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Douae B, Samir B, Meriam EA, Fatima-Zahra Y, Youssef A. Mercuric Chloride Aggravates Hyperglycemia-Induced Anxiety and Depressive-Like Behaviors in Type 2 Diabetic Rats: Breakdown of the Antioxidant Defense System. Biol Trace Elem Res 2025:10.1007/s12011-025-04640-y. [PMID: 40279082 DOI: 10.1007/s12011-025-04640-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 04/22/2025] [Indexed: 04/26/2025]
Abstract
Introduction Type 2 diabetes mellitus (T2DM) is a global health problem frequently associated with biochemical disturbance and also, with a range of mental health disorders including such as anxiety and depression. Whereas, mercury chloride (HgCl₂) is a common environmental pollutant, which is neurotoxic and induces oxidative stress, especially in metabolic disorders like diabetes. The purpose of this investigation is to evaluate the interaction between hyperglycemia-induced oxidative stress and HgCl₂ toxicity and to assess their far-reaching effect spotlighted on biochemical and behavioral disturbances. By analyzing key oxidative stress markers and anxiety- and depression-like behaviors. Experimental design was carried out as follow: control group, HgCl₂-treated group, diabetic group and diabetic HgCl₂-treated group. Type 2 diabetes was induced in a diabetic model via streptozotocin (STZ) and nicotinamide (NA) injections. For the HgCl₂-exposed groups, rats were administered 0.375 mg/kg/day of HgCl₂ orally for 45 consecutive days. Additionally, behavioral tests were performed to examine anxiety- and depression-like behaviors, and hematological, biochemical, oxidative stress markers were assessed to evaluate systemic and neurotoxic effects. The results showed significant increases in fasting blood glucose levels in diabetic and HgCl₂-treated diabetic groups compared to controls (p < 0.001). Body weight significantly decreased in all treated groups (p < 0.05), with the greatest reduction observed in the HgCl₂-treated diabetic group. Behavioral analysis revealed heightened anxiety and depression-like behaviors, particularly in the HgCl₂-treated diabetic group (p < 0.05). Biochemical assessments indicated significant disruptions in lipid profiles and hepatic and renal markers, with pronounced effects in HgCl₂-treated diabetic rats (p < 0.05). Oxidative stress markers demonstrated elevated malondialdehyde and nitric oxide levels in the liver, hippocampus, and prefrontal cortex, paired with diminished antioxidant defences, including catalase and superoxide dismutase activities (p < 0.05). These findings underscore the synergistic role of hyperglycemia and HgCl₂ exposure in amplifying oxidative damage and emotional disturbances, suggesting a critical interplay between metabolic and neurotoxic pathways.
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Affiliation(s)
- Benloughmari Douae
- Laboratory of Biology and Health, Biology Department, Ibn Tofail University, Faculty of Sciences, Kenitra, Morocco
| | - Bikri Samir
- Laboratory of Biology and Health, Biology Department, Ibn Tofail University, Faculty of Sciences, Kenitra, Morocco.
- Higher School of Technology, Ibn Tofail University, Kenitra, Morocco.
| | - El Aboubi Meriam
- Laboratory of Natural Resources and Sustainable Development, Biology Department, Ibn Tofail University, Faculty of Sciences, Kenitra, Morocco
| | - Yassif Fatima-Zahra
- Laboratory of Biology and Health, Biology Department, Ibn Tofail University, Faculty of Sciences, Kenitra, Morocco
| | - Aboussaleh Youssef
- Laboratory of Biology and Health, Biology Department, Ibn Tofail University, Faculty of Sciences, Kenitra, Morocco
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Ebeid A, Mokhtar F, Martinez-Lebron V, Park S, Degann S, Payano J, Vahora Z, Gray S, Johnson L, El-Maouche D, Abutaleb A. Use of noninvasive fibrosis calculators in an urban diabetes center suggests a large burden of undetected advanced liver disease. BMC Endocr Disord 2025; 25:53. [PMID: 40011894 PMCID: PMC11866707 DOI: 10.1186/s12902-025-01881-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 02/13/2025] [Indexed: 02/28/2025] Open
Abstract
BACKGROUND Metabolic dysfunction associated steatotic liver disease (MASLD) is prevalent in up to 60% of patients with type 2 diabetes mellitus (T2DM). T2DM accelerates the risk of hepatic fibrosis and hepatocellular carcinoma in patients with MASLD. Our goal in this study was to identify patients with suspected MASLD and hepatic fibrosis in a large T2DM clinic by using noninvasive fibrosis scoring systems. METHODS We conducted a retrospective study of patients with T2DM seen by our endocrinologists at the Medical Faculty Associates (MFA) Diabetes Center in Washington, DC, from November 1, 2021, until November 1, 2022. We included all subjects who were over 18 years old with a hemoglobin A1c (HbA1c) of 6.5 or higher. Patients with a history of significant alcohol consumption, decompensated cirrhosis, previous bariatric surgery, or prior chronic liver disease were excluded from the study. We identified patients at risk for hepatic fibrosis by using the Fibrosis-4 (FIB-4) Index, NAFLD Fibrosis Score (NFS) and AST to Platelet Ratio Index (APRI) when lab values were available. RESULTS A total of 1,411 patients were evaluated for T2DM by an endocrinology provider during the one-year period. Out of these, 336 patients met one or more of the exclusion criteria, leaving a total of 1075 patients included in the analysis. The majority were African American (n = 582, 54%), 261 were Caucasian (24.3%), and 85 were Hispanic (7.9%). Most patients were females (n = 675, 62.7%). The mean HbA1c was 8.1 ± 2.3. 643 patients (59.8%) were insulin dependent. Based on FIB-4 scores, we found that 35 (3.9%) patients had a score of > 2.67 associated with advanced fibrosis and 257 (29%) patients with scores of 1.3-2.67 had moderate fibrosis. Using the NFS calculator, there were 281 (28%) patients with values of > 0.675 consistent with F3-F4 disease. 715 (71.8%) patients with values of < 0.675 consistent with F0-F2 fibrosis. A total of 6(< 1%) patients met criteria for advanced fibrosis by APRI scoring. CONCLUSION In our urban Diabetes Center, utilizing the NFS calculator may detect many patients with advanced liver disease. Further research is needed to ensure the internal validity of the non-invasive tests in predicting liver fibrosis and to correlate these findings with transient elastography and other imaging evidence of fatty liver disease. CLINICAL TRIAL NUMBER Non-applicable.
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Affiliation(s)
- Ahmed Ebeid
- The George Washington University, Washington, DC, USA
| | - Fatma Mokhtar
- The George Washington University, Washington, DC, USA
| | | | - Susie Park
- Department of Medicine, The George Washington University Hospital, Washington, DC, USA
| | - Seta Degann
- Department of Medicine, The George Washington University Hospital, Washington, DC, USA
| | - Jeremy Payano
- Department of Surgery, The George Washington Transplant Institute, The George Washington University Hospital, Washington, DC, USA
| | - Zahid Vahora
- Department of Surgery, The George Washington Transplant Institute, The George Washington University Hospital, Washington, DC, USA
| | - Stephen Gray
- Department of Surgery, The George Washington Transplant Institute, The George Washington University Hospital, Washington, DC, USA
| | - Lynt Johnson
- Department of Surgery, The George Washington Transplant Institute, The George Washington University Hospital, Washington, DC, USA
| | - Diala El-Maouche
- Department of Endocrinology, The George Washington University Medical Faculty Associates, Washington, DC, USA
| | - Ameer Abutaleb
- Department of Surgery, The George Washington Transplant Institute, The George Washington University Hospital, Washington, DC, USA.
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Gadi Z, Kwanten WJ, Vonghia L, Francque SM. MASH to cirrhosis: bridging the gaps in MASLD management. Acta Clin Belg 2024; 79:441-450. [PMID: 39995021 DOI: 10.1080/17843286.2025.2466011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Accepted: 02/07/2025] [Indexed: 02/26/2025]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) represents a critical stage in the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), significantly increasing the risk of cirrhosis, hepatocellular carcinoma (HCC), and liver-related mortality. Despite the rising global prevalence of MASLD, gaps in understanding the pathophysiological mechanisms driving MASH to cirrhosis persist, leading to challenges in early diagnosis, prevention, and treatment. This review explores the current knowledge on MASH, focusing on its pathophysiology, clinical management, and treatment strategies in the advanced stages. The role of metabolic dysfunction, portal hypertension, decompensation, and HCC occurrence is highlighted, alongside an evaluation of therapeutic options including lifestyle intervention, bariatric surgery, pharmacological therapies and liver transplantation. Furthermore, we emphasize the need for a multidisciplinary care approach to improve patient outcomes and address the complex metabolic and hepatic interplay in MASLD. Bridging these gaps will require an integrated effort combining advanced diagnostic tools, novel treatments, and comprehensive care strategies.
