 10.1111/apt.70196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 04/14/2025] [Accepted: 05/03/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily managed through diet and lifestyle modifications. However, these behavioural interventions alone may not achieve disease regression or remission, and maintaining long-term adherence is challenging. Incretin mimetics and other gastrointestinal hormones targeting the pleiotropic pathophysiological pathways underlying MASLD have now emerged as promising disease-modifying therapies. AIMS This is a comprehensive review summarising the role of glucagon-like peptide-1 (GLP-1) receptor agonists and glucagon/glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor dual or triple agonists in the treatment of metabolic dysfunction-associated steatohepatitis (MASH). METHODS Only clinical trials with endpoints assessed by liver histology were included for a robust evaluation of therapeutic efficacy. RESULTS Recent evidence from phase 2 clinical trials for MASH demonstrated that pharmacological agents based on GLP-1 receptor agonism are effective in improving disease activity. Additionally, tirzepatide and survodutide showed potential clinical benefits in reducing fibrosis. Other cardiometabolic benefits observed include weight loss and improvements in glycaemic control and lipid profile. Adherence to treatment may be limited by gastrointestinal side effects, though they were found to be generally mild to moderate in severity. An interim analysis of the semaglutide phase 3 trial confirmed its efficacy in improving steatohepatitis and demonstrated its potential to improve fibrosis. CONCLUSIONS GLP-1 receptor agonists, alone or in combination with GIP and/or glucagon receptor agonists, represent promising, effective pharmacotherapies for the treatment of MASLD/MASH. Larger and longer-duration clinical trials are needed to further evaluate the efficacy and safety of GIP receptor and glucagon receptor agonism.
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Affiliation(s)
- Maryam Zafer
- MASLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, La Jolla, California, USA
| | - Federica Tavaglione
- MASLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, La Jolla, California, USA
| | - Manuel Romero-Gómez
- UCM Digestive Diseases and Ciberehd, Virgen Del Rocío University Hospital, Institute of Biomedicine of Seville (CSIC/HUVR/US), University of Seville, Seville, Spain
| | - Rohit Loomba
- MASLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, La Jolla, California, USA
- School of Public Health, University of California at San Diego, La Jolla, California, USA
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Rroji M, Spahia N, Figurek A, Spasovski G. Targeting Diabetic Atherosclerosis: The Role of GLP-1 Receptor Agonists, SGLT2 Inhibitors, and Nonsteroidal Mineralocorticoid Receptor Antagonists in Vascular Protection and Disease Modulation. Biomedicines 2025; 13:728. [PMID: 40149704 PMCID: PMC11940462 DOI: 10.3390/biomedicines13030728] [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: 02/09/2025] [Revised: 03/03/2025] [Accepted: 03/12/2025] [Indexed: 03/29/2025] Open
Abstract
Atherosclerosis is a closely related complication of diabetes mellitus (DM), driven by endothelial dysfunction, inflammation, and oxidative stress. The progression of atherosclerosis is accelerated by hyperglycemia, insulin resistance, and hyperlipidemia. Novel antidiabetic agents, SGLT2 inhibitors, and GLP-1 agonists improve glycemic control and offer cardiovascular protection, reducing the risk of major adverse cardiovascular events (MACEs) and heart failure hospitalization. These agents, along with nonsteroidal mineralocorticoid receptor antagonists (nsMRAs), promise to mitigate metabolic disorders and their impact on endothelial function, oxidative stress, and inflammation. This review explores the potential molecular mechanisms through which these drugs may prevent the development of atherosclerosis and cardiovascular disease (CVD), supported by a summary of preclinical and clinical evidence.
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Affiliation(s)
- Merita Rroji
- Department of Nephrology, University of Medicine Tirana, 1001 Tirana, Albania
- Department of Nephrology, University Hospital Center Mother Tereza, 1001 Tirana, Albania;
| | - Nereida Spahia
- Department of Nephrology, University Hospital Center Mother Tereza, 1001 Tirana, Albania;
| | - Andreja Figurek
- Institute of Anatomy, University of Zurich, 8057 Zurich, Switzerland;
| | - Goce Spasovski
- Department of Nephrology, University Sts. Cyril and Methodius, 1000 Skopje, North Macedonia;
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Do A, Zahrawi F, Mehal WZ. Therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH). Nat Rev Drug Discov 2025; 24:171-189. [PMID: 39609545 DOI: 10.1038/s41573-024-01084-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2024] [Indexed: 11/30/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe subgroup metabolic dysfunction-associated steatohepatitis (MASH) have become a global epidemic and are driven by chronic overnutrition and multiple genetic susceptibility factors. The physiological outcomes include hepatocyte death, liver inflammation and cirrhosis. The first therapeutic for MASLD and MASH, resmetirom, has recently been approved for clinical use and has energized this therapeutic space. However, there is still much to learn in clinical studies of MASH, such as the scale of placebo responses, optimal trial end points, the time required for fibrosis reversal and side effect profiles. This Review introduces aspects of disease pathogenesis related to drug development and discusses two main therapeutic approaches. Thyroid hormone receptor-β agonists, such as resmetirom, as well as fatty acid synthase inhibitors, target the liver and enable it to function within a toxic metabolic environment. In parallel, incretin analogues such as semaglutide improve metabolism, allowing the liver to self-regulate and reversing many aspects of MASH. We also discuss how combinations of therapeutics could potentially be used to treat patients.
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Affiliation(s)
- Albert Do
- Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
- Division of Gastroenterology, University of California, Davis, Davis, USA
| | - Frhaan Zahrawi
- Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Wajahat Z Mehal
- Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
- West Haven Veterans Hospital, West Haven, CT, USA.
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Nielsen MH, Nøhr-Meldgaard J, Møllerhøj MB, Oró D, Pors SE, Andersen MW, Kamzolas I, Petsalaki E, Vacca M, Harder LM, Perfield JW, Veidal S, Hansen HH, Feigh M. Characterization of six clinical drugs and dietary intervention in the nonobese CDAA-HFD mouse model of MASH and progressive fibrosis. Am J Physiol Gastrointest Liver Physiol 2025; 328:G51-G71. [PMID: 39404770 DOI: 10.1152/ajpgi.00110.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 09/13/2024] [Accepted: 09/23/2024] [Indexed: 12/17/2024]
Abstract
The choline-deficient l-amino acid defined-high-fat diet (CDAA-HFD) mouse model is widely used in preclinical metabolic dysfunction-associated steatohepatitis (MASH) research. To validate the CDAA-HFD mouse, we evaluated disease progression and responsiveness to dietary and pharmacological interventions with semaglutide, lanifibranor, elafibranor, obeticholic acid (OCA), firsocostat, and resmetirom. Disease phenotyping was performed in C57BL/6J mice fed CDAA-HFD for 3-20 wk and ranked using the MASLD Human Proximity Score (MHPS). Semaglutide, lanifibranor, elafibranor, OCA, firsocostat, or resmetirom were profiled as treatment intervention for 8 wk, starting after 6 wk of CDAA-HFD feeding. Semaglutide and lanifibranor were further evaluated as early (preventive) therapy for 9 wk, starting 3 wk after CDAA-HFD diet feeding. In addition, benefits of dietary intervention (chow reversal) for 8 wk were characterized following 6 wk of CDAA-HFD feeding. CDAA-HFD mice demonstrated a nonobese phenotype with fast onset and progression of MASH and fibrosis, high similarity to human MASH-fibrosis, and tumor development after 20 wk of diet-induction. Semaglutide and lanifibranor partially reversed fibrosis when administered as prevention but not as treatment intervention. Elafibranor was the only interventional drug therapy to improve fibrosis. In comparison, chow-reversal resulted in complete regression of steatosis with improved liver inflammation and fibrosis in CDAA-HFD mice. CDAA-HFD mice recapitulate histological hallmarks of advanced MASH with progressive severe fibrosis, however, in the absence of a clinical translational obese dysmetabolic phenotype. CDAA-HFD mice are suitable for profiling drug candidates directly targeting hepatic lipid metabolism, inflammation, and fibrosis. The timing of pharmacological intervention is critical for determining antifibrotic drug efficacy in the model.NEW & NOTEWORTHY The CDAA-HFD mouse model is widely used in preclinical MASH research, but validation of the model is lacking. This study presents the longitudinal characterization of disease progression. Furthermore, late-stage clinical compounds and dietary intervention (chow reversal) display distinct hepatoprotective effects in the model. Collectively, the study provides critical information guiding the use of the CDAA-HFD mouse model in preclinical drug discovery for MASH and fibrosis.
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Affiliation(s)
| | | | | | | | | | | | - Ioannis Kamzolas
- TVP Lab, WT/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
| | - Evangelia Petsalaki
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
| | - Michele Vacca
- TVP Lab, WT/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
- Laboratory of Liver Metabolism and MASLD, Roger Williams Institute of Hepatology, London, United Kingdom
| | - Lea Mørch Harder
- Research and Early Development, Novo Nordisk A/S, Måløv, Denmark
| | - James W Perfield
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States
| | - Sanne Veidal
- Research and Early Development, Novo Nordisk A/S, Måløv, Denmark
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Skrobucha A, Pindlowski P, Krajewska N, Grabowski M, Jonik S. Anti-inflammatory effects of glucagon-like peptide-1 (GLP-1) in coronary artery disease: a comprehensive review. Front Cardiovasc Med 2024; 11:1446468. [PMID: 39741663 PMCID: PMC11685754 DOI: 10.3389/fcvm.2024.1446468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Accepted: 11/21/2024] [Indexed: 01/03/2025] Open
Abstract
Coronary artery disease (CAD)-cardiovascular condition occuring due to atherosclerotic plaque accumulation in the epicardial arteries-is responsible for disabilities of millions of people worldwide and remains the most common single cause of death. Inflammation is the primary pathological mechanism underlying CAD, since is involved in atherosclerotic plaque formation. Glucagon-like peptide-1 (GLP-1) is a peptide hormone which role extends beyond well-known carbohydrates metabolism. In in vitro studies GLP-1 receptor agonism is associated with regulation of several inflammatory pathways, including cytokine production, lypotoxicity and macrophages differentiation. In this review, we aimed to provide a comprehensive summary of the potential relationship between anti-inflammatory effects of GLP-1 and CAD. We have described a well-established association of anti-inflammatory properties of GLP-1 and atherosclerosis in animals. Pre-clinical studies showed that anti-atherogenic effect of GLP-1 is independent of modulation of plasma lipid levels and depends on anti-inflammatory response. Human studies in this area are limited by small sample size and often nonrandomized character. However, beneficial impact of GLP-1 on endothelial function and microcirculatory integrity in patients with CAD have been described. Understanding atherosclerosis as a chronic inflammatory disease offers new opportunities for the prevention and treatment of CAD. Therefore, we emphasize the need for larger randomized controlled trials focusing on cardiovascular morbidity and mortality to verify the cardioprotective properties of GLP-1R agonists in patients with CAD.
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Affiliation(s)
- Alicja Skrobucha
- 1st Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
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Wang ZQ, Zhang JY, Tang X, Zhou JB. Hypoglycemic drugs, circulating inflammatory proteins, and gallbladder diseases: A mediation mendelian randomization study. Diabetes Res Clin Pract 2024; 217:111882. [PMID: 39366640 DOI: 10.1016/j.diabres.2024.111882] [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: 06/28/2024] [Revised: 08/31/2024] [Accepted: 10/01/2024] [Indexed: 10/06/2024]
Abstract
BACKGROUND The relationship of hypoglycemic drugs, inflammatory proteins and gallbladder diseases remain unknown. METHODS Four hypoglycemic drugs were selected as exposure: glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter 2 inhibitors (SGLT-2i), and metformin. The outcome were two gallbladder diseases: cholecystitis and cholelithiasis. Mendelian Randomization (MR) was employed to determine the association between hypoglycemic drugs and gallbladder diseases. RESULTS DPP-4i and SGLT-2i had no effect on cholecystitis and cholelithiasis. However, a causal relationship was found between inhibition of ETFDH gene, a target of metformin expressed in cultured fibroblasts, and cholelithiasis (OR: 0.84, 95 %CI: (0.72,0.97), p = 0.021), as well as between GLP1R expression in the brain caudate basal ganglia and cholecystitis (OR: 1.29, 95 %CI: (1.11,1.49), p = 0.001). The effect of ETFDH inhibition on cholelithiasis through Interleukin-10 receptor subunit beta (IL-10RB) levels and Neurotrophin-3 (NT-3) levels, with a mediated proportion of 8 % and 8 %, respectively. CONCLUSION Metformin plays a protective role in cholelithiasis, while GLP-1RA have a harmful effect on the risk of cholecystitis. Metformin may reduce the risk of cholelithiasis by modulating the levels of Neurotrophin-3 (NT-3) and Interleukin-10 receptor subunit beta (IL-10RB). Further clinical and mechanistic studies are required to confirm these findings.
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Affiliation(s)
- Zi-Qi Wang
- Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jin-Yan Zhang
- Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | | | - Jian-Bo Zhou
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
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Fu M, Li Q, Qian H, Min X, Yang H, Liu Z, Wu W, Zhong J, Xu H, Mei A, Chen J. Exendin-4 intervention attenuates atherosclerosis severity by modulating myeloid-derived suppressor cells and inflammatory cytokines in ApoE -/- mice. Int Immunopharmacol 2024; 140:112844. [PMID: 39094363 DOI: 10.1016/j.intimp.2024.112844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/21/2024] [Accepted: 07/29/2024] [Indexed: 08/04/2024]
Abstract
OBJECTIVE To investigate the impact of the glucagon-like peptide-1 (GLP-1) receptor agonist Exendin-4 on the proportion of myeloid-derived suppressor cells (MDSCs) in male ApoE-/- mice, and investigate alterations in the concentrations of inflammatory factors in plasma and spleen tissues and assess their correlation with MDSCs. METHODS Thirty male ApoE-/- mice were randomly divided into five groups (n = 6 per group): control group (CON), model group (MOD), Exendin-4 intervention group (MOD/Ex-4), Exendin-9-39 intervention group (MOD/Ex-9-39), and Exendin-4 + Exendin-9-39 combined intervention group (MOD/Ex-4 + Ex-9-39). After 4 weeks of drug intervention, changes in aortic plaque were observed using Oil Red O staining and H&E staining. Flow cytometry was employed to detect the content of myeloid-derived suppressor cells (MDSCs) in bone marrow and peripheral blood. ELISA was utilized to measure the concentrations of inflammatory factors in mouse peripheral blood plasma, while RT-qPCR was employed to quantify the expression levels of inflammatory factors in the spleen. Pearson correlation analysis was conducted to assess the relationship between MDSCs and inflammatory factors. RESULTS Mice in the MOD group had significantly higher body weight compared to the CON group, with a statistically significant difference (P<0.05). Following Exendin-4 intervention, body weight was reduced compared to the MOD group (P<0.05). Additionally, Exendin-4 treatment led to a significant reduction in atherosclerotic plaque compared to the MOD group (P<0.001). After Exendin-4 intervention, the proportion of MDSCs in the bone marrow was higher than in the MOD group (P<0.001), and the proportion of MDSCs in peripheral blood was significantly higher than in the MOD group (P<0.05). Further investigation revealed that Exendin-4 could regulate lipid levels in mice, decreasing concentrations of TG (P<0.01), TC (P<0.0001), and LDL-C (P<0.0001), while increasing HDL-C concentrations (P<0.01). Moreover, after Exendin-4 treatment, the level of the cytokine IL-6 in peripheral plasma was significantly lower compared to the MOD group (P<0.0001), while levels of IL-10 and TGF-β were significantly higher compared to the MOD group (P<0.0001). In the spleen, levels of the cytokines IL-10 (P<0.0001) and TGF-β (P<0.001) were significantly increased compared to the MOD group. Pearson correlation analysis showed that the proportion of MDSCs in peripheral blood was positively correlated with IL-10 and TGF-β levels in both the spleen and peripheral blood. Additionally, the proportion of MDSCs in the bone marrow was positively correlated with IL-10 and TGF-β levels in the spleen and peripheral blood. CONCLUSION Exendin-4 alleviates the severity of atherosclerosis. This process may be achieved by promoting the secretion of myeloid-derived suppressor cells (MDSCs) in the bone marrow and peripheral blood of atherosclerotic ApoE-/- mice, regulating the ratio of inflammatory factors in the body, reducing mouse body weight, and lowering blood lipids.
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Affiliation(s)
- Miaoxin Fu
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Qingmei Li
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China; Sheng Li OilField Central Hospital, Dong Ying, Shandong Province, China
| | - Hang Qian
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Xinwen Min
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Handong Yang
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Zhixin Liu
- Shiyan Key Laboratory of Virology, Hubei University of Medicine, Shiyan, China
| | - Wenwen Wu
- School of Public Health, Hubei University of Medicine, 442000 Shiyan, Hubei, China
| | - Jixin Zhong
- Department of Rheumatology and Immunology, Tongji Hospital, Huazhong University of Science and Technology, 430074 Wuhan, Hubei, China
| | - Hao Xu
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China.
| | - Aihua Mei
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China.
| | - Jun Chen
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China; Shiyan Key Laboratory of Virology, Hubei University of Medicine, Shiyan, China.
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Njei B, Al-Ajlouni Y, Lemos SY, Ugwendum D, Ameyaw P, Njei LP, Boateng S. Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cureus 2024; 16:e71366. [PMID: 39534801 PMCID: PMC11556413 DOI: 10.7759/cureus.71366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2024] [Indexed: 11/16/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a major global health challenge. glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential therapeutic benefits for MASLD patients, including improvements in liver function, inflammation, and fibrosis. This study aims to systematically review and meta-analyze randomized controlled trials (RCTs) to evaluate the efficacy and safety of GLP-1RAs in MASLD patients, focusing on hepatic outcomes, cardiovascular outcomes, anthropometric measurements, and mortality. Following PRISMA guidelines, a comprehensive database search was conducted to include RCTs assessing GLP-1RAs' effects on MASLD. Quality assessment was conducted using the Revised Cochrane Risk of Bias tool. Our meta-analysis used a random-effects model, calculating standardized mean differences for continuous outcomes to determine the agents' efficacy and safety. Additionally, funnel plots were generated to assess publication bias, ensuring the integrity of our meta-analytical findings. The review included 27 trials, revealing GLP-1RAs significantly improved hepatic function markers (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and liver fat content) and cardiovascular risk factors (fasting blood sugar, HbA1c levels, lipid profiles). Additionally, GLP-1RAs were associated with significant reductions in body weight, BMI, subcutaneous fat, and waist circumference. GLP-1RAs demonstrate a promising therapeutic role in managing MASLD, offering benefits that extend to improving liver function, mitigating cardiovascular risk, and promoting weight loss. Further research is needed to confirm these findings and optimize GLP-1RAs' usage in MASLD treatment.
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Affiliation(s)
- Basile Njei
- Department of Medicine, Yale School of Medicine, New Haven, USA
| | | | - Samira Y Lemos
- Department of Diabetes and Endocrinology, Yaoundé General Hospital, Yaoundé, CMR
| | - Derek Ugwendum
- Department of Internal Medicine, Richmond University Medical Center Affiliated with Mount Sinai Health System and Icahn School of Medicine at Mount Sinai, Staten Island, USA
| | - Prince Ameyaw
- Department of Internal Medicine, Bridgeport Hospital, Yale New Haven Health, Bridgeport, USA
| | - Lea-Pearl Njei
- Department of Biological Science, University of Maryland Baltimore County, Baltimore, USA
| | - Sarpong Boateng
- Department of Medicine, Bridgeport Hospital, Bridgeport, USA
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Liu M, Guo S, Li X, Tian Y, Yu Y, Tang L, Sun Q, Zhang T, Fan M, Zhang L, Xu Y, An J, Gao X, Han L, Zhang L. Semaglutide Alleviates Ovary Inflammation via the AMPK/SIRT1/NF‑κB Signaling Pathway in Polycystic Ovary Syndrome Mice. Drug Des Devel Ther 2024; 18:3925-3938. [PMID: 39247793 PMCID: PMC11380913 DOI: 10.2147/dddt.s484531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 08/26/2024] [Indexed: 09/10/2024] Open
Abstract
Background GLP-1 receptor agonists (GLP-1 RA) have been proven to treat several metabolic diseases; however, the effects of GLP-1 RA on polycystic ovary syndrome (PCOS) remain unclear. Here, we aimed to investigate whether semaglutide, a novel GLP-1 RA, could alleviate ovarian inflammation in PCOS mice. Methods Female C57BL/6J mice were subcutaneously injected with dehydroepiandrosterone for 21 days to establish the PCOS model. Then the mice were randomly divided into three groups: PCOS group (n = 6), S-0.42 group (semaglutide 0.42 mg/kg/w, n = 6), and S-0.84 group (semaglutide 0.84 mg/kg/w, n = 6). The remaining six mice were used as controls (NC). After 28 days of intervention, serum sex hormones and inflammatory cytokine levels were measured. Hematoxylin and eosin staining was used to observe the ovarian morphology. Immunohistochemical staining was used to detect the relative expression of CYP19A1, TNF-α, IL-6, IL-1β, and NF-κB in ovaries. CYP17A1 and StAR were detected using immunofluorescence staining. Finally, the relative expressions of AMPK, pAMPK, SIRT1, NF-κB, IκBα, pIκBα, TNF-α, IL-6, and IL-1β were measured using Western blotting. Results First, after intervention with semaglutide, the weight of the mice decreased, insulin resistance improved, and the estrous cycle returned to normal. Serum testosterone and IL-1β levels decreased significantly, whereas estradiol and progestin levels increased significantly. Follicular cystic dilation significantly improved. The expression of TNF-α, IL-6, IL-1β, NF-κB, CYP17A1, and StAR in the ovary was significantly downregulated, whereas CYP19A1 expression was upregulated after the intervention. Finally, we confirmed that semaglutide alleviates ovarian tissue inflammation and improves PCOS through the AMPK/SIRT1/NF-κB signaling pathway. Conclusion Semaglutide alleviates ovarian inflammation via the AMPK/SIRT1/NF‑κB signaling pathway in PCOS mice.
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Affiliation(s)
- Mei Liu
- Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China
| | - Sili Guo
- Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China
| | - Xiaohan Li
- Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China
| | - Yang Tian
- Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China
| | - Yanjie Yu
- Department of Ultrasound Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China
| | - Lili Tang
- Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China
| | - Qimei Sun
- Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China
| | - Ting Zhang
- Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China
| | - Mingwei Fan
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China
| | - Lili Zhang
- Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China
| | - Yingjiang Xu
- Department of Interventional Vascular Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China
| | - Jiajia An
- Department of Clinical Laboratory, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China
| | - Xiangqian Gao
- Department of Pathology, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China
| | - Lei Han
- Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China
| | - Lei Zhang
- Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China
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11
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Wu X, Yuan C, Pan J, Zhou Y, Pan X, Kang J, Ren L, Gong L, Li Y. CXCL9, IL2RB, and SPP1, potential diagnostic biomarkers in the co-morbidity pattern of atherosclerosis and non-alcoholic steatohepatitis. Sci Rep 2024; 14:16364. [PMID: 39013959 PMCID: PMC11252365 DOI: 10.1038/s41598-024-66287-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 07/01/2024] [Indexed: 07/18/2024] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a hepatocyte inflammation based on hepatocellular steatosis, yet there is no effective drug treatment. Atherosclerosis (AS) is caused by lipid deposition in the endothelium, which can lead to various cardiovascular diseases. NASH and AS share common risk factors, and NASH can also elevate the risk of AS, causing a higher morbidity and mortality rate for atherosclerotic heart disease. Therefore, timely detection and diagnosis of NASH and AS are particularly important. In this study, differential gene expression analysis and weighted gene co-expression network analysis were performed on the AS (GSE100927) and NASH (GSE89632) datasets to obtain common crosstalk genes, respectively. Then, candidate Hub genes were screened using four topological algorithms and externally validated in the GSE43292 and GSE63067 datasets to obtain Hub genes. Furthermore, immune infiltration analysis and gene set variation analysis were performed on the Hub genes to explore the underlying mechanisms. The DGIbd database was used to screen candidate drugs for AS and NASH. Finally, a NASH model was constructed using free fatty acid-induced human L02 cells, an AS model was constructed using lipopolysaccharide-induced HUVECs, and a co-morbidity model was constructed using L02 cells and HUVECs to verify Hub gene expression. The result showed that a total of 113 genes common to both AS and NASH were identified as crosstalk genes, and enrichment analysis indicated that these genes were mainly involved in the regulation of immune and metabolism-related pathways. 28 candidate Hub genes were screened according to four topological algorithms, and CXCL9, IL2RB, and SPP1 were identified as Hub genes after in vitro experiments and external dataset validation. The ROC curves and SVM modeling demonstrated the good diagnostic efficacy of these three Hub genes. In addition, the Hub genes are strongly associated with immune cell infiltration, especially macrophages and γ-δ T cell infiltration. Finally, five potential therapeutic drugs were identified. has-miR-185 and hsa-miR-335 were closely related to AS and NASH. This study demonstrates that CXCL9, IL2RB, and SPP1 may serve as potential biomarkers for the diagnosis of the co-morbidity patterns of AS and NASH and as potential targets for drug therapy.
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Affiliation(s)
- Xize Wu
- Liaoning University of Traditional Chinese Medicine, No. 79 Chongshan East Road, Huanggu District, Shenyang, 110847, Liaoning, China
- Nantong Hospital of Traditional Chinese Medicine, Nantong Hospital Affiliated to Nanjing University of Chinese Medicine, Nantong, 226000, Jiangsu, China
| | - Changbin Yuan
- Liaoning University of Traditional Chinese Medicine, No. 79 Chongshan East Road, Huanggu District, Shenyang, 110847, Liaoning, China
| | - Jiaxiang Pan
- The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, 110032, Liaoning, China
| | - Yi Zhou
- Liaoning University of Traditional Chinese Medicine, No. 79 Chongshan East Road, Huanggu District, Shenyang, 110847, Liaoning, China
| | - Xue Pan
- Liaoning University of Traditional Chinese Medicine, No. 79 Chongshan East Road, Huanggu District, Shenyang, 110847, Liaoning, China
- Dazhou Vocational College of Chinese Medicine, Dazhou, 635000, Sichuan, China
| | - Jian Kang
- Liaoning University of Traditional Chinese Medicine, No. 79 Chongshan East Road, Huanggu District, Shenyang, 110847, Liaoning, China
| | - Lihong Ren
- Nantong Hospital of Traditional Chinese Medicine, Nantong Hospital Affiliated to Nanjing University of Chinese Medicine, Nantong, 226000, Jiangsu, China.
| | - Lihong Gong
- Liaoning University of Traditional Chinese Medicine, No. 79 Chongshan East Road, Huanggu District, Shenyang, 110847, Liaoning, China.
- The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, 110032, Liaoning, China.
- Liaoning Provincial Key Laboratory of TCM Geriatric Cardio-Cerebrovascular Diseases, Shenyang, 110847, Liaoning, China.
| | - Yue Li
- The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, 110032, Liaoning, China.
- Liaoning Provincial Key Laboratory of TCM Geriatric Cardio-Cerebrovascular Diseases, Shenyang, 110847, Liaoning, China.
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12
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Zhong J, Chen H, Liu Q, Zhou S, Liu Z, Xiao Y. GLP-1 receptor agonists and myocardial metabolism in atrial fibrillation. J Pharm Anal 2024; 14:100917. [PMID: 38799233 PMCID: PMC11127228 DOI: 10.1016/j.jpha.2023.12.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 10/15/2023] [Accepted: 12/07/2023] [Indexed: 05/29/2024] Open
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Many medical conditions, including hypertension, diabetes, obesity, sleep apnea, and heart failure (HF), increase the risk for AF. Cardiomyocytes have unique metabolic characteristics to maintain adenosine triphosphate production. Significant changes occur in myocardial metabolism in AF. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been used to control blood glucose fluctuations and weight in the treatment of type 2 diabetes mellitus (T2DM) and obesity. GLP-1RAs have also been shown to reduce oxidative stress, inflammation, autonomic nervous system modulation, and mitochondrial function. This article reviews the changes in metabolic characteristics in cardiomyocytes in AF. Although the clinical trial outcomes are unsatisfactory, the findings demonstrate that GLP-1 RAs can improve myocardial metabolism in the presence of various risk factors, lowering the incidence of AF.