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Affiliation(s)
- Zouhir Gadi
- Department of Gastroenterology and Hepatology, Antwerp University Hospital (UZA), Antwerp, Belgium
- Laboratory of Experimental Medicine and Paediatrics (LEMP), Gastroenterology and Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Wilhelmus J Kwanten
- Department of Gastroenterology and Hepatology, Antwerp University Hospital (UZA), Antwerp, Belgium
- Laboratory of Experimental Medicine and Paediatrics (LEMP), Gastroenterology and Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Luisa Vonghia
- Department of Gastroenterology and Hepatology, Antwerp University Hospital (UZA), Antwerp, Belgium
- Laboratory of Experimental Medicine and Paediatrics (LEMP), Gastroenterology and Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Sven M Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital (UZA), Antwerp, Belgium
- Laboratory of Experimental Medicine and Paediatrics (LEMP), Gastroenterology and Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
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Wibulpolprasert P, Subpinyo B, Chirnaksorn S, Shantavasinkul PC, Putadechakum S, Phongkitkarun S, Sritara C, Angkathunyakul N, Sumritpradit P. Correlation between magnetic resonance imaging proton density fat fraction (MRI-PDFF) and liver biopsy to assess hepatic steatosis in obesity. Sci Rep 2024; 14:6895. [PMID: 38519637 PMCID: PMC10960039 DOI: 10.1038/s41598-024-57324-3] [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: 11/24/2023] [Accepted: 03/18/2024] [Indexed: 03/25/2024] Open
Abstract
Obesity is highly associated with Non-alcoholic fatty liver disease (NAFLD) and increased risk of liver cirrhosis and liver cancer-related death. We determined the diagnostic performance of the complex-based chemical shift technique MRI-PDFF for quantifying liver fat and its correlation with histopathologic findings in an obese population within 24 h before bariatric surgery. This was a prospective, cross-sectional, Institutional Review Board-approved study of PDFF-MRI of the liver and MRI-DIXON image volume before bariatric surgery. Liver tissues were obtained during bariatric surgery. The prevalence of NAFLD in the investigated cohort was as high as 94%. Histologic hepatic steatosis grades 0, 1, 2, and 3 were observed in 3 (6%), 25 (50%), 14 (28%), and 8 (16%) of 50 obese patients, respectively. The mean percentages of MRI-PDFF from the anterior and posterior right hepatic lobe and left lobe vs. isolate left hepatic lobe were 15.6% (standard deviation [SD], 9.28%) vs. 16.29% (SD, 9.25%). There was a strong correlation between the percentage of steatotic hepatocytes and MRI-PDFF in the left hepatic lobe (r = 0.82, p < 0.001) and the mean value (r = 0.78, p < 0.001). There was a strong correlation between MRI-derived subcutaneous adipose tissue volume and total body fat mass by dual-energy X-ray absorptiometry, especially at the L2-3 and L4 level (r = 0.85, p < 0.001). MRI-PDFF showed good performance in assessing hepatic steatosis and was an excellent noninvasive technique for monitoring hepatic steatosis in an obese population.
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Affiliation(s)
- Pornphan Wibulpolprasert
- Department of Diagnostic and Therapeutic Radiology, Mahidol University, Bangkok, 10400, Thailand
| | - Benya Subpinyo
- Department of Diagnostic and Therapeutic Radiology, Mahidol University, Bangkok, 10400, Thailand
| | | | | | | | - Sith Phongkitkarun
- Department of Diagnostic and Therapeutic Radiology, Mahidol University, Bangkok, 10400, Thailand
| | - Chanika Sritara
- Department of Diagnostic and Therapeutic Radiology, Mahidol University, Bangkok, 10400, Thailand
| | | | - Preeda Sumritpradit
- Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.
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Hegazi OE, Alalalmeh SO, Shahwan M, Jairoun AA, Alourfi MM, Bokhari GA, Alkhattabi A, Alsharif S, Aljehani MA, Alsabban AM, Almtrafi M, Zakri YA, AlMahmoud A, Alghamdi KM, Ashour AM, Alorfi NM. Exploring Promising Therapies for Non-Alcoholic Fatty Liver Disease: A ClinicalTrials.gov Analysis. Diabetes Metab Syndr Obes 2024; 17:545-561. [PMID: 38327733 PMCID: PMC10847589 DOI: 10.2147/dmso.s448476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 01/11/2024] [Indexed: 02/09/2024] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is a common disease and has been increasing in recent years. To date, no FDA-approved drug specifically targets NAFLD. Methods The terms "Non-alcoholic Fatty Liver Disease" and "NAFLD" were used in a search of ClinicalTrials.gov on August 24, 2023. Two evaluators independently examined the trials using predetermined eligibility criteria. Studies had to be interventional, NAFLD focused, in Phase IV, and completed to be eligible for this review. Results The ClinicalTrials.gov database was searched for trials examining pharmacotherapeutics in NAFLD. The search revealed 1364 trials, with 31 meeting the inclusion criteria. Out of these, 19 were finalized for evaluation. The dominant intervention model was Parallel. The most prevalent studies were in Korea (26.3%) and China (21.1%). The most common intervention was metformin (12.1%), with others like Exenatide and Pioglitazone accounting for 9.1%. Conclusion Therapeutics used to manage NAFLD are limited. However, various medications offer potential benefits. Further investigations are definitely warranted.
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Affiliation(s)
- Omar E Hegazi
- Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
- Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab Emirates
| | - Samer O Alalalmeh
- Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
- Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab Emirates
| | - Moyad Shahwan
- Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
- Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab Emirates
| | - Ammar Abdulrahman Jairoun
- Health and Safety Department, Dubai, United Arab Emirates
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Pulau Pinang, Malaysia
| | - Mansour M Alourfi
- Internal medicine Department, King Faisal Medical City for Southern Region, Abha, Saudi Arabia
- Department of gastroenterology, East Jeddah hospital, Jeddah, Saudi Arabia
| | | | | | - Saeed Alsharif
- Gastroenterology Department, Armed force Hospital of southern region, Khamis Mushait, Saudi Arabia
| | - Mohannad Abdulrahman Aljehani
- Division of Gastroenterology, Department of Medicine, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
| | | | - Mohammad Almtrafi
- Gastroenterology Section, Department of Medicine, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| | - Ysear Abdulaziz Zakri
- Gastroenterology Section, Department of Medicine, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| | - Abdullah AlMahmoud
- Gastroenterology Section, Internal Medicine Department, King Fahad Hospital, Jeddah, Saudi Arabia
| | - Khalid Mohammed Alghamdi
- Gastroenterology Section, Internal Medicine Department, King Fahad Hospital, Jeddah, Saudi Arabia
| | - Ahmed M Ashour
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Nasser M Alorfi
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
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Xiao Y, Zhang X, Yi D, Qiu F, Wu L, Tang Y, Wang N. Mediterranean diet affects the metabolic outcome of metabolic dysfunction-associated fatty liver disease. Front Nutr 2023; 10:1225946. [PMID: 37899839 PMCID: PMC10602910 DOI: 10.3389/fnut.2023.1225946] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 09/20/2023] [Indexed: 10/31/2023] Open
Abstract
The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is on the rise globally. It is currently one of the most prevalent liver diseases and one of the world's important public health problems. At present, there is no consensus on a pharmacological treatment for MAFLD. By contrast, lifestyle interventions based on exercise and a balanced diet are considered to be the cornerstone of MAFLD management. Mediterranean diet (MD) have a large content of polyphenols, polyunsaturated fatty acids, oleic acid, carotenoids and fiber, which carry out antioxidant, anti-inflammatory and antibacterial benefits. It has been considered to reduce the incidence rate of cardiovascular disease and type 2 diabetes. The purpose of this narrative review is therefore to summarize and analyze the evidence for the effect of MD on metabolic outcomes in MAFLD patients.