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Affiliation(s)
- Jiani Zhong
- Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Xiangya School of Medicine, Central South University, Changsha, 410008, China
| | - Hang Chen
- Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Xiangya School of Medicine, Central South University, Changsha, 410008, China
| | - Qiming Liu
- Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Shenghua Zhou
- Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Zhenguo Liu
- Center for Precision Medicine and Division of Cardiovascular Medicine, Department of Medicine, School of Medicine, University of Missouri, Columbia, MO, 65211, USA
| | - Yichao Xiao
- Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, 410011, China
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13
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Park B, Bakbak E, Teoh H, Krishnaraj A, Dennis F, Quan A, Rotstein OD, Butler J, Hess DA, Verma S. GLP-1 receptor agonists and atherosclerosis protection: the vascular endothelium takes center stage. Am J Physiol Heart Circ Physiol 2024; 326:H1159-H1176. [PMID: 38426865 DOI: 10.1152/ajpheart.00574.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 02/12/2024] [Accepted: 02/21/2024] [Indexed: 03/02/2024]
Abstract
Atherosclerotic cardiovascular disease is a chronic condition that often copresents with type 2 diabetes and obesity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin mimetics endorsed by major professional societies for improving glycemic status and reducing atherosclerotic risk in people living with type 2 diabetes. Although the cardioprotective efficacy of GLP-1RAs and their relationship with traditional risk factors are well established, there is a paucity of publications that have summarized the potentially direct mechanisms through which GLP-1RAs mitigate atherosclerosis. This review aims to narrow this gap by providing comprehensive and in-depth mechanistic insight into the antiatherosclerotic properties of GLP-1RAs demonstrated across large outcome trials. Herein, we describe the landmark cardiovascular outcome trials that triggered widespread excitement around GLP-1RAs as a modern class of cardioprotective agents, followed by a summary of the origins of GLP-1RAs and their mechanisms of action. The effects of GLP-1RAs at each major pathophysiological milestone of atherosclerosis, as observed across clinical trials, animal models, and cell culture studies, are described in detail. Specifically, this review provides recent preclinical and clinical evidence that suggest GLP-1RAs preserve vessel health in part by preventing endothelial dysfunction, achieved primarily through the promotion of angiogenesis and inhibition of oxidative stress. These protective effects are in addition to the broad range of atherosclerotic processes GLP-1RAs target downstream of endothelial dysfunction, which include systemic inflammation, monocyte recruitment, proinflammatory macrophage and foam cell formation, vascular smooth muscle cell proliferation, and plaque development.
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Affiliation(s)
- Brady Park
- Division of Cardiac Surgery, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Keenan Research Centre of Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Ehab Bakbak
- Division of Cardiac Surgery, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Keenan Research Centre of Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
| | - Hwee Teoh
- Division of Cardiac Surgery, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Keenan Research Centre of Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
| | - Aishwarya Krishnaraj
- Division of Cardiac Surgery, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Keenan Research Centre of Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Fallon Dennis
- Division of Cardiac Surgery, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Keenan Research Centre of Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Adrian Quan
- Division of Cardiac Surgery, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Keenan Research Centre of Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
| | - Ori D Rotstein
- Keenan Research Centre of Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Division of General Surgery, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, Texas, United States
- Department of Medicine, University of Mississippi, Jackson, Mississippi, United States
| | - David A Hess
- Keenan Research Centre of Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
- Molecular Medicine Research Laboratories, Robarts Research Institute, London, Ontario, Canada
| | - Subodh Verma
- Division of Cardiac Surgery, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Keenan Research Centre of Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Department of Surgery, University of Toronto, Toronto, Ontario, Canada
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Hachuła M, Kosowski M, Ryl S, Basiak M, Okopień B. Impact of Glucagon-Like Peptide 1 Receptor Agonists on Biochemical Markers of the Initiation of Atherosclerotic Process. Int J Mol Sci 2024; 25:1854. [PMID: 38339133 PMCID: PMC10855444 DOI: 10.3390/ijms25031854] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/11/2024] [Accepted: 01/31/2024] [Indexed: 02/12/2024] Open
Abstract
Atherosclerosis stands out as one of the leading causes of global mortality. The inflammatory response against vascular wall components plays a pivotal role in the atherogenic process. The initiation of this process is notably driven by oxidized low-density lipoprotein (oxLDL) and a range of pro-inflammatory cytokines, with interleukin-1β (Il-1β) and tumor necrosis factor α (TNFα) emerging as particularly significant in the early stages of atherosclerotic plaque formation. In recent years, researchers worldwide have been diligently exploring innovative therapeutic approaches for metabolic diseases, recognizing their impact on the atherogenesis process. Our study aimed to investigate the influence of glucagon-like peptide 1 receptor agonists (GLP-1RA) on cytokine concentrations associated with the initiation of atherosclerotic plaque formation in a group of patients with type 2 diabetes and dyslipidemia. The study encompassed 50 subjects aged 41-81 (mean: 60.7), all diagnosed with type 2 diabetes, dyslipidemia and confirmed atherosclerosis based on B-mode ultrasound. Following a 180-day treatment with dulaglutide or semaglutide, we observed a statistically significant reduction in biochemical markers (oxLDL, TNFα and Il-1β) associated with the initiation of the atherosclerotic process (p < 0.001) within our study group. In addition to the already acknowledged positive effects of GLP-1RA on the metabolic parameters of treated patients, these drugs demonstrated a notable reduction in proinflammatory cytokine concentrations and may constitute an important element of therapy aimed at reducing cardiovascular risk.
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Affiliation(s)
- Marcin Hachuła
- Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland; (M.H.); (M.K.)
| | - Michał Kosowski
- Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland; (M.H.); (M.K.)
| | - Sabina Ryl
- Department of Anaesthesiology and Intensive Care, Municipal Hospital in Zabrze-Biskupice, Zamkowa 4, 41-803 Zabrze, Poland;
| | - Marcin Basiak
- Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland; (M.H.); (M.K.)
| | - Bogusław Okopień
- Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland; (M.H.); (M.K.)
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15
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Adeghate EA. GLP-1 receptor agonists in the treatment of diabetic non-alcoholic steatohepatitis patients. Expert Opin Pharmacother 2024; 25:223-232. [PMID: 38458647 DOI: 10.1080/14656566.2024.2328796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 03/06/2024] [Indexed: 03/10/2024]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disease affecting almost 30% of the world population. Approximately 25% of people with NAFLD develop nonalcoholic steatohepatitis (NASH), the fulminant version of the disease. Diabetes mellitus is present in 22.5% of people with NAFLD and 44.60% of individuals with NASH. This review was undertaken to examine the current contribution of glucagon-like peptide 1 (GLP-1) receptor agonists to the pharmacotherapy of diabetic nonalcoholic steatohepatitis. AREAS COVERED The author analyzed the current status of GLP-1 receptor agonists for pharmacotherapy of diabetic NASH. Research data and literature reports were taken from the database and or websites of Diabetes UK, American Diabetes Association, ClinicalTrials.gov, PubMed, and Scopus. The keywords utilized included type 2 diabetes, GLP-1, NASH, NAFLD, and clinical trials. EXPERT OPINION Since diabetic NASH is associated with obesity, diabetes mellitus, oxidative stress and inflammation, drugs capable of mitigating all of these conditions simultaneously, are most ideal for the treatment of diabetic NASH. These drugs include (in order of relevance), GLP-1 receptor agonists, GLP-1 and GIP dual receptor agonists, sodium-glucose co-transporter-2 (SGLT2) inhibitors, and pioglitazone. The future, FDA-approved drug for diabetic NASH treatment will likely be GLP-1 agonist, which could be used as monotherapy or in combination with other drugs.
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Affiliation(s)
- Ernest A Adeghate
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- Zayed Centre for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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16
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Melander SA, Kayed A, Andreassen KV, Karsdal MA, Henriksen K. OXM-104, a potential candidate for the treatment of obesity, NASH and type 2 diabetes. Eur J Pharmacol 2024; 962:176215. [PMID: 38056618 DOI: 10.1016/j.ejphar.2023.176215] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 11/08/2023] [Accepted: 11/16/2023] [Indexed: 12/08/2023]
Abstract
OBJECTIVE Dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonists are therapeutic agents with an interesting liver-specific mode of action suitable for metabolic complications. In this study, dual GLP-1 and glucagon receptor agonist OXM-104 is compared head-to-head with the once-daily dual GLP-1 and glucagon receptor agonist cotadutide and GLP-1 receptor agonist semaglutide to explore the metabolic efficacy of OXM-104. METHODS The in vitro potencies of OXM-104, cotadutide and semaglutide were assessed using reporter assays. In addition, in vivo efficacy was investigated using mouse models of diet-induced obesity (DIO mice), diabetes (db/db mice) and diet-induced NASH mice (MS-NASH). RESULTS OXM-104 was found to only activate the GLP-1 and glucagon with no cross-reactivity at the (GIP) receptor. Cotadutide was also found to activate the GLP-1 and glucagon receptors, whereas semaglutide only showed activity at the GLP-1 receptor. OXM-104, cotadutide, and semaglutide elicited marked reductions in body weight and improved glucose control. In contrast, hepatoprotective effects, i.e., reductions in steatosis and fibrosis, as well as liver fibrotic biomarkers, were more prominent with OXM-104 and cotadutide than those seen with semaglutide, demonstrated by an improved NAFLD activity score (NAS) by OXM-104 and cotadutide, underlining the importance of the glucagon receptor. CONCLUSION These results show that dual GLP-1 and glucagon receptor agonism is superior to GLP-1 alone. OXM-104 was found to be a promising therapeutic candidate for the treatment of metabolic complications such as obesity, type 2 diabetes and NASH.
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Affiliation(s)
| | | | | | | | - Kim Henriksen
- Nordic Bioscience, 2730 Herlev, Denmark; KeyBioscience AG, Stans, Switzerland
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17
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Jiang H, Zang L. GLP-1/GLP-1RAs: New Options for the Drug Treatment of NAFLD. Curr Pharm Des 2024; 30:100-114. [PMID: 38532322 DOI: 10.2174/0113816128283153231226103218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 12/14/2023] [Indexed: 03/28/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a global public health concern. Currently, the cornerstone of NAFLD treatment is lifestyle modification and, if necessary, weight loss. However, compliance is a challenge, and this approach alone may not be sufficient to halt and treat the more serious disease development, so medication is urgently needed. Nevertheless, no medicines are approved to treat NAFLD. Glucagon-like peptide-1 (GLP-1) is an enteropeptide hormone that inhibits glucagon synthesis, promotes insulin secretion, and delays gastric emptying. GLP-1 has been found in recent studies to be beneficial for the management of NAFLD, and the marketed GLP-1 agonist drugs have different degrees of effectiveness for NAFLD while lowering blood glucose. In this article, we review GLP-1 and its physiological roles, the pathogenesis of NAFLD, the correlation between NAFLD and GLP-1 signaling, and potential strategies for GLP-1 treatment of NAFLD.
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Affiliation(s)
- Haoran Jiang
- Laboratory of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Linquan Zang
- Laboratory of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
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18
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Hansen HH, Pors S, Andersen MW, Vyberg M, Nøhr-Meldgaard J, Nielsen MH, Oró D, Madsen MR, Lewinska M, Møllerhøj MB, Madsen AN, Feigh M. Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis. Sci Rep 2023; 13:23056. [PMID: 38155202 PMCID: PMC10754821 DOI: 10.1038/s41598-023-50328-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 12/18/2023] [Indexed: 12/30/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is emerging as a major cause of hepatocellular carcinoma (HCC), however, it is not resolved if compounds in late-stage clinical development for NASH may have additional therapeutic benefits in NASH-driven HCC (NASH-HCC). Here, we profiled monotherapy with semaglutide (glucagon-like-receptor-1 receptor agonist) and lanifibranor (pan-peroxisome proliferator-activated receptor agonist) in a diet-induced obese (DIO) mouse model of NASH-HCC. Disease progression was characterized in male C57BL/6 J mice fed the GAN (Gubra Amylin NASH) diet high in fat, fructose and cholesterol for 12-72 weeks (n = 15 per group). Other GAN DIO-NASH-HCC mice fed the GAN diet for 54 weeks and with biopsy-confirmed NASH (NAFLD Activity Score ≥ 5) and advanced fibrosis (stage F3) received vehicle (n = 16), semaglutide (30 nmol/kg, s.c., n = 15), or lanifibranor (30 mg/kg, p.o., n = 15) once daily for 14 weeks. GAN DIO-NASH-HCC mice demonstrated progressive NASH, fibrosis and HCC burden. Tumors presented with histological and molecular signatures of poor prognostic HCC. Consistent with clinical trial outcomes in NASH patients, both lanifibranor and semaglutide improved NASH while only lanifibranor reduced fibrosis in GAN DIO-NASH-HCC mice. Notably, only semaglutide reduced tumor burden in GAN DIO-NASH-HCC mice. In conclusion, the GAN DIO-NASH-HCC mouse is a clinical translational model of NASH-HCC. Semaglutide improves both NASH and tumor burden in GAN DIO-NASH-HCC mice, highlighting the suitability of this preclinical model for profiling novel drug therapies targeting NASH-HCC.
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Affiliation(s)
| | - Susanne Pors
- Gubra, Hørsholm Kongevej 11B, DK-2970, Hørsholm, Denmark
| | | | - Mogens Vyberg
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | | | | | - Denise Oró
- Gubra, Hørsholm Kongevej 11B, DK-2970, Hørsholm, Denmark
| | | | | | | | | | - Michael Feigh
- Gubra, Hørsholm Kongevej 11B, DK-2970, Hørsholm, Denmark
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Smiriglia A, Lorito N, Serra M, Perra A, Morandi A, Kowalik MA. Sex difference in liver diseases: How preclinical models help to dissect the sex-related mechanisms sustaining NAFLD and hepatocellular carcinoma. iScience 2023; 26:108363. [PMID: 38034347 PMCID: PMC10682354 DOI: 10.1016/j.isci.2023.108363] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2023] Open
Abstract
Only a few preclinical findings are confirmed in the clinic, posing a critical issue for clinical development. Therefore, identifying the best preclinical models can help to dissect molecular and mechanistic insights into liver disease pathogenesis while being clinically relevant. In this context, the sex relevance of most preclinical models has been only partially considered. This is particularly significant in NAFLD and HCC, which have a higher prevalence in men when compared to pre-menopause women but not to those in post-menopausal status, suggesting a role for sex hormones in the pathogenesis of the diseases. This review gathers the sex-relevant findings and the available preclinical models focusing on both in vitro and in vivo studies and discusses the potential implications and perspectives of introducing the sex effect in the selection of the best preclinical model. This is a critical aspect that would help to tailor personalized therapies based on sex.
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Affiliation(s)
- Alfredo Smiriglia
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Nicla Lorito
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Marina Serra
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
| | - Andrea Perra
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
| | - Andrea Morandi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Marta Anna Kowalik
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
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20
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Sheth S, Patel A, Foreman M, Mumtaz M, Reddy A, Sharaf R, Sheth S, Lucke-Wold B. The protective role of GLP-1 in neuro-ophthalmology. EXPLORATION OF DRUG SCIENCE 2023; 1:221-238. [PMID: 37711214 PMCID: PMC10501042 DOI: 10.37349/eds.2023.00015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 05/22/2023] [Indexed: 09/16/2023]
Abstract
Despite recent advancements in the field of neuro-ophthalmology, the rising rates of neurological and ophthalmological conditions, mismatches between supply and demand of clinicians, and an aging population underscore the urgent need to explore new therapeutic approaches within the field. Glucagon-like peptide 1 receptor agonists (GLP-1RAs), traditionally used in the treatment of type 2 diabetes, are becoming increasingly appreciated for their diverse applications. Recently, GLP-1RAs have been approved for the treatment of obesity and recognized for their cardioprotective effects. Emerging evidence indicates some GLP-1RAs can cross the blood-brain barrier and may have neuroprotective effects. Therefore, this article aims to review the literature on the neurologic and neuro-ophthalmic role of glucagon-like peptide 1 (GLP-1). This article describes GLP-1 peptide characteristics and the mechanisms mediating its known role in increasing insulin, decreasing glucagon, delaying gastric emptying, and promoting satiety. This article identifies the sources and targets of GLP-1 in the brain and review the mechanisms which mediate its neuroprotective effects, as well as implications for Alzheimer's disease (AD) and Parkinson's disease (PD). Furthermore, the preclinical works which unravel the effects of GLP-1 in ocular dynamics and the preclinical literature regarding GLP-1RA use in the management of several neuro-ophthalmic conditions, including diabetic retinopathy (DR), glaucoma, and idiopathic intracranial hypertension (IIH) are discussed.
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Affiliation(s)
- Sohum Sheth
- College of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Aashay Patel
- College of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Marco Foreman
- College of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Mohammed Mumtaz
- College of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Akshay Reddy
- College of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Ramy Sharaf
- College of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Siddharth Sheth
- College of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA
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21
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Wang Y, Wang Y, Wu Y, Wang Y. Dulaglutide Ameliorates Intrauterine Adhesion by Suppressing Inflammation and Epithelial-Mesenchymal Transition via Inhibiting the TGF-β/Smad2 Signaling Pathway. Pharmaceuticals (Basel) 2023; 16:964. [PMID: 37513876 PMCID: PMC10384231 DOI: 10.3390/ph16070964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 06/30/2023] [Accepted: 07/04/2023] [Indexed: 07/30/2023] Open
Abstract
Intrauterine adhesion (IUA) is a common gynecological disease with limited therapeutic options. Dulaglutide is a long-acting glucagon-like peptide-1 (GLP-1) analog with some anti-fibrotic and anti-inflammatory properties; however, its action on IUA remains uncertain. The purpose of the experiments in this study was to explore the effect of dulaglutide on IUA and to elucidate its mechanism to provide new ideas for the clinical treatment of IUA. An IUA mouse model was established via mechanical curettage and inflammation induction; mice received subcutaneous injection with three doses of dulaglutide once a day for two weeks (treatment) or equal amounts of sterile ddH2O (control), and sham-operated mice were treated similarly to the control mice. Mice were sacrificed, and uterine tissues were subjected to hematoxylin and eosin (H&E) and Masson's trichrome staining for histomorphological and pathological analyses and real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting (WB) for gene and protein expression analyses. Dulaglutide improved the shape of the uterine cavity, increased endometrial thickness and the number of glands, and significantly reduced the area of collagen fiber deposition in the endometrium. It significantly reduced collagen type I A 1 (COL1A1), interleukin-1beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), C-C motif chemokine ligand 2 (CCL2), F4/80 (macrophage), vimentin and transforming growth factor-beta (TGF-β) mRNA levels and COL1A1, IL-1β, IL-6, TNF-α, F4/80, vimentin, E-cadherin, TGF-β, and p-Smad2 protein expression levels. This study demonstrates that dulaglutide reduces inflammatory responses by inhibiting M1 macrophage polarization and inflammatory factor release and may ameliorate fibrosis by inhibiting epithelial-mesenchymal transition (EMT) via TGF-β/Smad2 signaling.
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Affiliation(s)
- Yifan Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China
| | - Yixiang Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China
| | - Yang Wu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China
| | - Yiqing Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China
- Gansu International Scientific and Technological Cooperation Base of Reproductive Medicine Transformation Application, Gansu Key Laboratory of Reproductive Medicine and Embryo, Lanzhou 730000, China
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22
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Ying Z, van Eenige R, Ge X, van Marwijk C, Lambooij JM, Guigas B, Giera M, de Boer JF, Coskun T, Qu H, Wang Y, Boon MR, Rensen PCN, Kooijman S. Combined GIP receptor and GLP1 receptor agonism attenuates NAFLD in male APOE∗3-Leiden.CETP mice. EBioMedicine 2023; 93:104684. [PMID: 37379656 DOI: 10.1016/j.ebiom.2023.104684] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 06/30/2023] Open
Abstract
BACKGROUND Combined glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP1R) agonism is superior to single GLP1R agonism with respect to glycemic control and weight loss in obese patients with or without type 2 diabetes. As insulin resistance and obesity are strong risk factors for nonalcoholic fatty liver disease (NAFLD), in the current study we investigated the effects of combined GIPR/GLP1R agonism on NAFLD development. METHODS Male APOE∗3-Leiden.CETP mice, a humanized model for diabetic dyslipidemia and NAFLD when fed a high-fat high-cholesterol diet, received subcutaneous injections with either vehicle, a GIPR agonist, a GLP1R agonist, or both agonists combined every other day. FINDINGS GIPR and GLP1R agonism reduced body weight and additively lowered fasting plasma levels of glucose, triglycerides and total cholesterol. Strikingly, we report an additive reduction in hepatic steatosis as evidenced by lower hepatic lipid content and NAFLD scores. Underlying the lipid-lowering effects were a reduced food intake and intestinal lipid absorption and an increased uptake of glucose and triglyceride-derived fatty acids by energy-combusting brown adipose tissue. Combined GIPR/GLP1R agonism also attenuated hepatic inflammation as evidenced by a decreased number of monocyte-derived Kupffer cells and a reduced expression of inflammatory markers. Together, the reduced hepatic steatosis and inflammation coincided with lowered markers of liver injury. INTERPRETATION We interpretate that GIPR and GLP1R agonism additively attenuate hepatic steatosis, lower hepatic inflammation, ameliorate liver injury, together preventing NAFLD development in humanized APOE∗3-Leiden.CETP mice. We anticipate that combined GIPR/GLP1R agonism is a promising strategy to attenuate NAFLD progression in humans. FUNDING This work was supported by a grant from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences [CVON-GENIUS-II] to P.C.N.R., a Lilly Research Award Program [LRAP] Award to P.C.N.R. and S.K., a Dutch Heart Foundation [2017T016] grant to S.K., and an NWO-VENI grant [09150161910073] to M.R.B.; J.F.D.B. is supported by the Nutrition and Health initiative of the University of Groningen; Z.Y. is supported by a full-time PhD scholarship from the China Scholarship Council (201806850094 to Z.Y.).
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Affiliation(s)
- Zhixiong Ying
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Robin van Eenige
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Xiaoke Ge
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Christy van Marwijk
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Joost M Lambooij
- Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Bruno Guigas
- Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands
| | - Martin Giera
- The Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
| | - Jan Freark de Boer
- Departments of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Tamer Coskun
- Department of Diabetes/Endocrine, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, United States
| | - Hongchang Qu
- Department of Diabetes/Endocrine, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, United States
| | - Yanan Wang
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Med-X Institute, Center for Immunological and Metabolic Diseases and Department of Endocrinology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, China
| | - Mariëtte R Boon
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Patrick C N Rensen
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Sander Kooijman
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
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23
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Yan C, Ma X, Lam SM, Zhang Y, Cao Y, Dong Y, Su L, Shui G, Feng Y. Exendin-4 attenuates atherosclerosis progression via controlling hematopoietic stem/progenitor cell proliferation. J Mol Cell Biol 2023; 15:mjad014. [PMID: 36866528 PMCID: PMC10478625 DOI: 10.1093/jmcb/mjad014] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 12/01/2022] [Accepted: 03/01/2023] [Indexed: 03/04/2023] Open
Abstract
Beyond glycemic control, applications of glucagon-like peptide-1 receptor (GLP-1r) agonists (GLP-1 RAs) inhibit inflammation and plaque development in murine atherosclerotic models. However, whether they modulate hematopoietic stem/progenitor cells (HSPCs) to prohibit skewed myelopoiesis in hypercholesteremia remains unknown. In this study, GLP-1r expression in fluorescence-activated cell sorting (FACS)-sorted wild-type HSPCs was determined by capillary western blotting. Bone marrow cells (BMCs) of wild-type or GLP-1r-/- mice were transplanted into lethally irradiated low-density lipoprotein receptor deficient (LDLr-/-) recipients followed by high-fat diet (HFD) for chimerism analysis by FACS. In parallel, LDLr-/- mice were placed on HFD for 6 weeks and then treated with saline or Exendin-4 (Ex-4) for another 6 weeks. HSPC frequency and cell cycle were analyzed by FACS, and intracellular metabolite levels were assessed by targeted metabolomics. The results demonstrated that HSPCs expressed GLP-1r and transplantation of GLP-1r-/- BMCs resulted in skewed myelopoiesis in hypercholesterolemic LDLr-/- recipients. In vitro, Ex-4 treatment of FACS-purified HSPCs suppressed cell expansion and granulocyte production induced by LDL. In vivo, Ex-4 treatment inhibited plaque progression, suppressed HSPC proliferation, and modified glycolytic and lipid metabolism in HSPCs of hypercholesteremic LDLr-/- mice. In conclusion, Ex-4 could directly inhibit HSPC proliferation induced by hypercholesteremia.
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Affiliation(s)
- Cen Yan
- Department of Science and Development, Beijing Youan hospital, Capital Medical University, Beijing 100069, China
| | - Xiaojuan Ma
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
| | - Sin Man Lam
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yuejie Zhang
- Department of Science and Development, Beijing Youan hospital, Capital Medical University, Beijing 100069, China
| | - Yu Cao
- Department of Science and Development, Beijing Youan hospital, Capital Medical University, Beijing 100069, China
| | - Yuan Dong
- Department of Science and Development, Beijing Youan hospital, Capital Medical University, Beijing 100069, China
| | - Li Su
- Neuroscience Research Institute, Peking University Center of Medical and Health Analysis, Peking University, Beijing 100191, China
| | - Guanghou Shui
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yingmei Feng
- Department of Science and Development, Beijing Youan hospital, Capital Medical University, Beijing 100069, China
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24
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Frankowski R, Kobierecki M, Wittczak A, Różycka-Kosmalska M, Pietras T, Sipowicz K, Kosmalski M. Type 2 Diabetes Mellitus, Non-Alcoholic Fatty Liver Disease, and Metabolic Repercussions: The Vicious Cycle and Its Interplay with Inflammation. Int J Mol Sci 2023; 24:ijms24119677. [PMID: 37298632 DOI: 10.3390/ijms24119677] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/26/2023] [Accepted: 05/31/2023] [Indexed: 06/12/2023] Open
Abstract
The prevalence of metabolic-related disorders, such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (DM2), has been increasing. Therefore, developing improved methods for the prevention, treatment, and detection of these two conditions is also necessary. In this study, our primary focus was on examining the role of chronic inflammation as a potential link in the pathogenesis of these diseases and their interconnections. A comprehensive search of the PubMed database using keywords such as "non-alcoholic fatty liver disease", "type 2 diabetes mellitus", "chronic inflammation", "pathogenesis", and "progression" yielded 177 relevant papers for our analysis. The findings of our study revealed intricate relationships between the pathogenesis of NAFLD and DM2, emphasizing the crucial role of inflammatory processes. These connections involve various molecular functions, including altered signaling pathways, patterns of gene methylation, the expression of related peptides, and up- and downregulation of several genes. Our study is a foundational platform for future research into the intricate relationship between NAFLD and DM2, allowing for a better understanding of the underlying mechanisms and the potential for introducing new treatment standards.