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Affiliation(s)
- Yuji Xiao
- School of Public Health, Dalian Medical University, Dalian, Liaoning, China
- Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Xue Zhang
- School of Public Health, Dalian Medical University, Dalian, Liaoning, China
- The Second People’s Hospital of Dalian, Dalian, Liaoning, China
| | - Dongxin Yi
- School of Public Health, Dalian Medical University, Dalian, Liaoning, China
| | - Fangyi Qiu
- School of Public Health, Dalian Medical University, Dalian, Liaoning, China
| | - Lei Wu
- Department of Radiobiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Yiyong Tang
- Department of Cardiovascular Ultrasound, The Second Affiliated Hospital of Dalian Medical University, Liaoning, China
| | - Ningning Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, Dalian, Liaoning, China
- Global Health Research Center, Dalian Medical University, Dalian, Liaoning, China
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He Y, Wang H, Lin S, Chen T, Chang D, Sun Y, Wang C, Liu Y, Lu Y, Song J, Li S, Xu W, Lin Y, Zheng Y, Zhou X, Huang Q, Huang M. Advanced effect of curcumin and resveratrol on mitigating hepatic steatosis in metabolic associated fatty liver disease via the PI3K/AKT/mTOR and HIF-1/VEGF cascade. Biomed Pharmacother 2023; 165:115279. [PMID: 37544281 DOI: 10.1016/j.biopha.2023.115279] [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: 05/22/2023] [Revised: 07/29/2023] [Accepted: 07/31/2023] [Indexed: 08/08/2023] Open
Abstract
Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease that has no viable treatment. Curcumin (Cur) and resveratrol (Res) are two natural products that have been studied for their potential to ameliorate MAFLD. However, while these compounds have been investigated individually, their combined use and the potential for a synergistic or augmented effect remain unexplored. This study aims to investigate the effect of curcumin (Cur) and resveratrol (Res) as a potential combination therapy on MAFLD. Cur, Res and Cur+Res were tested in palmitic acid (PA)-induced-HepG2 cells. MAFLD model was established using Goto-Kakizaki rats. The animals were treated with vehicle control (model group), Cur (150 mg/kg), Res (150 mg/kg), Cur+Res (150 mg/kg, 8:2, w/w), or metformin (Met, positive control, 400 mg/kg/day) via oral gavage for 4 weeks. Wistar rats were used as the control group. Network pharmacology was conducted to elucidate the molecular actions of Cur and Res, followed by q-PCR and immunoblotting in vivo. Cur+Res exhibited synergistic effects in reducing triglyceride, total cholesterol and lipid accumulation in PA-induced HepG2 cells. The combination also markedly attenuated hepatic steatosis in the MAFLD rats. Network pharmacology illustrated that the interaction of Cur and Res was associated with the modulation of multiple molecular targets associated with the PI3K/AKT/mTOR and HIF-1 signaling pathways. Experimental results confirmed that Cur+Res nomalised the gene targets and protein expressions in the PI3K/AKT/mTOR and HIF-1 signaling pathways, including PI3K, mTOR, STAT-3, HIF-1α, and VEGF. The present study demonstrated an advanced effect of Cur and Res in combination to attenuate MAFLD, and the mechanism is at least partly associated with the modulation of the PI3K/AKT/mTOR and HIF-1 signaling pathways.
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Affiliation(s)
- Yuhui He
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350100, China
| | - Huan Wang
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350100, China
| | - Shiling Lin
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350100, China
| | - Tao Chen
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350100, China
| | - Dennis Chang
- NICM Health Research Institute, Western Sydney University, Westmead, NSW 2145, Australia
| | - Yibin Sun
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350100, China
| | - Chenxiang Wang
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350100, China
| | - Yang Liu
- NICM Health Research Institute, Western Sydney University, Westmead, NSW 2145, Australia
| | - Yusheng Lu
- Fujian-Taiwan-Hongkong-Macao Science and Technology Cooperation Base of Intelligent Pharmaceutics, College of Material and Chemical Engineering, Minjiang University, Fuzhou 350108, China
| | - Jianyuan Song
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou 350100, China
| | - Shaohua Li
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350100, China
| | - Wen Xu
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350100, China
| | - Yanxiang Lin
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350100, China
| | - Yanfang Zheng
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350100, China.
| | - Xian Zhou
- NICM Health Research Institute, Western Sydney University, Westmead, NSW 2145, Australia.
| | - Qiumei Huang
- Guangdong Food and Drug Vocational College, Guangzhou 510520, China.
| | - Mingqing Huang
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350100, China.
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O'Croinin C, Garcia Guerra A, Doschak MR, Löbenberg R, Davies NM. Therapeutic Potential and Predictive Pharmaceutical Modeling of Stilbenes in Cannabis sativa. Pharmaceutics 2023; 15:1941. [PMID: 37514127 PMCID: PMC10386382 DOI: 10.3390/pharmaceutics15071941] [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: 06/23/2023] [Revised: 07/10/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Cannabis sativa is a plant used for recreational and therapeutic purposes; however, many of the secondary metabolites in the plant have not been thoroughly investigated. Stilbenes are a class of compounds with demonstrated anti-inflammatory and antioxidant properties and are present in cannabis. Many stilbenes present in cannabis have been investigated for their therapeutic effects. Fourteen stilbenes have been identified to be present in cannabis, all of which are structurally dihydrostilbenoids, with half possessing a prenylated moiety. The stilbenes summarized in this analysis show varying degrees of therapeutic benefits ranging from anti-inflammatory, antiviral, and anti-cancer to antioxidant effects. Many of the identified stilbenes have been researched to a limited extent for potential health benefits. In addition, predictive in silico modeling was performed on the fourteen identified cannabis-derived stilbenes. This modeling provides prospective activity, pharmacokinetic, metabolism, and permeability data, setting the groundwork for further investigation into these poorly characterized compounds.
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Affiliation(s)
- Conor O'Croinin
- Faculty of Pharmacy and Pharmaceutical Sciences, Katz Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Andres Garcia Guerra
- Faculty of Pharmacy and Pharmaceutical Sciences, Katz Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Michael R Doschak
- Faculty of Pharmacy and Pharmaceutical Sciences, Katz Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Raimar Löbenberg
- Faculty of Pharmacy and Pharmaceutical Sciences, Katz Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Neal M Davies
- Faculty of Pharmacy and Pharmaceutical Sciences, Katz Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB T6G 2E1, Canada
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Muthiah M, Ng CH, Chan KE, Fu CE, Lim WH, Tan DJH, Nah B, Kong G, Xiao J, Yong JN, Tan B, Syn N, Wang JW, Sayed N, Tan E, Chew NW, Dan YY, Siddiqui MS, Sanyal AJ, Noureddin M. Type 2 diabetes mellitus in metabolic-associated fatty liver disease vs. type 2 diabetes mellitus non-alcoholic fatty liver disease: a longitudinal cohort analysis. Ann Hepatol 2023; 28:100762. [PMID: 36182031 DOI: 10.1016/j.aohep.2022.100762] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/30/2022] [Accepted: 09/10/2022] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Type 2 Diabetes Mellitus (T2DM) is comorbidity commonly presenting with fatty liver. A recently proposed definition of "metabolic associated fatty liver disease" (MAFLD) is thought to replace non-alcoholic fatty liver disease (NAFLD). Yet, despite the significant prevalence of T2DM among fatty liver, there remains limited evidence on the impact of the change in the definition of T2DM. MATERIALS AND METHODS The current study uses data from the United States National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Survival analysis was conducted with a cox regression and sub-distribution hazard ratio for competing risk events. RESULTS 6727 patients had a diagnosis of T2DM. 4982 individuals with T2DM had MAFLD and 2032 were MAFLD(+)/NAFLD(-), while 2950 patients were MAFLD(+)/NAFLD(+). The new definition increased fatty liver diagnosis by 68.89%. Patients who were classified as MAFLD(+)/NAFLD(-) were at a higher risk of major adverse cardiovascular events, advanced fibrosis, all-cause and cardiovascular-related mortality compared to MAFLD(+)/NAFLD(+). In MAFLD(+)/NAFLD(-), viral hepatitis significantly increases the odds of advanced fibrosis (OR: 6.77, CI: 3.92 to 11.7, p < 0.001) and all-cause mortality (HR: 1.75, CI: 1.29 to 2.40, p < 0.001). CONCLUSIONS The identification and treatment of NAFLD in patients with T2DM is a major concern and the premature change to MAFLD results in an over-diagnosis of fatty liver, exaggerated mortality, and morbidity in patients with T2DM. The definition of MAFLD causes further heterogeneity in fatty liver disease/NAFLD.
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Affiliation(s)
- Mark Muthiah
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Cheng Han Ng
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore.