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Affiliation(s)
- Rafał Frankowski
- Students' Research Club, Department of Clinical Pharmacology, Medical University of Lodz, 90-153 Lodz, Poland
| | - Mateusz Kobierecki
- Students' Research Club, Department of Clinical Pharmacology, Medical University of Lodz, 90-153 Lodz, Poland
| | - Andrzej Wittczak
- Students' Research Club, Department of Clinical Pharmacology, Medical University of Lodz, 90-153 Lodz, Poland
| | | | - Tadeusz Pietras
- Department of Clinical Pharmacology, Medical University of Lodz, 90-153 Lodz, Poland
| | - Kasper Sipowicz
- Department of Interdisciplinary Disability Studies, The Maria Grzegorzewska University in Warsaw, 02-353 Warsaw, Poland
| | - Marcin Kosmalski
- Department of Clinical Pharmacology, Medical University of Lodz, 90-153 Lodz, Poland
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25
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Mehdi SF, Pusapati S, Anwar MS, Lohana D, Kumar P, Nandula SA, Nawaz FK, Tracey K, Yang H, LeRoith D, Brownstein MJ, Roth J. Glucagon-like peptide-1: a multi-faceted anti-inflammatory agent. Front Immunol 2023; 14:1148209. [PMID: 37266425 PMCID: PMC10230051 DOI: 10.3389/fimmu.2023.1148209] [Citation(s) in RCA: 93] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 04/26/2023] [Indexed: 06/03/2023] Open
Abstract
Inflammation contributes to many chronic conditions. It is often associated with circulating pro-inflammatory cytokines and immune cells. GLP-1 levels correlate with disease severity. They are often elevated and can serve as markers of inflammation. Previous studies have shown that oxytocin, hCG, ghrelin, alpha-MSH and ACTH have receptor-mediated anti-inflammatory properties that can rescue cells from damage and death. These peptides have been studied well in the past century. In contrast, GLP-1 and its anti-inflammatory properties have been recognized only recently. GLP-1 has been proven to be a useful adjuvant therapy in type-2 diabetes mellitus, metabolic syndrome, and hyperglycemia. It also lowers HbA1C and protects cells of the cardiovascular and nervous systems by reducing inflammation and apoptosis. In this review we have explored the link between GLP-1, inflammation, and sepsis.
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Affiliation(s)
- Syed Faizan Mehdi
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Suma Pusapati
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Muhammad Saad Anwar
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Durga Lohana
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Parkash Kumar
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | | | - Fatima Kausar Nawaz
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Kevin Tracey
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Huan Yang
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Derek LeRoith
- Division of Endocrinology, Diabetes & Bone Disease, Icahn School of Medicine at Mt. Sinai, New York, NY, United States
| | | | - Jesse Roth
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
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26
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Inia JA, Stokman G, Morrison MC, Worms N, Verschuren L, Caspers MPM, Menke AL, Petitjean L, Chen L, Petitjean M, Jukema JW, Princen HMG, van den Hoek AM. Semaglutide Has Beneficial Effects on Non-Alcoholic Steatohepatitis in Ldlr-/-.Leiden Mice. Int J Mol Sci 2023; 24:ijms24108494. [PMID: 37239841 DOI: 10.3390/ijms24108494] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/04/2023] [Accepted: 05/07/2023] [Indexed: 05/28/2023] Open
Abstract
Semaglutide, a glucagon-like peptide-1 receptor agonist, is an antidiabetic medication that has recently been approved for the treatment of obesity as well. Semaglutide is postulated to be a promising candidate for the treatment of non-alcoholic steatohepatitis (NASH). Here, Ldlr-/-.Leiden mice received a fast-food diet (FFD) for 25 weeks, followed by another 12 weeks on FFD with daily subcutaneous injections of semaglutide or vehicle (control). Plasma parameters were evaluated, livers and hearts were examined, and hepatic transcriptome analysis was performed. In the liver, semaglutide significantly reduced macrovesicular steatosis (-74%, p < 0.001) and inflammation (-73%, p < 0.001) and completely abolished microvesicular steatosis (-100%, p < 0.001). Histological and biochemical assessment of hepatic fibrosis showed no significant effects of semaglutide. However, digital pathology revealed significant improvements in the degree of collagen fiber reticulation (-12%, p < 0.001). Semaglutide did not affect atherosclerosis relative to controls. Additionally, we compared the transcriptome profile of FFD-fed Ldlr-/-.Leiden mice with a human gene set that differentiates human NASH patients with severe fibrosis from those with mild fibrosis. In FFD-fed Ldlr-/-.Leiden control mice, this gene set was upregulated as well, while semaglutide predominantly reversed this gene expression. Using a translational model with advanced NASH, we demonstrated that semaglutide is a promising candidate with particular potential for the treatment of hepatic steatosis and inflammation, while for the reversal of advanced fibrosis, combinations with other NASH agents may be necessary.
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Affiliation(s)
- José A Inia
- Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands
- Cardiology, Leiden University Medical Center (LUMC), 2333 ZA Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center (LUMC), 2300 RC Leiden, The Netherlands
| | - Geurt Stokman
- Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands
| | - Martine C Morrison
- Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands
| | - Nicole Worms
- Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands
| | - Lars Verschuren
- Microbiology and Systems Biology, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands
| | - Martien P M Caspers
- Microbiology and Systems Biology, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands
| | - Aswin L Menke
- Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands
| | | | - Li Chen
- PharmaNest Inc., Princeton, NJ 08540, USA
| | | | - J Wouter Jukema
- Cardiology, Leiden University Medical Center (LUMC), 2333 ZA Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center (LUMC), 2300 RC Leiden, The Netherlands
- Netherlands Heart Institute, 3511 EP Utrecht, The Netherlands
| | - Hans M G Princen
- Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands
| | - Anita M van den Hoek
- Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands
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27
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Yabut JM, Drucker DJ. Glucagon-like Peptide-1 Receptor-based Therapeutics for Metabolic Liver Disease. Endocr Rev 2023; 44:14-32. [PMID: 35907261 DOI: 10.1210/endrev/bnac018] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Indexed: 01/14/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) controls islet hormone secretion, gut motility, and body weight, supporting development of GLP-1 receptor agonists (GLP-1RA) for the treatment of type 2 diabetes (T2D) and obesity. GLP-1RA exhibit a favorable safety profile and reduce the incidence of major adverse cardiovascular events in people with T2D. Considerable preclinical data, supported by the results of clinical trials, link therapy with GLP-RA to reduction of hepatic inflammation, steatosis, and fibrosis. Mechanistically, the actions of GLP-1 on the liver are primarily indirect, as hepatocytes, Kupffer cells, and stellate cells do not express the canonical GLP-1R. GLP-1RA reduce appetite and body weight, decrease postprandial lipoprotein secretion, and attenuate systemic and tissue inflammation, actions that may contribute to attenuation of metabolic-associated fatty liver disease (MAFLD). Here we discuss evolving concepts of GLP-1 action that improve liver health and highlight evidence that links sustained GLP-1R activation in distinct cell types to control of hepatic glucose and lipid metabolism, and reduction of experimental and clinical nonalcoholic steatohepatitis (NASH). The therapeutic potential of GLP-1RA alone, or in combination with peptide agonists, or new small molecule therapeutics is discussed in the context of potential efficacy and safety. Ongoing trials in people with obesity will further clarify the safety of GLP-1RA, and pivotal studies underway in people with NASH will define whether GLP-1-based medicines represent effective and safe therapies for people with MAFLD.
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Affiliation(s)
- Julian M Yabut
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Daniel J Drucker
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, ON, Canada
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28
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Dong Z, Sun X, Tang Y, Luo S, Jia H, Xu Q, Jiang Q, Loor JJ, Xu W, Xu C. β-hydroxybutyrate impairs monocyte function via the ROS-NLR family pyrin domain-containing three inflammasome (NLRP3) pathway in ketotic cows. Front Vet Sci 2022; 9:925900. [PMID: 36105004 PMCID: PMC9464975 DOI: 10.3389/fvets.2022.925900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
Cows with ketosis display severe metabolic stress and immune dysfunction which renders them more susceptible to infections. Monocytes, one of the major subtypes of white blood cells, play an important role in innate immune defense against infections. Thus, the aim of this study was to investigate alterations in immune function, reactive oxygen species (ROS) production and activity of the NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway in monocytes (CD14+) of cows with clinical ketosis (CK). Twelve healthy multiparous Holstein cows [blood β-hydroxybutyrate (BHB) concentration < 1.2 mM] and 12 cows with CK (BHB > 3.0 mM) at 3 to 14 days in milk were used for blood sample collection. To determine effects of BHB on phagocytosis, ROS and protein abundance of the NLRP3 inflammasome pathway in vitro, monocytes isolated from healthy cows were treated with 3.0 mM BHB for 0, 6, 12 or 24 h. Dry matter intake (22.7 vs. 19.0 kg) was lower in cows with CK. Serum concentrations of fatty acids (0.30 vs. 0.88 mM) and BHB (0.52 vs. 3.78 mM) were greater in cows with CK, whereas concentration of glucose was lower (4.09 vs. 2.23 mM). The adhesion, migration and phagocytosis of monocytes were lower in cows with CK, but apoptosis and ROS content were greater. Protein abundance of NLRP3, cysteinyl aspartate specific proteinase 1 (caspase 1) and interleukin-1B p17 (IL1B p17) were greater in monocytes of cows with CK, while abundance of NADPH oxidase isoform 2 (NOX2) was lower. Compared with 0 h BHB, ROS content and apoptosis were greater in the monocytes challenged for 6, 12 or 24 h BHB. Compared with 0 h BHB, protein abundance of NLRP3, caspase 1, IL1B p17 and concentration of IL1B in medium were greater in the monocytes challenged for 6, 12 or 24 h BHB. However, compared with 0 h BHB, protein abundance of NOX2 and phagocytosis of monocytes were lower in the monocytes challenged for 6, 12 or 24 h BHB. Overall, the data suggested that exogenous BHB activated the ROS-NLRP3 pathway, which might be partly responsible for immune dysfunction of dairy cows with CK.
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Affiliation(s)
- Zhihao Dong
- Heilongjiang Provincial Key Laboratory of Prevention and Control of Bovine Diseases, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Xudong Sun
- Heilongjiang Provincial Key Laboratory of Prevention and Control of Bovine Diseases, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Yan Tang
- Heilongjiang Provincial Key Laboratory of Prevention and Control of Bovine Diseases, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Shengbin Luo
- Heilongjiang Provincial Key Laboratory of Prevention and Control of Bovine Diseases, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Hongdou Jia
- Heilongjiang Provincial Key Laboratory of Prevention and Control of Bovine Diseases, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Qiushi Xu
- Heilongjiang Provincial Key Laboratory of Prevention and Control of Bovine Diseases, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Qianming Jiang
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL, United States
| | - Juan J. Loor
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL, United States
| | - Wei Xu
- Department of Biosystems, Biosystems Technology Cluster, KULeuven, Geel, Belgium
| | - Chuang Xu
- Heilongjiang Provincial Key Laboratory of Prevention and Control of Bovine Diseases, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
- *Correspondence: Chuang Xu
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Exendin-4 Exacerbates Burn-Induced Mortality in Mice by Switching to Th2 Response. J Surg Res 2022; 280:333-347. [PMID: 36030610 DOI: 10.1016/j.jss.2022.07.029] [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: 02/22/2022] [Revised: 07/14/2022] [Accepted: 07/28/2022] [Indexed: 11/21/2022]
Abstract
INTRODUCTION To determine if Exendin-4 could be a therapeutic agent for burn-induced hyperglycemia. MATERIALS AND METHODS Male Balb/c mice received a bolus of Exendin-4 intraperitoneally immediately after 15% total body surface area scald injury. Tail glucose levels were recorded and T-cell functions were analyzed at 4 h and 24 h postburn (pb). Pancreatic pathology was observed consecutively. The secretions of cytokines were detected in serum, spleen, and lung. Apoptosis of splenic CD3+ T-cells was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and flow cytometry. RESULTS Although Exendin-4 could attenuate burn-induced hyperglycemia in mice at 4 h pb, it accelerated their survival dose dependently with progressive depletion of splenocyte number. T-cell function underwent two-phasic changes following Exendin-4 treatment. Compared to placebo mice, T-cell from Exendin-4-treated mice was manifested with increased proliferation, while decreased IL-2 secretion and lower ratio of IL-4/IFN-γ at 4 h pb. However, at 24 h pb, it showed decreased proliferation, while increased IL-2 secretion and higher ratio of IL-4/IFN-γ. Exendin-4 could elicit higher circulating IL-6 and IL-10 levels at 4 h pb, which were pronounced in the lung at 24 h pb. In the meanwhile, severe inflammation could be found in the pancreas. At 24 h pb, the numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling or caspase-3 positive cells and the apoptosis of CD3+ T-cells were significantly increased in the spleens of Exendin-4 mice relative to placebo mice. CONCLUSIONS These data support a pathogenic role of Exendin-4 signaling during thermal injury, warning against its clinical application in acute insults.
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Ying Z, Tramper N, Zhou E, Boon MR, Rensen PCN, Kooijman S. Role of thermogenic adipose tissue in lipid metabolism and atherosclerotic cardiovascular disease: lessons from studies in mice and humans. Cardiovasc Res 2022; 119:905-918. [PMID: 35944189 PMCID: PMC10153643 DOI: 10.1093/cvr/cvac131] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 05/09/2022] [Accepted: 06/02/2022] [Indexed: 11/12/2022] Open
Abstract
Brown adipocytes within brown adipose tissue (BAT) and beige adipocytes within white adipose tissue dissipate nutritional energy as heat. Studies in mice have shown that activation of thermogenesis in brown and beige adipocytes enhances the lipolytic processing of triglyceride-rich lipoproteins (TRLs) in plasma to supply these adipocytes with fatty acids for oxidation. This process results in formation of TRL remnants that are removed from the circulation through binding of apolipoprotein E (ApoE) on their surface to the low-density lipoprotein receptor (LDLR) on hepatocytes, followed by internalization. Concomitantly, lipolytic processing of circulating TRLs leads to generation of excess surface phospholipids that are transferred to nascent high-density lipoproteins (HDL), increasing their capacity for reverse cholesterol transport. Activation of thermogenic adipocytes thus lowers circulating triglycerides and non-HDL-cholesterol, while it increases HDL-cholesterol. The combined effect is protection from atherosclerosis development, which becomes evident in humanized mouse models with an intact ApoE-LDLR clearance pathway only, and is additive to the effects of classical lipid-lowering drugs including statins and proprotein convertase subtilisin/kexin type 9 inhibitors. A large recent study revealed that the presence of metabolically active BAT in humans is associated with lower triglycerides, higher HDL-cholesterol and lower risk of cardiovascular diseases. This narrative review aims to provide leads for further exploration of thermogenic adipose tissue as a therapeutic target. To this end, we describe the latest knowledge on the role of BAT in lipoprotein metabolism and address, for example, the discovery of the β2-adrenergic receptor as the dominant adrenergic receptor in human thermogenic adipocytes.
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Affiliation(s)
- Zhixiong Ying
- Department of Medicine, Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Naomi Tramper
- Department of Medicine, Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Enchen Zhou
- Department of Medicine, Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Mariëtte R Boon
- Department of Medicine, Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
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GLP-1 Receptor Agonists in Neurodegeneration: Neurovascular Unit in the Spotlight. Cells 2022; 11:cells11132023. [PMID: 35805109 PMCID: PMC9265397 DOI: 10.3390/cells11132023] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 06/21/2022] [Accepted: 06/23/2022] [Indexed: 02/07/2023] Open
Abstract
Defects in brain energy metabolism and proteopathic stress are implicated in age-related degenerative neuronopathies, exemplified by Alzheimer’s disease (AD) and Parkinson’s disease (PD). As the currently available drug regimens largely aim to mitigate cognitive decline and/or motor symptoms, there is a dire need for mechanism-based therapies that can be used to improve neuronal function and potentially slow down the underlying disease processes. In this context, a new class of pharmacological agents that achieve improved glycaemic control via the glucagon-like peptide 1 (GLP-1) receptor has attracted significant attention as putative neuroprotective agents. The experimental evidence supporting their potential therapeutic value, mainly derived from cellular and animal models of AD and PD, has been discussed in several research reports and review opinions recently. In this review article, we discuss the pathological relevance of derangements in the neurovascular unit and the significance of neuron–glia metabolic coupling in AD and PD. With this context, we also discuss some unresolved questions with regard to the potential benefits of GLP-1 agonists on the neurovascular unit (NVU), and provide examples of novel experimental paradigms that could be useful in improving our understanding regarding the neuroprotective mode of action associated with these agents.
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Bendotti G, Montefusco L, Lunati ME, Usuelli V, Pastore I, Lazzaroni E, Assi E, Seelam AJ, El Essawy B, Jang Y, Loretelli C, D'Addio F, Berra C, Ben Nasr M, Zuccotti G, Fiorina P. The anti-inflammatory and immunological properties of GLP-1 Receptor Agonists. Pharmacol Res 2022; 182:106320. [PMID: 35738455 DOI: 10.1016/j.phrs.2022.106320] [Citation(s) in RCA: 143] [Impact Index Per Article: 47.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/16/2022] [Accepted: 06/16/2022] [Indexed: 12/29/2022]
Abstract
In the last few years, a great interest has emerged in investigating the pleiotropic effects of Glucagon Like Peptide-1 Receptor Agonists (GLP-1RAs). While GLP-1RAs ability to lower plasma glucose and to induce weight loss has allowed them to be approved for the treatment of diabetes and obesity, consistent evidences from in vitro studies and preclinical models suggested that GLP-1RAs have anti-inflammatory properties and that may modulate the immune-system. Notably, such anti-inflammatory effects target different pathways in different tissues, underling the broad spectrum of GLP-1RAs actions. This review examines some of the currently proposed molecular mechanisms of GLP-1RAs actions and explores their potential benefits in reducing inflammatory responses, which may well suggest a future therapeutic use of GLP-1RAs in new indications.
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Affiliation(s)
- Giulia Bendotti
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Laura Montefusco
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | | | - Vera Usuelli
- International Center for T1D, Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Ida Pastore
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Elisa Lazzaroni
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Emma Assi
- International Center for T1D, Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Andy Joe Seelam
- International Center for T1D, Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Basset El Essawy
- Transplantation Research Center, Nephrology Division, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Medicine, Al-Azhar University, Cairo, Egypt
| | - Yun Jang
- Institute of Organ Transplantation, Tongji Hospital and Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cristian Loretelli
- International Center for T1D, Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Francesca D'Addio
- International Center for T1D, Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Cesare Berra
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS Multimedica, Milan, Italy
| | - Moufida Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - GianVincenzo Zuccotti
- Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano and Department of Pediatrics, Buzzi Children's Hospital, Milan, Italy
| | - Paolo Fiorina
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy; International Center for T1D, Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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Galatou E, Mourelatou E, Hatziantoniou S, Vizirianakis IS. Nonalcoholic Steatohepatitis (NASH) and Atherosclerosis: Explaining Their Pathophysiology, Association and the Role of Incretin-Based Drugs. Antioxidants (Basel) 2022; 11:1060. [PMID: 35739957 PMCID: PMC9220192 DOI: 10.3390/antiox11061060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 11/17/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is the most severe manifestation of nonalcoholic fatty liver disease (NAFLD), a common complication of type 2 diabetes, and may lead to cirrhosis and hepatocellular carcinoma. Oxidative stress and liver cell damage are the major triggers of the severe hepatic inflammation that characterizes NASH, which is highly correlated with atherosclerosis and coronary artery disease. Regarding drug therapy, research on the role of GLP-1 analogues and DPP4 inhibitors, novel classes of antidiabetic drugs, is growing. In this review, we outline the association between NASH and atherosclerosis, the underlying molecular mechanisms, and the effects of incretin-based drugs, especially GLP-1 RAs, for the therapeutic management of these conditions.
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Affiliation(s)
- Eleftheria Galatou
- Department of Life & Health Sciences, School of Sciences and Engineering, University of Nicosia, 2417 Nicosia, Cyprus;
| | - Elena Mourelatou
- Department of Life & Health Sciences, School of Sciences and Engineering, University of Nicosia, 2417 Nicosia, Cyprus;
| | - Sophia Hatziantoniou
- Laboratory of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, University of Patras, 26504 Patras, Greece;
| | - Ioannis S. Vizirianakis
- Department of Life & Health Sciences, School of Sciences and Engineering, University of Nicosia, 2417 Nicosia, Cyprus;
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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Shou X, Wang Y, Duan C, Yuan G, Wei N, Yang Y, Hu Y. Knowledge Domain and Emerging Trends of Glucagon-Like Peptide 1 Receptor Agonists in Cardiovascular Research: A Bibliometric Analysis. Curr Probl Cardiol 2022:101194. [PMID: 35395332 DOI: 10.1016/j.cpcardiol.2022.101194] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 04/02/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND Patients with type 2 diabetes (T2DM) are more likely to have cardiovascular disease (CVD). Glucose-lowering drugs with cardiovascular benefits represented by Glucagon-like peptide 1 receptor agonists (GLP1RAs) were discovered and gained more and more attention. METHODS Data from 1985 to the 2021 were downloaded in the Web of Science Core Collection (WoSCC) database. CiteSpaceV was used for bibliometric analysis to find research hotspots and frontiers. RESULTS The 2088 papers were published by 74 countries (regions), 876 institutions, and 2203 authors. The annual publications increased over time from 2005 to 2020. DIABETES OBESITY METABOLISM published the most papers. The USA and China were the top 2 productive nations. The leading institution was the University of Copenhagen, and the most productive researcher was John B Buse. The most cited paper is "Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes" (by Marso SP, 2016). The research hotspots include the effects of GLP1RA on cardiovascular outcomes, efficacy, complicated metabolic abnormalities, protective mechanisms, and other novel anti-diabetic drugs for cardiovascular protection. Research frontiers include cardiovascular studies on semaglutide, as well as the most prominent research approach in the field-placebo-controlled trial. CONCLUSION Numerous countries, institutions, and authors have focused on GLP1RA in cardiovascular research and a great deal of literature has been published. Five research hotspots and two frontiers illustrate the current status and emerging trends of GLP1RA in cardiovascular research. The cardiovascular effects and clinical efficacy of GLP1RA are a current hot topic that is rapidly evolving and of high research value.
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Affiliation(s)
- Xintian Shou
- Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yumeng Wang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Chenglin Duan
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Guozhen Yuan
- Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Namin Wei
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yihan Yang
- Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuanhui Hu
- Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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Møllerhøj MB, Veidal SS, Thrane KT, Oró D, Overgaard A, Salinas CG, Madsen MR, Pfisterer L, Vyberg M, Simon E, Broermann A, Vrang N, Jelsing J, Feigh M, Hansen HH. Hepatoprotective effects of semaglutide, lanifibranor and dietary intervention in the GAN diet‐induced obese and biopsy‐confirmed mouse model of NASH. Clin Transl Sci 2022; 15:1167-1186. [PMID: 35143711 PMCID: PMC9099137 DOI: 10.1111/cts.13235] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 12/23/2021] [Accepted: 01/18/2022] [Indexed: 11/30/2022] Open
Abstract
Non‐alcoholic steatohepatitis (NASH) has emerged as a major challenge for public health because of high global prevalence and lack of evidence‐based therapies. Most animal models of NASH lack sufficient validation regarding disease progression and pharmacological treatment. The Gubra‐Amylin NASH (GAN) diet‐induced obese (DIO) mouse demonstrate clinical translatability with respect to disease etiology and hallmarks of NASH. This study aimed to evaluate disease progression and responsiveness to clinically effective interventions in GAN DIO‐NASH mice. Disease phenotyping was performed in male C57BL/6J mice fed the GAN diet high in fat, fructose, and cholesterol for 28–88 weeks. GAN DIO‐NASH mice with biopsy‐confirmed NASH and fibrosis received low‐caloric dietary intervention, semaglutide (30 nmol/kg/day, s.c.) or lanifibranor (30 mg/kg/day, p.o.) for 8 and 12 weeks, respectively. Within‐subject change in nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) and fibrosis stage was evaluated using automated deep learning‐based image analysis. GAN DIO‐NASH mice showed clear and reproducible progression in NASH, fibrosis stage, and tumor burden with high incidence of hepatocellular carcinoma. Consistent with clinical trial outcomes, semaglutide and lanifibranor improved NAS, whereas only lanifibranor induced regression in the fibrosis stage. Dietary intervention also demonstrated substantial benefits on metabolic outcomes and liver histology. Differential therapeutic efficacy of semaglutide, lanifibranor, and dietary intervention was supported by quantitative histology, RNA sequencing, and blood/liver biochemistry. In conclusion, the GAN DIO‐NASH mouse model recapitulates various histological stages of NASH and faithfully reproduces histological efficacy profiles of compounds in advanced clinical development for NASH. Collectively, these features highlight the utility of GAN DIO‐NASH mice in preclinical drug development.
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Affiliation(s)
| | | | | | - Denise Oró
- Gubra, Hørsholm Kongevej 11B, DK‐2970 Hørsholm Denmark
| | | | | | | | - Larissa Pfisterer
- Boehringer‐Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss Germany
| | - Mogens Vyberg
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University Copenhagen Denmark
| | - Eric Simon
- Boehringer‐Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss Germany
| | - Andre Broermann
- Boehringer‐Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss Germany
| | - Niels Vrang
- Gubra, Hørsholm Kongevej 11B, DK‐2970 Hørsholm Denmark
| | - Jacob Jelsing
- Gubra, Hørsholm Kongevej 11B, DK‐2970 Hørsholm Denmark
| | - Michael Feigh
- Gubra, Hørsholm Kongevej 11B, DK‐2970 Hørsholm Denmark
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McLean BA, Wong CK, Kaur KD, Seeley RJ, Drucker DJ. Differential importance of endothelial and hematopoietic cell GLP-1Rs for cardiometabolic versus hepatic actions of semaglutide. JCI Insight 2021; 6:153732. [PMID: 34673572 PMCID: PMC8663785 DOI: 10.1172/jci.insight.153732] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 09/30/2021] [Indexed: 01/24/2023] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used to treat diabetes and obesity and reduce rates of major cardiovascular events, such as stroke and myocardial infarction. Nevertheless, the identity of GLP-1R–expressing cell types mediating the cardiovascular benefits of GLP-1RA remains incompletely characterized. Herein, we investigated the importance of murine Glp1r expression within endothelial and hematopoietic cells. Mice with targeted inactivation of Glp1r in Tie2+ cells exhibited reduced levels of Glp1r mRNA transcripts in aorta, liver, spleen, blood, and gut. Glp1r expression in bone marrow cells was very low and not further reduced in Glp1rTie2–/– mice. The GLP-1RA semaglutide reduced the development of atherosclerosis induced by viral PCSK9 expression in both Glp1rTie2+/+ and Glp1rTie2–/– mice. Hepatic Glp1r mRNA transcripts were reduced in Glp1rTie2–/– mice, and liver Glp1r expression was localized to γδ T cells. Moreover, semaglutide reduced hepatic Tnf, Abcg1, Tgfb1, Cd3g, Ccl2, and Il2 expression; triglyceride content; and collagen accumulation in high-fat, high-cholesterol diet–fed Glp1rTie2+/+ mice but not Glp1rTie2–/– mice. Collectively, these findings demonstrate that Tie2+ endothelial or hematopoietic cell GLP-1Rs are dispensable for the antiatherogenic actions of GLP-1RA, whereas Tie2-targeted GLP-1R+ cells are required for a subset of the antiinflammatory actions of semaglutide in the liver.
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Affiliation(s)
- Brent A McLean
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Chi Kin Wong
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Kiran Deep Kaur
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Daniel J Drucker
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
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Long-chain monounsaturated fatty acids improve endothelial function with altering microbial flora. Transl Res 2021; 237:16-30. [PMID: 33775867 DOI: 10.1016/j.trsl.2021.03.016] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 03/18/2021] [Accepted: 03/20/2021] [Indexed: 01/04/2023]
Abstract
Fish oil-derived long-chain monounsaturated fatty acids (LCMUFAs) with a carbon chain length longer than 18 units ameliorate cardiovascular risk in mice. In this study, we investigated whether LCMUFAs could improve endothelial functions in mice and humans. In a double-blind, randomized, placebo-controlled, parallel-group, multi-center study, healthy subjects were randomly assigned to either an LCMUFA oil (saury oil) or a control oil (olive and tuna oils) group. Sixty subjects were enrolled and administrated each oil for 4 weeks. For the animal study, ApoE-/- mice were fed a Western diet supplemented with 3% of either gadoleic acid (C20:1) or cetoleic acid (C22:1) for 12 weeks. Participants from the LCMUFA group showed improvements in endothelial function and a lower trimethylamine-N-oxide level, which is a predictor of coronary artery disease. C20:1 and C22:1 oils significantly improved atherosclerotic lesions and plasma levels of several inflammatory cytokines, including IL-6 and TNF-α. These beneficial effects were consistent with an improvement in the gut microbiota environment, as evident from the decreased ratio of Firmicutes and/ or Bacteroidetes, increase in the abundance of Akkermansia, and upregulation of short-chain fatty acid (SCFA)-induced glucagon-like peptide-1 (GLP-1) expression and serum GLP-1 level. These data suggest that LCMUFAs alter the microbiota environment that stimulate the production of SCFAs, resulting in the induction of GLP-1 secretion. Fish oil-derived long-chain monounsaturated fatty acids might thus help to protect against cardiovascular disease.