| | - Kai En Chan
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
| | - Clarissa Elysia Fu
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
| | - Wen Hui Lim
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
| | - Darren Jun Hao Tan
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
| | - Benjamin Nah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Gwyneth Kong
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
| | - Jieling Xiao
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
| | - Jie Ning Yong
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
| | - Bryan Tan
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
| | - Nicholas Syn
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore
| | - Jiong-Wei Wang
- Department of Surgery, Cardiovascular Research Institute (CVRI), National University Heart Centre Singapore; Nanomedicine Translational Research Programme, Centre for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Nilofer Sayed
- Department of Surgery, Cardiovascular Research Institute (CVRI), National University Heart Centre Singapore; Nanomedicine Translational Research Programme, Centre for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Eunice Tan
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Nicholas Ws Chew
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore; Department of Cardiology, National University Heart Centre, National University Hospital, Singapore
| | - Yock Young Dan
- MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Mohammad Shadab Siddiqui
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia
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10
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Urbizo-Reyes U, Liceaga AM, Reddivari L, Li S, Kim KH, Cox AD, Anderson JM. Canary Seed ( Phalaris canariensis L.) Peptides Prevent Obesity and Glucose Intolerance in Mice Fed a Western Diet. Int J Mol Sci 2022; 23:ijms232314927. [PMID: 36499253 PMCID: PMC9736008 DOI: 10.3390/ijms232314927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 12/03/2022] Open
Abstract
Previous research showed that canary seed (Phalaris canariensis L.) peptides (CSP) possess robust in vitro antiobesity properties via inhibition of pancreatic lipase (PL). Nevertheless, no studies have yet explored their antiobesity properties in vivo. Consequently, we investigated the effects of CSP in C57BL/6J mice under a Western diet (WD). Mice were assigned into groups and fed a normal diet (ND) or a WD accompanied by an oral dose of CSP (250 or 500 mg/kg/day), orlistat (40 mg/kg/day), or distilled water. The results showed that consuming CSP can provide metabolic benefits, including preventing weight gain by up to 20%, increasing glucose tolerance, and reducing insulin, leptin, and LDL/VLDL levels in plasma. Conversely, total ghrelin was unaffected by CSP-500, but decreased by CSP-250, and amplified by orlistat. Surprisingly, CSP-250 was more effective in preventing weight gain and promoting satiety than CSP-500. Parallel to this, protein absorption in CSP-500 was decreased, supported by a rise in fecal crude protein (+3.5%). Similarly, fecal fat was increased by orlistat (38%) and was unaffected by CSP-250 (3.0%) and CSP (3.0%), comparatively to WD (2.5%). Despite this, both CSP treatments were equally effective in decreasing hepatic steatosis and avoiding hyperlipidemia. Furthermore, the enzymatic analysis showed that CSP-PL complexes dissociated faster (15 min) than orlistat-PL complexes (41 min). Lastly, CSP did not affect expression of hepatic lipid oxidation genes ACO and PPAR-α, but reduced the expression of the hydrolase gene LPL, and lipogenesis related genes FAS and ACC. Taken together, these results suggest that CSP antiobesity mechanism relies on lipid metabolism retardation to increase fat transit time and subsequently suppress hunger.
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Affiliation(s)
- Uriel Urbizo-Reyes
- Protein Chemistry and Bioactive Peptides Laboratory, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA
- Department of Food Science, Purdue University, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA
| | - Andrea M. Liceaga
- Protein Chemistry and Bioactive Peptides Laboratory, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA
- Department of Food Science, Purdue University, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA
- Correspondence:
| | - Lavanya Reddivari
- Department of Food Science, Purdue University, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA
| | - Shiyu Li
- Department of Food Science, Purdue University, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA
| | - Kee-Hong Kim
- Department of Food Science, Purdue University, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA
| | - Abigail D. Cox
- College of Veterinary Medicine, Purdue University, 625 Harrison Street, West Lafayette, IN 47907, USA
| | - Joseph M. Anderson
- Department of Agronomy, Purdue University, 915 W. State St., West Lafayette, IN 47907, USA
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11
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Ghaddar B, Gence L, Veeren B, Bringart M, Bascands JL, Meilhac O, Diotel N. Aqueous Extract of Psiloxylon mauritianum, Rich in Gallic Acid, Prevents Obesity and Associated Deleterious Effects in Zebrafish. Antioxidants (Basel) 2022; 11:antiox11071309. [PMID: 35883799 PMCID: PMC9312056 DOI: 10.3390/antiox11071309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 06/26/2022] [Accepted: 06/26/2022] [Indexed: 12/04/2022] Open
Abstract
Obesity has reached epidemic proportions, and its prevalence tripled worldwide between 1975 and 2016, especially in Reunion Island, a French overseas region. Psiloxylon mauritianum, an endemic medicinal plant from Reunion Island registered in the French pharmacopeia, has recently gained interest in combating metabolic disorders because of its traditional lipid-lowering and “anti-diabetic” use. However, scientific data are lacking regarding its toxicity and its real benefits on metabolic diseases. In this study, we aim to determine the toxicity of an aqueous extract of P. mauritianum on zebrafish eleutheroembryos following the OECD toxicity assay (Organization for Economic Cooperation and Development, guidelines 36). After defining a non-toxic dose, we determined by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) that this extract is rich in gallic acid but contains also caffeoylquinic acid, kaempferol and quercetin, as well as their respective derivatives. We also showed that the non-toxic dose exhibits lipid-lowering effects in a high-fat-diet zebrafish larvae model. In a next step, we demonstrated its preventive effects on body weight gain, hyperglycemia and liver steatosis in a diet-induced obesity model (DIO) performed in adults. It also limited the deleterious effects of overfeeding on the central nervous system (i.e., cerebral oxidative stress, blood-brain barrier breakdown, neuro-inflammation and blunted neurogenesis). Interestingly, adult DIO fish treated with P. mauritianum display normal feeding behavior but higher feces production. This indicates that the “anti-weight-gain” effect is probably due to the action of P. mauritianum on the intestinal lipid absorption and/or on the microbiota, leading to the increase in feces production. Therefore, in our experimental conditions, the aqueous extract of P. mauritianum exhibited “anti-weight-gain” properties, which prevented the development of obesity and its deleterious effects at the peripheral and central levels. These effects should be further investigated in preclinical models of obese/diabetic mice, as well as the impact of P. mauritianum on the gut microbiota.
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Affiliation(s)
- Batoul Ghaddar
- Université de La Réunion, INSERM, UMR 1188, Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), 97400 Saint-Denis, La Réunion, France; (B.G.); (L.G.); (B.V.); (M.B.); (J.-L.B.); (O.M.)
| | - Laura Gence
- Université de La Réunion, INSERM, UMR 1188, Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), 97400 Saint-Denis, La Réunion, France; (B.G.); (L.G.); (B.V.); (M.B.); (J.-L.B.); (O.M.)
| | - Bryan Veeren
- Université de La Réunion, INSERM, UMR 1188, Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), 97400 Saint-Denis, La Réunion, France; (B.G.); (L.G.); (B.V.); (M.B.); (J.-L.B.); (O.M.)
| | - Matthieu Bringart
- Université de La Réunion, INSERM, UMR 1188, Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), 97400 Saint-Denis, La Réunion, France; (B.G.); (L.G.); (B.V.); (M.B.); (J.-L.B.); (O.M.)
| | - Jean-Loup Bascands
- Université de La Réunion, INSERM, UMR 1188, Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), 97400 Saint-Denis, La Réunion, France; (B.G.); (L.G.); (B.V.); (M.B.); (J.-L.B.); (O.M.)
| | - Olivier Meilhac
- Université de La Réunion, INSERM, UMR 1188, Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), 97400 Saint-Denis, La Réunion, France; (B.G.); (L.G.); (B.V.); (M.B.); (J.-L.B.); (O.M.)
- CHU de La Réunion, 97400 Saint-Denis, La Réunion, France
| | - Nicolas Diotel
- Université de La Réunion, INSERM, UMR 1188, Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), 97400 Saint-Denis, La Réunion, France; (B.G.); (L.G.); (B.V.); (M.B.); (J.-L.B.); (O.M.)
- Correspondence:
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12
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Namvarjah F, Shokri-Afra H, Moradi-Sardareh H, Khorzoughi RB, Pasalar P, Panahi G, Meshkani R. Chlorogenic acid improves anti-lipogenic activity of metformin by positive regulating of AMPK signaling in HepG2 cells. Cell Biochem Biophys 2022; 80:537-545. [PMID: 35704155 DOI: 10.1007/s12013-022-01077-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/06/2022] [Indexed: 11/25/2022]
Abstract
Metformin improves lipid profile, however, combination therapy is developing to increase its effectiveness and reduce the deleterious effects of metformin. Chlorogenic acid (CGA) has exhibited lipid-lowering effects. This study aimed to investigate the combined effect of metformin and CGA on lipid accumulation, as well as to elucidate the engaged mechanism in HepG2 cells. To find the non-lethal doses of metformin and CGA, MTT assay was performed. High Glucose (HG) at 33 mM was used to induce lipogenesis in HepG2 cells. Following treatment with different concentrations of metformin and CGA, total lipid content (Oil Red O-staining), triglyceride level, the genes expression of SREBP-1c and FAS, and phosphorylation of AMPK and ACC were measured. Both Metformin and CGA decreased HG-induced lipid accumulation individually, by decreasing total lipid content and triglyceride level. The lowest effective doses of metformin and CGA were 0.25 mM and 5 μM, respectively, which significantly reduced SREBP-1c and FAS genes expression. The combination of these concentrations reinforced these effects. The phosphorylation of AMPK and ACC were more increased by metformin in combination with CGA than both individually. Our findings suggest that CGA synergistically enhances metformin lipid reducing action via the regulating of involved factors in fatty acid synthesis. Therefore, co-administration of metformin with CGA may have further medical value in treating lipid metabolism disorders.
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Affiliation(s)
- Fatemeh Namvarjah
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hajar Shokri-Afra
- Gut and Liver Research Center, Non-communicable Disease Institute, Mazandaran University of Medical Sciences, Sari, Iran.
| | | | - Reyhaneh Babaei Khorzoughi
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Parvin Pasalar
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ghodratollah Panahi
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Meshkani
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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13
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Singh L, Bhatti R. Cellular and molecular mechanisms involved in metabolic disorders. DRUG DELIVERY SYSTEMS FOR METABOLIC DISORDERS 2022:21-29. [DOI: 10.1016/b978-0-323-99616-7.00015-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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14
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Nyasordzi J, Conrad J, Goletzke J, Ludwig-Walz H, Herder C, Roden M, Wudy SA, Hua Y, Remer T, Buyken AE. Early life factors and their relevance for markers of cardiometabolic risk in early adulthood. Nutr Metab Cardiovasc Dis 2021; 31:2109-2121. [PMID: 34023180 DOI: 10.1016/j.numecd.2021.03.024] [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: 01/06/2021] [Revised: 03/09/2021] [Accepted: 03/25/2021] [Indexed: 11/15/2022]
Abstract
BACKGROUND AND AIMS Early life exposures could be pertinent risk factors of cardiometabolic diseases in adulthood. We assessed the prospective associations of early life factors with markers of cardiometabolic risk among healthy German adults. METHODS AND RESULTS We examined 348 term-born DONALD Study participants with measurement of fasting blood at the age of 18-24 years to assess metabolic indices: fatty liver index (FLI), hepatic steatosis index (HSI), pro-inflammatory score and insulin sensitivity (HOMA2-%S). Early life factors (maternal weight in early pregnancy, maternal early pregnancy BMI, gestational weight gain (GWG), maternal age, birth weight and full breastfeeding (>17 weeks)) were assessed at enrolment of the offspring into the study. Multivariable linear regression models were used to analyze associations between early life factors and markers of cardiometabolic risk in early adulthood with adjustment for potential confounders. A higher early pregnancy BMI was related to notably higher levels of offspring FLI, HSI, pro-inflammatory score and a lower HOMA2-%S (all p < 0.0001). Similarly, a higher gestational weight gain was associated with a higher FLI (p = 0.044), HSI (p = 0.016), pro-inflammatory score (p = 0.032) and a lower HOMA2-%S among females (p = 0.034). Full breastfeeding was associated with a lower adult FLI (p = 0.037). A casual mediation analysis showed that these associations were mediated by offspring adult waist circumference (WC). CONCLUSION This study suggests that early pregnancy BMI, gestational weight gain, and full breastfeeding are relevant for offspring markers of cardiometabolic risk which seems to be mediated by body composition in young adulthood.
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Affiliation(s)
- Juliana Nyasordzi
- Department of Sports and Health, Institute of Nutrition, Consumption and Health, Paderborn University, Germany; University of Health and Allied Sciences, Ho, Volta Region, Ghana.
| | - Johanna Conrad
- Institute of Nutritional and Food Sciences, Nutritional Epidemiology, University of Bonn, Bonn, Germany.
| | - Janina Goletzke
- Department of Sports and Health, Institute of Nutrition, Consumption and Health, Paderborn University, Germany.
| | - Helena Ludwig-Walz
- DONALD Study Dortmund, Department of Nutrition and Food Sciences (IEL), Nutritional Epidemiology, University of Bonn, Dortmund, Germany; Department of Nutritional, Food and Consumer Sciences, Fulda University of Applied Sciences, Germany.
| | - Christian Herder
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Pediatric Endocrinology and Diabetology, Laboratory for Translational Hormone Analytics, Peptide Hormone Research Unit, Center of Child and Adolescent Medicine, Justus Liebig University Giessen, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Pediatric Endocrinology and Diabetology, Laboratory for Translational Hormone Analytics, Peptide Hormone Research Unit, Center of Child and Adolescent Medicine, Justus Liebig University Giessen, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
| | - Stefan A Wudy
- Pediatric Endocrinology and Diabetology, Laboratory for Translational Hormone Analytics, Peptide Hormone Research Unit, Center of Child and Adolescent Medicine, Justus Liebig University Giessen, Germany.
| | - Yifan Hua
- DONALD Study Dortmund, Department of Nutrition and Food Sciences (IEL), Nutritional Epidemiology, University of Bonn, Dortmund, Germany; Department of Nutritional, Food and Consumer Sciences, Fulda University of Applied Sciences, Germany.
| | - Thomas Remer
- DONALD Study Dortmund, Department of Nutrition and Food Sciences (IEL), Nutritional Epidemiology, University of Bonn, Dortmund, Germany; Department of Nutritional, Food and Consumer Sciences, Fulda University of Applied Sciences, Germany.
| | - Anette E Buyken
- Department of Sports and Health, Institute of Nutrition, Consumption and Health, Paderborn University, Germany.
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15
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Maheshwari G, Wen G, Gessner DK, Ringseis R, Lochnit G, Eder K, Zorn H, Timm T. Tandem mass tag-based proteomics for studying the effects of a biotechnologically produced oyster mushroom against hepatic steatosis in obese Zucker rats. J Proteomics 2021; 242:104255. [PMID: 33957313 DOI: 10.1016/j.jprot.2021.104255] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/22/2021] [Accepted: 04/28/2021] [Indexed: 12/12/2022]
Abstract
Hepatic steatosis is a very common response to liver injury and often attributed to metabolic disorders. Prior studies have demonstrated the efficacy of a biotechnologically produced oyster mushroom (Pleurotus sajor-caju, PSC) in alleviating hepatic steatosis in obese Zucker rats. This study aims to elucidate molecular events underlying the anti-steatotic effects of PSC. Tandem mass tag (TMT) peptide labeling coupled with LC-MS/MS/MS was used to quantify and compare proteins in the livers of lean Zucker rats fed a control diet (LC), obese Zucker rats fed the same control diet (OC) and obese Zucker rats fed the control diet supplemented with 5% PSC (OPSC) for 4 weeks. Using this technique 3128 proteins could be quantified, out of which 108 were differentially abundant between the OPSC and OC group. Functional enrichment analysis of the up-regulated proteins showed that these proteins were mainly involved in metabolic processes, while the down-regulated proteins were involved in inflammatory processes. Results from proteomic analysis were successfully validated for two up-regulated (carbonic anhydrase 3, regucalcin) and two down-regulated (cadherin-17, ceruloplasmin) proteins by means of immunoblotting. SIGNIFICANCE: Valorization of low-grade agricultural waste by edible fungi, such as the mushroom Pleurotus sajor-caju (PSC), represents a promising strategy for the production of protein rich biomass since they boast of a unique enzyme system that has the ability to recover nutrients and energy from biodegradable waste. Herein, we describe the metabolic effects of PSC feeding using a combined quantitative proteomics and bioinformatics approach. In total, 108 proteins were identified to be regulated by PSC feeding in the liver of the obese rats. Complementary usage of a bioinformatics approach allowed us to decipher the mechanisms underlying the recently observed lipid-lowering and anti-inflammatory activity of PSC feeding in obese Zucker rats, namely a reduction of fatty acid synthesis, an improvement of hepatoprotective mechanisms and an enhancement of anti-inflammatory effects.
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Affiliation(s)
- Garima Maheshwari
- Institute of Food Chemistry and Food Biotechnology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 17, 35392 Giessen, Germany; Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany
| | - Gaiping Wen
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany
| | - Denise K Gessner
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany
| | - Robert Ringseis
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany
| | - Günter Lochnit
- Protein Analytics, Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-University Giessen, Friedrichstrasse 24, 35392 Giessen, Germany
| | - Klaus Eder
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany
| | - Holger Zorn
- Institute of Food Chemistry and Food Biotechnology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 17, 35392 Giessen, Germany; Fraunhofer Institute for Molecular Biology and Applied Ecology, Ohlebergsweg 12, 35392 Giessen, Germany.
| | - Thomas Timm
- Protein Analytics, Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-University Giessen, Friedrichstrasse 24, 35392 Giessen, Germany
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16
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Medeiros LMD, Stahlschmidt R, Ferracini AC, Souza CMD, Juliato CRT, Mazzola PG. Switching of Hormone Therapies in Breast Cancer Women. REVISTA BRASILEIRA DE GINECOLOGIA E OBSTETRÍCIA 2021; 43:185-189. [PMID: 33465792 PMCID: PMC10183841 DOI: 10.1055/s-0040-1719149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
OBJECTIVE The objective of the present study was to analyze the reasons that led to hormone therapies (HTs) regimen changes in women with breast cancer. METHODS This was a retrospective cross-sectional study from a single-institution Brazilian cancer center with patient records diagnosed with breast cancer between January 2012 and January 2017. RESULTS From 1,555 women who were in treatment with HT, 213 (13.7%) women had HT switched, either tamoxifen to anastrozole or vice-versa. Most women included in the present study who switched HT were > 50 years old, postmenopausal, Caucasian, and had at least one comorbidity. From the group with therapy change, 'disease progression' was reason of change in 124 (58.2%) cases, and in 65 (30.5%) patients, 'presence of side effects' was the reason. From those women who suffered with side effects, 24 (36.9%) had comorbidities. CONCLUSION The present study demonstrated a low rate of HT switch of tamoxifen to anastrozole. Among the reasons for changing therapy, the most common was disease progression, which includes cancer recurrence, metastasis or increased tumor. Side effects were second; furthermore, age and comorbidities are risk factors for side effects.