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Ahmadi A, Panahi Y, Johnston TP, Sahebkar A. Antidiabetic drugs and oxidized low-density lipoprotein: A review of anti-atherosclerotic mechanisms. Pharmacol Res 2021; 172:105819. [PMID: 34400317 DOI: 10.1016/j.phrs.2021.105819] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/12/2021] [Accepted: 08/12/2021] [Indexed: 02/07/2023]
Abstract
Cardiovascular disease is one of the leading causes of mortality globally. Atherosclerosis is an important step towards different types of cardiovascular disease. The role of oxidized low-density lipoprotein (oxLDL) in the initiation and progression of atherosclerosis has been thoroughly investigated in recent years. Moreover, clinical trials have established that diabetic patients are at a greater risk of developing atherosclerotic plaques. Hence, we aimed to review the clinical and experimental impacts of various classes of antidiabetic drugs on the circulating levels of oxLDL. Metformin, pioglitazone, and dipeptidyl peptidase-4 inhibitors were clinically associated with a suppressive effect on oxLDL in patients with impaired glucose tolerance. However, there is an insufficient number of studies that have clinically evaluated the relationship between oxLDL and newer agents such as agonists of glucagon-like peptide 1 receptor or inhibitors of sodium-glucose transport protein 2. Next, we attempted to explore the multitude of mechanisms that antidiabetic agents exert to counter the undesirable effects of oxLDL in macrophages, endothelial cells, and vascular smooth muscle cells. In general, antidiabetic drugs decrease the uptake of oxLDL by vascular cells and reduce subsequent inflammatory signaling, which prevents macrophage adhesion and infiltration. Moreover, these agents suppress the oxLDL-induced transformation of macrophages into foam cells by either inhibiting oxLDL entrance, or by facilitating its efflux. Thus, the anti-inflammatory, anti-oxidant, and anti-apoptotic properties of antidiabetic agents abrogate changes induced by oxLDL, which can be extremely beneficial in controlling atherosclerosis in diabetic patients.
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Affiliation(s)
- Ali Ahmadi
- Pharmacotherapy Department, Faculty of Pharmacy, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Yunes Panahi
- Pharmacotherapy Department, Faculty of Pharmacy, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Medicine, The University of Western Asutralia, Perth, Australia; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 9177948567, Iran.
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Radbakhsh S, Atkin SL, Simental-Mendia LE, Sahebkar A. The role of incretins and incretin-based drugs in autoimmune diseases. Int Immunopharmacol 2021; 98:107845. [PMID: 34126341 DOI: 10.1016/j.intimp.2021.107845] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/25/2021] [Accepted: 05/31/2021] [Indexed: 02/07/2023]
Abstract
Incretin hormones, including glucagon-like peptide (GLP)-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP), are gastrointestinal peptides secreted from enteroendocrine cells. These hormones play significant roles in many physiological processes via binding to G-protein coupled receptors (GPCRs) on different organs and tissues; one of them is the immunomodulatory effect on the immune system and its molecular components such as cytokines and chemokines. Anti-inflammatory effects of incretins and dependent molecules involving long-acting analogs and DPP4 inhibitors through regulation of T and B cell activation may attenuate autoimmune diseases caused by immune system disorders in mistakenly recognizing self as the foreign agent. In this review, we investigate incretin effects on the immune system response and the potential benefits of incretin-based therapy for treating autoimmune diseases.
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Affiliation(s)
- Shabnam Radbakhsh
- Department of Medical Biotechnology and Nanotechnology, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | | | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Medicine, The University of Western Australia, Perth, Australia; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Ma X, Liu Z, Ilyas I, Little PJ, Kamato D, Sahebka A, Chen Z, Luo S, Zheng X, Weng J, Xu S. GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential. Int J Biol Sci 2021; 17:2050-2068. [PMID: 34131405 PMCID: PMC8193264 DOI: 10.7150/ijbs.59965] [Citation(s) in RCA: 140] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 04/28/2021] [Indexed: 12/11/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is closely associated with cardiovascular diseases (CVD), including atherosclerosis, hypertension and heart failure. Some anti-diabetic medications are linked with an increased risk of weight gain or hypoglycemia which may reduce the efficacy of the intended anti-hyperglycemic effects of these therapies. The recently developed receptor agonists for glucagon-like peptide-1 (GLP-1RAs), stimulate insulin secretion and reduce glycated hemoglobin levels without having side effects such as weight gain and hypoglycemia. In addition, GLP1-RAs demonstrate numerous cardiovascular protective effects in subjects with or without diabetes. There have been several cardiovascular outcomes trials (CVOTs) involving GLP-1RAs, which have supported the overall cardiovascular benefits of these drugs. GLP1-RAs lower plasma lipid levels and lower blood pressure (BP), both of which contribute to a reduction of atherosclerosis and reduced CVD. GLP-1R is expressed in multiple cardiovascular cell types such as monocyte/macrophages, smooth muscle cells, endothelial cells, and cardiomyocytes. Recent studies have indicated that the protective properties against endothelial dysfunction, anti-inflammatory effects on macrophages and the anti-proliferative action on smooth muscle cells may contribute to atheroprotection through GLP-1R signaling. In the present review, we describe the cardiovascular effects and underlying molecular mechanisms of action of GLP-1RAs in CVOTs, animal models and cultured cells, and address how these findings have transformed our understanding of the pharmacotherapy of T2DM and the prevention of CVD.
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Affiliation(s)
- Xiaoxuan Ma
- Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Zhenghong Liu
- Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Iqra Ilyas
- Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Peter J Little
- Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, QLD 4575, Australia.,School of Pharmacy, Pharmacy Australia Centre of Excellence, the University of Queensland, Woolloongabba, Queensland 4102, Australia
| | - Danielle Kamato
- School of Pharmacy, Pharmacy Australia Centre of Excellence, the University of Queensland, Woolloongabba, Queensland 4102, Australia
| | - Amirhossein Sahebka
- Halal Research Center of IRI, FDA, Tehran, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad, Iran
| | - Zhengfang Chen
- Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu 215500, Jiangsu Province, China
| | - Sihui Luo
- Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Xueying Zheng
- Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Jianping Weng
- Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Suowen Xu
- Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
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Ramadan MS, Russo V, Nigro G, Durante-Mangoni E, Zampino R. Interplay between Heart Disease and Metabolic Steatosis: A Contemporary Perspective. J Clin Med 2021; 10:1569. [PMID: 33917867 PMCID: PMC8068259 DOI: 10.3390/jcm10081569] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 03/26/2021] [Accepted: 04/03/2021] [Indexed: 12/12/2022] Open
Abstract
The liver-heart axis is a growing field of interest owing to rising evidence of complex bidirectional interplay between the two organs. Recent data suggest non-alcoholic fatty liver disease (NAFLD) has a significant, independent association with a wide spectrum of structural and functional cardiac diseases, and seems to worsen cardiovascular disease (CVD) prognosis. Conversely, the effect of cardiac disease on NAFLD is not well studied and data are mostly limited to cardiogenic liver disease. We believe it is important to further investigate the heart-liver relationship because of the tremendous global health and economic burden the two diseases pose, and the impact of such investigations on clinical decision making and management guidelines for both diseases. In this review, we summarize the current knowledge on NAFLD diagnosis, its systemic manifestations, and associations with CVD. More specifically, we review the pathophysiological mechanisms that govern the interplay between NAFLD and CVD and evaluate the relationship between different CVD treatments and NAFLD progression.
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Affiliation(s)
- Mohammad Said Ramadan
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Vincenzo Russo
- Department of Translational Medical Sciences, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy; (V.R.); (G.N.)
- Cardiology Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
| | - Gerardo Nigro
- Department of Translational Medical Sciences, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy; (V.R.); (G.N.)
- Cardiology Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
| | - Emanuele Durante-Mangoni
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
- Infectious and Transplant Medicine Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy;
| | - Rosa Zampino
- Infectious and Transplant Medicine Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy;
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
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Andreadou I, Daiber A, Baxter GF, Brizzi MF, Di Lisa F, Kaludercic N, Lazou A, Varga ZV, Zuurbier CJ, Schulz R, Ferdinandy P. Influence of cardiometabolic comorbidities on myocardial function, infarction, and cardioprotection: Role of cardiac redox signaling. Free Radic Biol Med 2021; 166:33-52. [PMID: 33588049 DOI: 10.1016/j.freeradbiomed.2021.02.012] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/03/2021] [Accepted: 02/06/2021] [Indexed: 02/06/2023]
Abstract
The morbidity and mortality from cardiovascular diseases (CVD) remain high. Metabolic diseases such as obesity, hyperlipidemia, diabetes mellitus (DM), non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) as well as hypertension are the most common comorbidities in patients with CVD. These comorbidities result in increased myocardial oxidative stress, mainly from increased activity of nicotinamide adenine dinucleotide phosphate oxidases, uncoupled endothelial nitric oxide synthase, mitochondria as well as downregulation of antioxidant defense systems. Oxidative and nitrosative stress play an important role in ischemia/reperfusion injury and may account for increased susceptibility of the myocardium to infarction and myocardial dysfunction in the presence of the comorbidities. Thus, while early reperfusion represents the most favorable therapeutic strategy to prevent ischemia/reperfusion injury, redox therapeutic strategies may provide additive benefits, especially in patients with heart failure. While oxidative and nitrosative stress are harmful, controlled release of reactive oxygen species is however important for cardioprotective signaling. In this review we summarize the current data on the effect of hypertension and major cardiometabolic comorbidities such as obesity, hyperlipidemia, DM, NAFLD/NASH on cardiac redox homeostasis as well as on ischemia/reperfusion injury and cardioprotection. We also review and discuss the therapeutic interventions that may restore the redox imbalance in the diseased myocardium in the presence of these comorbidities.
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Affiliation(s)
- Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece.
| | - Andreas Daiber
- Department of Cardiology 1, Molecular Cardiology, University Medical Center, Langenbeckstr. 1, 55131, Mainz, Germany; Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Langenbeckstr, Germany.
| | - Gary F Baxter
- Division of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, United Kingdom
| | | | - Fabio Di Lisa
- Department of Biomedical Sciences, University of Padova, Italy; Neuroscience Institute, National Research Council of Italy (CNR), Padova, Italy
| | - Nina Kaludercic
- Neuroscience Institute, National Research Council of Italy (CNR), Padova, Italy
| | - Antigone Lazou
- Laboratory of Animal Physiology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece
| | - Zoltán V Varga
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, Hungary
| | - Coert J Zuurbier
- Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Rainer Schulz
- Institute of Physiology, Justus Liebig University Giessen, Giessen, Germany.
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; Pharmahungary Group, Szeged, Hungary
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Zhou R, Lin C, Cheng Y, Zhuo X, Li Q, Xu W, Zhao L, Yang L. Liraglutide Alleviates Hepatic Steatosis and Liver Injury in T2MD Rats via a GLP-1R Dependent AMPK Pathway. Front Pharmacol 2021; 11:600175. [PMID: 33746742 PMCID: PMC7970416 DOI: 10.3389/fphar.2020.600175] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), ranging from non-alcoholic fatty liver to non-alcoholic steatohepatitis, can be prevalent in patients with type 2 diabetes mellitus (T2DM). However, no antidiabetic drug has been approved for the treatment of NAFLD in T2DM patients. Multiple daily injections of basal-bolus insulin are often the final therapeutic option for T2DM. We found that insulin treatment aggravated hepatic steatosis and oxidative stress in Zucker diabetic fatty (ZDF) rats. In addition to glycaemic control, we demonstrated the stimulatory role of liraglutide in relieving hepatic steatosis and liver injury in ZDF rats. Interestingly, liraglutide could also alleviate insulin-aggravated hepatic fatty accumulation. The glucagon-like peptide-1 (GLP-1) agonists liraglutide and Ex-4 activated the expression of peroxisome proliferator-activated receptor alpha (PPARα) via a GLP-1 receptor-dependent 5′ AMP-activated protein kinase pathway. As a nuclear transcription factor, PPARα could mediate the effect of GLP-1 in alleviating hepatic steatosis by differentially regulating the expression of its target genes, including acetyl CoA carboxylase and carnitine palmitoyl transferase la both in vitro and in vivo. Moreover, GLP-1 could relieve liver injury by decreasing oxidative stress stimulated by hepatic steatosis. Insulin might aggravate hepatic steatosis and liver injury by inhibiting GLP-1R expression. The findings indicate the feasibility of liraglutide treatment combined with basal insulin in attenuating hepatic steatosis and liver injury in ZDF rats. This knowledge, and the evidence for the underlying mechanism, provide a theoretical basis for the combination treatment recommended by the latest clinical practice guidelines for T2DM.
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Affiliation(s)
- Rui Zhou
- Department of Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Chuman Lin
- Department of Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yanzhen Cheng
- Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyun Zhuo
- Department of Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Qinghua Li
- Department of Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Wen Xu
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liang Zhao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Li Yang
- Department of Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia. Int J Mol Sci 2021; 22:ijms22020660. [PMID: 33440821 PMCID: PMC7826980 DOI: 10.3390/ijms22020660] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/04/2021] [Accepted: 01/07/2021] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD. In the present review, we summarized experimental studies and clinical trials of recent anti-diabetic and lipid-lowering therapies targeted to reduce CVD. Specifically, incretin-based therapies, sodium-glucose co-transporter 2 inhibitors, and proprotein convertase subtilisin kexin 9 inactivating therapies are described. Moreover, the novel molecular mechanisms explaining the CVD protection of the drugs reviewed here indicate major effects on vascular cells, inflammatory cells, and cardiomyocytes, beyond their expected anti-diabetic and lipid-lowering control. The revealed key mechanism is a prevention of acute cardiovascular events by restraining atherosclerosis at early stages, with decreased leukocyte adhesion, recruitment, and foam cell formation, and increased plaque stability and diminished necrotic core in advanced plaques. These emergent cardiometabolic therapies have a promising future to reduce CVD burden.