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Affiliation(s)
| | - Rebeca Stahlschmidt
- Graduate Program in Medical Sciences, Faculty of Medical Sciences, Universidade de Campinas (Unicamp), Campinas, SP, Brazil
| | - Amanda Canato Ferracini
- Graduate Program in Medical Sciences, Faculty of Medical Sciences, Universidade de Campinas (Unicamp), Campinas, SP, Brazil
| | - Cinthia Madeira de Souza
- Graduate Program in Medical Sciences, Faculty of Medical Sciences, Universidade de Campinas (Unicamp), Campinas, SP, Brazil
| | - Cassia Raquel Teatin Juliato
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Universidade de Campinas (Unicamp), Campinas, SP, Brazil
| | - Priscila Gava Mazzola
- Faculty of Pharmaceutical Sciences, Universidade de Campinas (Unicamp), Campinas, SP, Brazil
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17
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Barbosa RJ, Ratti da Silva G, Cola IM, Kuchler JC, Coelho N, Barboza LN, Menetrier JV, de Souza R, Zonta FN, Froehlich DL, Jacomassi E, Soares AA, Velasques LG, Veiga ADA, Souza LMD, Lovato ECW, Ribeiro-Paes JT, Gasparotto Junior A, Acco A, Lívero FADR. Promising therapeutic use of Baccharis trimera (less.) DC. as a natural hepatoprotective agent against hepatic lesions that are caused by multiple risk factors. JOURNAL OF ETHNOPHARMACOLOGY 2020; 254:112729. [PMID: 32145332 DOI: 10.1016/j.jep.2020.112729] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 02/03/2020] [Accepted: 02/29/2020] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Baccharis trimera (Less.) DC is a perennial subshrub, popularly known as "carqueja," that belongs to the Asteraceae family. Ethnobotanical studies indicate that this species is used for the treatment of diabetes and digestive and liver diseases. However, studies that sought to validate its popular use were conducted using ethanolic extracts of the plant, which does not reflect the ethnomedicinal use of this species in humans. AIM OF THE STUDY Non-alcoholic fatty liver disease (NAFLD) is characterized by triglyceride accumulation in the liver that can progress to cirrhosis and hepatocellular carcinoma. Because of the severity of this disease, less toxic and more effective therapeutic agents need to be developed. B. trimera may be a promising therapeutic alternative, but its activity against multiple risk factors for liver disease (e.g., smoking, dyslipidemia, and diabetes mellitus) has not been studied. The present study investigated the effects of an ethnomedicinal form of a B. trimera preparation in a rat model of NAFLD that is associated with multiple risk factors. MATERIAL AND METHODS Phytochemical analysis of the ethanolic soluble fraction of B. trimera extract was performed using ultra-performance liquid chromatography coupled to high-resolution mass spectrometry. Streptozotocin was used to induce diabetes in male Wistar rats. The rats received a 0.5% cholesterol-enriched diet and were exposed to cigarette smoke (9 cigarettes/day, 5 days/week, for 4 weeks). In the last 2 weeks, the animals were orally treated with vehicle (negative control group), B. trimera extract (30, 100, and 300 mg/kg), or insulin + simvastatin. One group of rats that was not exposed to these risk factors was also evaluated. Blood was collected for glucose, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) analysis. The liver and feces were collected for lipid quantification. The liver was additionally processed for histopathological analysis. RESULTS The model successfully induced NAFLD and increased levels of glucose, AST, and ALT in the negative control group. Treatment with the B. trimera extract (30 and 100 mg/kg) and insulin + simvastatin decreased hepatic and fecal lipids. In contrast to insulin + simvastatin treatment, all three doses of B. trimera effectively reduced AST and ALT levels. CONCLUSION B. trimera may be promising as a hepatoprotective agent against hepatic lesions that are caused by multiple risk factors.
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Affiliation(s)
- Rodrigo Jachimowski Barbosa
- Laboratory of Preclinical Research of Natural Products, Post-Graduate Program in Medicinal Plants and Phytotherapeutics in Basic Attention, Paranaense University, Umuarama, PR, Brazil
| | - Gustavo Ratti da Silva
- Laboratory of Preclinical Research of Natural Products, Post-Graduate Program in Medicinal Plants and Phytotherapeutics in Basic Attention, Paranaense University, Umuarama, PR, Brazil
| | - Itaruã Machri Cola
- Laboratory of Preclinical Research of Natural Products, Post-Graduate Program in Medicinal Plants and Phytotherapeutics in Basic Attention, Paranaense University, Umuarama, PR, Brazil
| | | | - Natalia Coelho
- Laboratory of Preclinical Research of Natural Products, Post-Graduate Program in Medicinal Plants and Phytotherapeutics in Basic Attention, Paranaense University, Umuarama, PR, Brazil
| | - Lorena Neris Barboza
- Laboratory of Preclinical Research of Natural Products, Post-Graduate Program in Medicinal Plants and Phytotherapeutics in Basic Attention, Paranaense University, Umuarama, PR, Brazil
| | - Jacqueline Vergutz Menetrier
- Laboratory of Preclinical Research of Natural Products, Post-Graduate Program in Medicinal Plants and Phytotherapeutics in Basic Attention, Paranaense University, Umuarama, PR, Brazil
| | - Ronaldo de Souza
- Laboratory of Preclinical Research of Natural Products, Post-Graduate Program in Medicinal Plants and Phytotherapeutics in Basic Attention, Paranaense University, Umuarama, PR, Brazil
| | | | | | - Ezilda Jacomassi
- Laboratory of Preclinical Research of Natural Products, Post-Graduate Program in Medicinal Plants and Phytotherapeutics in Basic Attention, Paranaense University, Umuarama, PR, Brazil
| | - Andréia Assunção Soares
- Laboratory of Preclinical Research of Natural Products, Post-Graduate Program in Medicinal Plants and Phytotherapeutics in Basic Attention, Paranaense University, Umuarama, PR, Brazil
| | - Leonardo Garcia Velasques
- Laboratory of Preclinical Research of Natural Products, Post-Graduate Program in Medicinal Plants and Phytotherapeutics in Basic Attention, Paranaense University, Umuarama, PR, Brazil
| | - Alan de Almeida Veiga
- Institute of Research Pelé Pequeno Príncipe, Pequeno Príncipe Faculty, Curitiba, PR, Brazil
| | - Lauro Mera de Souza
- Institute of Research Pelé Pequeno Príncipe, Pequeno Príncipe Faculty, Curitiba, PR, Brazil
| | - Evellyn Claudia Wietzkoski Lovato
- Laboratory of Preclinical Research of Natural Products, Post-Graduate Program in Medicinal Plants and Phytotherapeutics in Basic Attention, Paranaense University, Umuarama, PR, Brazil
| | | | - Arquimedes Gasparotto Junior
- Laboratory of Electrophysiology and Cardiovascular Pharmacology, Faculty of Health Sciences, Federal University of Grande Dourados, Dourados, MS, Brazil.
| | - Alexandra Acco
- Laboratory of Pharmacology and Metabolism, Post-Graduate Program of Pharmacology, Federal University of Paraná, Curitiba, PR, Brazil
| | - Francislaine Aparecida Dos Reis Lívero
- Laboratory of Preclinical Research of Natural Products, Post-Graduate Program in Medicinal Plants and Phytotherapeutics in Basic Attention, Paranaense University, Umuarama, PR, Brazil.