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Sofogianni A, Filippidis A, Chrysavgis L, Tziomalos K, Cholongitas E. Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update. World J Hepatol 2020; 12:493-505. [PMID: 32952876 PMCID: PMC7475780 DOI: 10.4254/wjh.v12.i8.493] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 05/02/2020] [Accepted: 06/20/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the predominant cause of chronic liver disease worldwide. NAFLD progresses in some cases to non-alcoholic steatohepatitis (NASH), which is characterized, in addition to liver fat deposition, by hepatocyte ballooning, inflammation and liver fibrosis, and in some cases may lead to hepatocellular carcinoma. NAFLD prevalence increases along with the rising incidence of type 2 diabetes mellitus (T2DM). Currently, lifestyle interventions and weight loss are used as the major therapeutic strategy in the vast majority of patients with NAFLD. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used in the management of T2DM and do not have major side effects like hypoglycemia. In patients with NAFLD, the GLP-1 receptor production is down-regulated. Recently, several animal and human studies have emphasized the role of GLP-1RAs in ameliorating liver fat accumulation, alleviating the inflammatory environment and preventing NAFLD progression to NASH. In this review, we summarize the updated literature data on the beneficial effects of GLP-1RAs in NAFLD/NASH. Finally, as GLP-1RAs seem to be an attractive therapeutic option for T2DM patients with concomitant NAFLD, we discuss whether GLP-1RAs should represent the first line pharmacotherapy for these patients.
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Affiliation(s)
- Areti Sofogianni
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki 54636, Greece
| | - Athanasios Filippidis
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki 54636, Greece
| | - Lampros Chrysavgis
- First Department of Internal Medicine, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Konstantinos Tziomalos
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki 54636, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens 11527, Greece.
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Yaribeygi H, Maleki M, Sathyapalan T, Jamialahmadi T, Sahebkar A. Anti-inflammatory potentials of incretin-based therapies used in the management of diabetes. Life Sci 2020; 241:117152. [PMID: 31837333 DOI: 10.1016/j.lfs.2019.117152] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/01/2019] [Accepted: 12/07/2019] [Indexed: 12/25/2022]
Abstract
GLP-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase 4 inhibitors (DPP-4i) are two classes of antidiabetic agents used in the management of diabetes based on incretin hormones. There is emerging evidence that they have anti-inflammatory effects. Since most long-term complications of diabetes have a background of chronic inflammation, these agents may be beneficial against diabetic complications not only due to their hypoglycemic potential but also via their anti-inflammatory effects. However, the exact molecular mechanisms by which GLP-1RAs and DPP-4i exert their anti-inflammatory effects are not clearly understood. In this review, we discuss the potential molecular pathways by which these incretin-based therapies exert their anti-inflammatory effects.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
| | - Mina Maleki
- Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Thozhukat Sathyapalan
- Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, United Kingdom of Great Britain and Northern Ireland
| | - Tannaz Jamialahmadi
- Halal Research Center of IRI, FDA, Tehran, Iran; Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Godoy-Matos AF, Silva Júnior WS, Valerio CM. NAFLD as a continuum: from obesity to metabolic syndrome and diabetes. Diabetol Metab Syndr 2020; 12:60. [PMID: 32684985 PMCID: PMC7359287 DOI: 10.1186/s13098-020-00570-y] [Citation(s) in RCA: 381] [Impact Index Per Article: 76.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 07/08/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The prevalence of non-alcoholic fatty liver disease (NAFLD) has been increasing rapidly. It is nowadays recognized as the most frequent liver disease, affecting a quarter of global population and regularly coexisting with metabolic disorders such as type 2 diabetes, hypertension, obesity, and cardiovascular disease. In a more simplistic view, NAFLD could be defined as an increase in liver fat content, in the absence of secondary cause of steatosis. In fact, the clinical onset of the disease is a much more complex process, closely related to insulin resistance, limited expandability and dysfunctionality of adipose tissue. A fatty liver is a main driver for a new recognized liver-pancreatic α-cell axis and increased glucagon, contributing to diabetes pathophysiology. MAIN TEXT This review will focus on the clinical and pathophysiological connections between NAFLD, insulin resistance and type 2 diabetes. We reviewed non-invasive methods and several scoring systems for estimative of steatosis and fibrosis, proposing a multistep process for NAFLD evaluation. We will also discuss treatment options with a more comprehensive view, focusing on the current available therapies for obesity and/or type 2 diabetes that impact each stage of NAFLD. CONCLUSION The proper understanding of NAFLD spectrum-as a continuum from obesity to metabolic syndrome and diabetes-may contribute to the early identification and for establishment of targeted treatment.
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Affiliation(s)
- Amélio F. Godoy-Matos
- Metabolism Department, Instituto Estadual de Diabetes e Endocrinologia (IEDE), Pontifical Catholic University of Rio de Janeiro (PUC-Rio), Rio de Janeiro, RJ CEP 20211-340 Brazil
| | - Wellington S. Silva Júnior
- Endocrinology Discipline, Faculty of Medicine, Center of Natural, Human, Health, and Technology Sciences, Federal University of Maranhão (UFMA), Pinheiro, MA CEP 65200-000 Brazil
| | - Cynthia M. Valerio
- Metabolism Department, Instituto Estadual de Diabetes e Endocrinologia (IEDE), Pontifical Catholic University of Rio de Janeiro (PUC-Rio), Rio de Janeiro, RJ CEP 20211-340 Brazil
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Shah FA, Mahmud H, Gallego-Martin T, Jurczak MJ, O’Donnell CP, McVerry BJ. Therapeutic Effects of Endogenous Incretin Hormones and Exogenous Incretin-Based Medications in Sepsis. J Clin Endocrinol Metab 2019; 104:5274-5284. [PMID: 31216011 PMCID: PMC6763279 DOI: 10.1210/jc.2019-00296] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 06/13/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Sepsis, a complex disorder characterized by a dysregulated immune response to an inciting infection, affects over one million Americans annually. Dysglycemia during sepsis hospitalization confers increased risk of organ dysfunction and death, and novel targets for the treatment of sepsis and maintenance of glucose homeostasis are needed. Incretin hormones are secreted by enteroendocrine cells in response to enteral nutrients and potentiate insulin release from pancreatic β cells in a glucose-dependent manner, thereby reducing the risk of insulin-induced hypoglycemia. Incretin hormones also reduce systemic inflammation in preclinical studies, but studies of incretins in the setting of sepsis are limited. METHODS In this bench-to-bedside mini-review, we detail the evidence to support incretin hormones as a therapeutic target in patients with sepsis. We performed a PubMed search using the medical subject headings "incretins," "glucagon-like peptide-1," "gastric inhibitory peptide," "inflammation," and "sepsis." RESULTS Incretin-based therapies decrease immune cell activation, inhibit proinflammatory cytokine release, and reduce organ dysfunction and mortality in preclinical models of sepsis. Several small clinical trials in critically ill patients have suggested potential benefit in glycemic control using exogenous incretin infusions, but these studies had limited power and were performed in mixed populations. Further clinical studies examining incretins specifically in septic populations are needed. CONCLUSIONS Targeting the incretin hormone axis in sepsis may provide a means of not only promoting euglycemia in sepsis but also attenuating the proinflammatory response and improving clinical outcomes.
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Affiliation(s)
- Faraaz Ali Shah
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
- Veteran Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
- Correspondence and Reprint Requests: Faraaz Ali Shah, MD, MPH, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, 3459 Fifth Avenue NW, 628 MUH, Pittsburgh, Pennsylvania 15213. E-mail:
| | - Hussain Mahmud
- Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Teresa Gallego-Martin
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Michael J Jurczak
- Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Christopher P O’Donnell
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Bryan J McVerry
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
- Center for Medicine and the Microbiome, University of Pittsburgh, Pittsburgh, Pennsylvania
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49
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Rein-Fischboeck L, Haberl EM, Pohl R, Feder S, Liebisch G, Krautbauer S, Buechler C. Variations in hepatic lipid species of age-matched male mice fed a methionine-choline-deficient diet and housed in different animal facilities. Lipids Health Dis 2019; 18:172. [PMID: 31521175 PMCID: PMC6745065 DOI: 10.1186/s12944-019-1114-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 08/30/2019] [Indexed: 02/06/2023] Open
Abstract
Background Non-alcoholic steatohepatitis (NASH) is a common disease and feeding mice a methionine-choline-deficient (MCD) diet is a frequently used model to study its pathophysiology. Genetic and environmental factors influence NASH development and liver lipid content, which was studied herein using C57BL/6 J mice bred in two different animal facilities. Methods Age-matched male C57BL/6 J mice bred in two different animal facilities (later on referred to as WT1 and WT2) at the University Hospital of Regensburg were fed identical MCD or control chows for 2 weeks. Hepatic gene and protein expression and lipid composition were determined. Results NASH was associated with increased hepatic triglycerides, which were actually higher in WT1 than WT2 liver in both dietary groups. Cholesterol contributes to hepatic injury but was only elevated in WT2 NASH liver. Ceramides account for insulin resistance and cell death, and ceramide species d18:1/16:0 and d18:1/18:0 were higher in the NASH liver of both groups. Saturated sphingomyelins only declined in WT1 NASH liver. Lysophosphatidylcholine concentrations were quite normal in NASH and only one of the 12 altered phosphatidylcholine species declined in NASH liver of both groups. Very few phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol species were comparably regulated in NASH liver of both animal groups. Seven of these lipid species declined and two increased in NASH. Notably, hepatic mRNA expression of proinflammatory (F4/80, CD68, IL-6, TNF and chemerin) and profibrotic genes (TGF beta and alpha SMA) was comparable in WT1 and WT2 mice. Conclusions Mice housed and bred in different animal facilities had comparable disease severity of NASH whereas liver lipids varied among the groups. Thus, there was no specific lipid signature for NASH in the MCD model. Electronic supplementary material The online version of this article (10.1186/s12944-019-1114-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lisa Rein-Fischboeck
- Department of Internal Medicine I, Regensburg University Hospital, D-93042, Regensburg, Germany
| | - Elisabeth M Haberl
- Department of Internal Medicine I, Regensburg University Hospital, D-93042, Regensburg, Germany
| | - Rebekka Pohl
- Department of Internal Medicine I, Regensburg University Hospital, D-93042, Regensburg, Germany
| | - Susanne Feder
- Department of Internal Medicine I, Regensburg University Hospital, D-93042, Regensburg, Germany
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany
| | - Sabrina Krautbauer
- Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany
| | - Christa Buechler
- Department of Internal Medicine I, Regensburg University Hospital, D-93042, Regensburg, Germany.
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50
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van Eyk HJ, Blauw LL, Bizino MB, Wang Y, van Dijk KW, de Mutsert R, Smit JWA, Lamb HJ, Jazet IM, Rensen PCN. Hepatic triglyceride content does not affect circulating CETP: lessons from a liraglutide intervention trial and a population-based cohort. Sci Rep 2019; 9:9996. [PMID: 31292457 PMCID: PMC6620358 DOI: 10.1038/s41598-019-45593-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 06/06/2019] [Indexed: 12/29/2022] Open
Abstract
Cholesteryl ester transfer protein (CETP) is mainly expressed by Kupffer cells in the liver. A reduction of hepatic triglyceride content (HTGC) by pioglitazone or caloric restriction is accompanied by a decrease in circulating CETP. Since GLP-1 analogues also reduce HTGC, we assessed whether liraglutide decreases CETP. Furthermore, we investigated the association between HTGC and CETP in a population-based cohort. In a placebo-controlled trial, 50 patients with type 2 diabetes were randomly assigned to treatment with liraglutide or placebo added to standard care. In this trial and in 1,611 participants of the Netherlands Epidemiology of Obesity (NEO) study, we measured HTGC and circulating CETP by proton magnetic resonance spectroscopy and ELISA, respectively. The HTGC was decreased in the liraglutide group (-6.3%; 95%CI of difference [-9.5, -3.0]) but also in the placebo group (-4.0%; 95%CI[-6.0, -2.0]), without between-group differences. CETP was not decreased by liraglutide (-0.05 µg/mL; 95%CI[-0.13, 0.04]) or placebo (-0.04 µg/mL; 95%CI[-0.12, 0.04]). No association was present between HTGC and CETP at baseline (β: 0.002 µg/mL per %TG, 95%CI[-0.005, 0.009]) and between the changes after treatment with liraglutide (β: 0.003 µg/mL per %TG, 95%CI[-0.010, 0.017]) or placebo (β: 0.006 µg/mL per %TG, 95%CI[-0.012,0.024]). Also, in the cohort n o association between HTGC and CETP was present (β: -0.001 µg/mL per SD TG, 95%CI[-0.005, 0.003]). A reduction of HTGC after treatment with liraglutide or placebo does not decrease circulating CETP. Also, no association between HTGC and CETP was present in a large cohort. These findings indicate that circulating CETP is not determined by HTGC.Clinical Trial Registration: Clinicaltrials.gov (NCT01761318).
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Affiliation(s)
- Huub J van Eyk
- Department Medicine, Div. Endocrinology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
- Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands.
| | - Lisanne L Blauw
- Department Medicine, Div. Endocrinology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
- Department Epidemiology, LUMC, Leiden, The Netherlands
| | - Maurice B Bizino
- Department Medicine, Div. Endocrinology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
- Department Radiology, LUMC, Leiden, The Netherlands
| | - Yanan Wang
- Department Medicine, Div. Endocrinology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands
| | - Ko Willems van Dijk
- Department Medicine, Div. Endocrinology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands
- Department Human Genetics, LUMC, Leiden, The Netherlands
| | | | - Johannes W A Smit
- Department Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Hildo J Lamb
- Department Radiology, LUMC, Leiden, The Netherlands
| | - Ingrid M Jazet
- Department Medicine, Div. Endocrinology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands
| | - Patrick C N Rensen
- Department Medicine, Div. Endocrinology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands
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