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Li HN, Zhao LL, Zhou DY, Chen DQ. Ganoderma Lucidum Polysaccharides Ameliorates Hepatic Steatosis and Oxidative Stress in db/db Mice via Targeting Nuclear Factor E2 (Erythroid-Derived 2)-Related Factor-2/Heme Oxygenase-1 (HO-1) Pathway. Med Sci Monit 2020; 26:e921905. [PMID: 32245940 PMCID: PMC7154563 DOI: 10.12659/msm.921905] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Background Type 2 diabetes mellitus (T2DM) and its comorbidities, including obesity, hypertension, and hyperlipidemia, are commonly associated with non-alcoholic fatty liver disease (NAFLD). Ganoderma lucidum polysaccharide (GDLP) is one of the central bioactive components in Ganoderma lucidum with anti-inflammatory, antioxidant, and hepatoprotective properties. However, the effect and mechanisms of GDLP in hepatic steatosis remain largely unknown. In the present study, we aimed to investigate the function of GDLP in hepatic steatosis and the underlying mechanism. Material/Methods In this study, male db/db mice were received with a high-fat diet (HFD) to investigate the effect of GDLP in T2DM-induced hepatic steatosis. The biological characteristics of the hepatic steatosis were evaluated through the detection of clinical indicators, including biochemical parameters, histopathology, and related cytokine levels. Additionally, the protein expression levels of Nrf2 (nuclear factor E2 (erythroid-derived 2)-related factor-2) signaling pathway were investigated by using western blotting and immunohistochemical staining. Results The levels of food/water intake, body weight, fasting blood glucose, plasma lipids, urinary biomarkers, hepatic lipid accumulation, and tumor necrosis factor (TNF)-α were observably decreased in GDLP-treated db/db mice. Additionally, administration of GDLP increased the expression of various antioxidases, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), whereas it reduced the level of malonaldehyde (MDA). Furthermore, GDLP was significantly promoted protein expression level of Nrf2 and its downstream target gene HO-1 (heme oxygenase-1) while decreased TNF-α expression. Conclusions These results indicate that GDLP against T2DM-induced hepatic steatosis, oxidative stress, and inflammation by improving the Nrf2/HO-1 signaling pathway in db/db mice, suggesting the GDLP may serve as an effective strategy for in fatty liver treatment.
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Affiliation(s)
- Hong Ning Li
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China (mainland)
| | - Ling Li Zhao
- Hangzhou AIMA Maternity Hospital, Hangzhou, Zhejiang, China (mainland)
| | - Di Yi Zhou
- Zhejiang Integrated Traditional and Western Medicine Hospital, Hangzhou, Zhejiang, China (mainland)
| | - Dan Qing Chen
- Women Hospital School of Medicine Zhejiang University, Hangzhou, Zhejiang, China (mainland)
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Rendina-Ruedy E, Rosen CJ. Lipids in the Bone Marrow: An Evolving Perspective. Cell Metab 2020; 31:219-231. [PMID: 31668874 PMCID: PMC7004849 DOI: 10.1016/j.cmet.2019.09.015] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 09/05/2019] [Accepted: 09/20/2019] [Indexed: 12/15/2022]
Abstract
Because of heavy energy demands to maintain bone homeostasis, the skeletal system is closely tied to whole-body metabolism via neuronal and hormonal mediators. Glucose, amino acids, and fatty acids are the chief fuel sources for bone resident cells during its remodeling. Lipids, which can be mobilized from intracellular depots in the bone marrow, can be a potent source of fatty acids. Thus, while it has been suggested that adipocytes in the bone marrow act as "filler" and are detrimental to skeletal homeostasis, we propose that marrow lipids are, in fact, essential for proper bone functioning. As such, we examine the prevailing evidence regarding the storage, use, and export of lipids within the skeletal niche, including from both in vitro and in vivo model systems. We also highlight the numerous challenges that remain to fully appreciate the relationship of lipid turnover to skeletal homeostasis.
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Affiliation(s)
- Elizabeth Rendina-Ruedy
- Center for Molecular Medicine, Research Institute, Maine Medical Center, Scarborough, ME 04074, USA; Vanderbilt Center for Bone Biology, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
| | - Clifford J Rosen
- Center for Molecular Medicine, Research Institute, Maine Medical Center, Scarborough, ME 04074, USA
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20
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Kalemba KM, Wang Y, Xu H, Chiles E, McMillin SM, Kwon H, Su X, Wondisford FE. Glycerol induces G6pc in primary mouse hepatocytes and is the preferred substrate for gluconeogenesis both in vitro and in vivo. J Biol Chem 2019; 294:18017-18028. [PMID: 31645433 PMCID: PMC6885632 DOI: 10.1074/jbc.ra119.011033] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/15/2019] [Indexed: 12/27/2022] Open
Abstract
Gluconeogenesis (GNG) is de novo production of glucose from endogenous carbon sources. Although it is a commonly studied pathway, particularly in disease, there is a lack of consensus about substrate preference. Moreover, primary hepatocytes are the current gold standard for in vitro liver studies, but no direct comparison of substrate preference at physiological fasting concentrations has been performed. We show that mouse primary hepatocytes prefer glycerol to pyruvate/lactate in glucose production assays and 13C isotope tracing studies at the high concentrations commonly used in the literature, as well as at more relevant fasting, physiological concentrations. In addition, when glycerol, pyruvate/lactate, and glutamine are all present, glycerol is responsible for over 75% of all glucose carbons labeled. We also found that glycerol can induce a rate-limiting enzyme of GNG, glucose-6-phosphatase. Lastly, we suggest that glycerol is a better substrate than pyruvate to test in vivo production of glucose in fasting mice. In conclusion, glycerol is the major carbon source for GNG in vitro and in vivo and should be compared with other substrates when studying GNG in the context of metabolic disease states.
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Affiliation(s)
- Katarzyna M Kalemba
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey 08901
| | - Yujue Wang
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey 08901
| | - Huiting Xu
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey 08901
| | - Eric Chiles
- Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey 08903
| | - Sara M McMillin
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina
| | - Hyokjoon Kwon
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey 08901
| | - Xiaoyang Su
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey 08901; Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey 08903
| | - Fredric E Wondisford
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey 08901; Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey 08903.
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21
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Zhou JY, Poudel A, Welchko R, Mekala N, Chandramani-Shivalingappa P, Rosca MG, Li L. Liraglutide improves insulin sensitivity in high fat diet induced diabetic mice through multiple pathways. Eur J Pharmacol 2019; 861:172594. [PMID: 31412267 DOI: 10.1016/j.ejphar.2019.172594] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 08/01/2019] [Accepted: 08/07/2019] [Indexed: 02/07/2023]
Abstract
Glucagon like peptide-1 (GLP-1) promotes postprandial insulin secretion. Liraglutide, a full agonist of the GLP-1 receptor, reduces body weight, improve insulin sensitivity, and alleviate Non Alcoholic Fatty Liver Disease (NAFLD). However, the underlying mechanisms remain unclear. This study aims to explore the underlying mechanisms and cell signaling pathways involved in the anti-obesity and anti-inflammatory effects of liraglutide. Mice were fed a high fat high sucrose diet to induce diabetes, diabetic mice were divided into two groups and injected with liraglutide or vehicle for 14 days. Liraglutide treatment improved insulin sensitivity, accompanied with reduced expression of the phosphorylated Acetyl-CoA carboxylase-2 (ACC2) and upregulation of long chain acyl CoA dehydrogenase (LCAD) in insulin sensitive tissues. Furthermore, liraglutide induced adenosine monophosphate-activated protein kinase-α (AMPK-α) and Sirtuin-1(Sirt-1) protein expression in liver and perigonadal fat. Liraglutide induced elevation of fatty acid oxidation in these tissues may be mediated through the AMPK-Sirt-1 cell signaling pathway. In addition, liraglutide induced brown adipocyte differentiation in skeletal muscle, including induction of uncoupling protein-1 (UCP-1) and PR-domain-containing-16 (PRDM-16) protein in association with induction of SIRT-1. Importantly, liraglutide displayed anti-inflammation effect. Specifically, liraglutide led to a significant reduction in circulating interleukin-1 β (IL-1 β) and interleukin-6 (IL-6) as well as hepatic IL-1 β and IL-6 content. The expression of inducible nitric oxide synthase (iNOS-1) and cyclooxygenase-2 (COX-2) in insulin sensitive tissues was also reduced following liraglutide treatment. In conclusion, liraglutide improves insulin sensitivity through multiple pathways resulting in reduction of inflammation, elevation of fatty acid oxidation, and induction of adaptive thermogenesis.
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Affiliation(s)
- Joseph Yi Zhou
- College of Medicine, Central Michigan University, MI, 48859, USA
| | - Anil Poudel
- Department of Physician Assistant, College of Health Professions, Central Michigan University MI, 48859, USA
| | - Ryan Welchko
- Department of Physician Assistant, College of Health Professions, Central Michigan University MI, 48859, USA
| | - Naveen Mekala
- College of Medicine, Central Michigan University, MI, 48859, USA
| | | | | | - Lixin Li
- Department of Physician Assistant, College of Health Professions, Central Michigan University MI, 48859, USA.
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Zsóri G, Illés D, Ivány E, Kosár K, Holzinger G, Tajti M, Pálinkás E, Szabovik G, Nagy A, Palkó A, Czakó L. In New-Onset Diabetes Mellitus, Metformin Reduces Fat Accumulation in the Liver, But Not in the Pancreas or Pericardium. Metab Syndr Relat Disord 2019; 17:289-295. [PMID: 31013454 DOI: 10.1089/met.2018.0086] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background: Nonalcoholic fatty pancreas and liver disease (NAFPD and NAFLD) and pericardial adipose tissue (PAT) are often associated with type 2 diabetes mellitus (T2DM). Our aim was to evaluate the incidence rate of NAFLD and NAFPD, PAT size, and the effect of metformin treatment on NAFLD, NAFPD, and PAT in new-onset T2DM (NODM). Methods: Seventeen patients with NODM and 10 subjects used as a control group were involved in the study. Computed tomography (CT) and laboratory tests were performed before the beginning of metformin therapy and 4 months afterward. PAT and the amount of fat in the pancreas and liver were determined by X-ray attenuation during unenhanced CT examination and compared with the values for the control subjects. Results: Metabolic parameters improved significantly after metformin therapy. NAFLD was diagnosed in 64.7% of the patients with NODM and in 10% of the control subjects. The radiation absorption of the liver was significantly lower in the patients with NODM compared with the control group and significantly higher after metformin therapy compared with the baseline values. Only six patients (35.3%) had NAFLD after metformin therapy. NAFPD was diagnosed in 82.3% of the patients with NODM and in 20% of the control subjects. The radiation absorption of the pancreas was significantly lower in the patients with NODM compared with the control group but did not change significantly after treatment. PAT size was significantly larger in the patients with NODM and did not change significantly after metformin treatment. Conclusions: NAFLD, NAFPD, and increased PAT were detected in the majority of patients with NODM. Metformin therapy decreased the amount of fat in the liver in parallel with an improvement in the metabolic parameters and may, thus, be beneficial for preventing the late consequences of NAFLD.
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Affiliation(s)
- Gábor Zsóri
- 1 First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Dóra Illés
- 1 First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Emese Ivány
- 1 First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Klára Kosár
- 1 First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Gábor Holzinger
- 1 First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Máté Tajti
- 1 First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Eszter Pálinkás
- 1 First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Géza Szabovik
- 2 Department of Radiology, University of Szeged, Szeged, Hungary
| | - András Nagy
- 2 Department of Radiology, University of Szeged, Szeged, Hungary
| | - András Palkó
- 2 Department of Radiology, University of Szeged, Szeged, Hungary
| | - László Czakó
- 1 First Department of Medicine, University of Szeged, Szeged, Hungary
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Pinzón-García AD, Orellano LAA, de Lazari MGT, Campos PP, Cortes ME, Sinisterra RD. Evidence of hypoglycemic, lipid-lowering and hepatoprotective effects of the Bixin and Bixin: β-CD inclusion compound in high-fat-fed obese mice. Biomed Pharmacother 2018; 106:363-372. [DOI: 10.1016/j.biopha.2018.06.144] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 06/18/2018] [Accepted: 06/25/2018] [Indexed: 12/21/2022] Open
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Fluoxetine induces lipid metabolism abnormalities by acting on the liver in patients and mice with depression. Acta Pharmacol Sin 2018; 39:1463-1472. [PMID: 30150788 DOI: 10.1038/aps.2017.207] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2017] [Accepted: 12/14/2017] [Indexed: 12/20/2022]
Abstract
Depressive disorders are frequently managed with long-term use of antidepressant medication. Fluoxetine (FLX) is the first selective serotonin reuptake inhibitor to be widely available for the treatment of depression. The present study focuses on the effects and mechanisms of the lipid metabolism abnormalities caused by FLX in patients and in a mouse model of depression. Depression severity was assessed by the Hamilton Depression Scale (HAMD). Triglyceride (TG), cholesterol (TC) and low-density lipoprotein (LDL) serum levels were assessed in 28 patients with depression, aged 31.2±3.3 years, treated with FLX (20 to 60 mg/day) for 8 weeks. Meanwhile, the serum levels of other lipid metabolism-related parameters, such as high-density lipoprotein (HDL), apolipoprotein A1 (APOA1) and apolipoprotein B (ApoB), were also determined. The infiuence of FLX on the hepatic lipid profile and hepatic gene expression of both lipogenic and lipolytic enzymes was evaluated in a mouse model of depression treated with FLX (10 mg·kg-1·d-1, ip) for 4 weeks. We showed that the serum TG, TC and LDL levels were significantly increased in patients with depression after FLX treatment. The elevation in serum TG levels in the patients was not affected by gender or family history. FLX treatment did not significantly alter serum HDL, APOA1 or APOB levels in the patients. We further demonstrated in mice with depression that FLX treatment increased the hepatic TG level by increasing the expression of lipogenic enzymes and decreasing the expression of lipolytic enzymes in the liver. Antidepressive therapy with FLX is associated with lipid metabolism abnormalities, which are in part mediated by disturbances in hepatic lipid metabolism homeostasis. The findings contribute to the uncovering of metabolic adverse reactions in the pharmacological therapy of depression.
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Abstract
Nitric oxide (NO), generated from L-arginine and oxygen by NO synthases, is a pleiotropic signaling molecule involved in cardiovascular and metabolic regulation. More recently, an alternative pathway for the formation of this free radical has been explored. The inorganic anions nitrate (NO3-) and nitrite (NO2-), originating from dietary and endogenous sources, generate NO bioactivity in a process involving seemingly symbiotic oral bacteria and host enzymes in blood and tissues. The described cardio-metabolic effects of dietary nitrate from experimental and clinical studies include lowering of blood pressure, improved endothelial function, increased exercise performance, and reversal of metabolic syndrome, as well as antidiabetic effects. The mechanisms underlying the salutary metabolic effects of nitrate are being revealed and include interaction with mitochondrial respiration, activation of key metabolic regulatory pathways, and reduction of oxidative stress. Here we review the recent advances in the nitrate-nitrite-NO pathway, focusing on metabolic effects in health and disease.
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26
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Pivonello R, Muscogiuri G, Holder G, Paul M, Sarp S, Lesogor A, Jordaan P, Eisinger J, Colao A. Long-term safety of long-acting octreotide in patients with diabetic retinopathy: results of pooled data from 2 randomized, double-blind, placebo-controlled phase 3 studies. Endocrine 2018; 60:65-72. [PMID: 29116540 PMCID: PMC5845597 DOI: 10.1007/s12020-017-1448-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 09/30/2017] [Indexed: 12/16/2022]
Abstract
PURPOSE Octreotide (OCT) has been successfully used for treatment of acromegaly and neuroendocrine tumors for more than 30 years. However, long-term safety of OCT has not been documented in placebo-controlled setting. This present analysis pooled safety data from two similarly-designed, randomized, and placebo-controlled studies to evaluate long-term safety of long-acting OCT (20, 30 mg); targeted post-hoc analyzes focused on cardiac, hepatic, and renal safety. METHODS Two studies (NCT00131144, NCT001308450) were conducted in patients with diabetic retinopathy (OCT20 = 191, OCT30 = 348, placebo = 347). In this analysis, patients were stratified based on baseline glomerular filtration rate. Hepatic, cardiac, and renal adverse events (AEs) were identified by standardized MedDRA queries. RESULTS Median duration of exposure was >3.5 years. Most common AEs reported with OCT were diarrhea, cholelithiasis, hypoglycemia, nasopharyngitis, and hypertension. Incidence of cardiac events (QT prolongation and arrhythmia) with OCT20 and OCT30 were comparable to placebo (OCT20, RR = 1.11 [95% CI, 0.61-2.03]; OCT30, RR = 1.09 [95% CI, 0.70-1.68]). For ECG findings, changes in QTcF were similar in treatment groups, and outliers did not exceed 480 ms. Incidence of cardiac ischemia was lower with OCT than placebo (OCT20 = 12.6%, OCT30 = 10.6%, placebo = 15.3%). Incidence of liver-related AEs was higher with OCT30 than placebo (RR = 2.04 [95% CI, 1.28-3.26]); incidences were comparable with OCT20 and placebo (RR = 1.50 [95% CI, 0.69-3.25]). Overall incidences of renal AEs were comparable between treatment groups (OCT20 = 5.8%; OCT30 = 6.3%; placebo = 7.2%). Drug-related SAEs were reported more frequently with OCT (OCT20 = 7.9%; OCT30 = 10.1%; placebo = 3.5%); predominantly gallbladder-related, GI-related, and hypoglycemia. CONCLUSIONS The results from these long-term placebo-controlled studies confirm the established safety profile of long-acting OCT, in particular low risk of cardiac, hepatic and renal toxicity in a high-risk population.
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Affiliation(s)
- Rosario Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.
| | - Giovanna Muscogiuri
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | | | | | | | | | | | | | - Annamaria Colao
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
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Molecular Mechanisms Underlying Curcumin-Mediated Therapeutic Effects in Type 2 Diabetes and Cancer. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:9698258. [PMID: 29743988 PMCID: PMC5884026 DOI: 10.1155/2018/9698258] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 02/12/2018] [Accepted: 02/15/2018] [Indexed: 01/14/2023]
Abstract
The growing prevalence of age-related diseases, especially type 2 diabetes mellitus (T2DM) and cancer, has become global health and economic problems. Due to multifactorial nature of both diseases, their pathophysiology is not completely understood so far. Compelling evidence indicates that increased oxidative stress, resulting from an imbalance between production of reactive oxygen species (ROS) and their clearance by antioxidant defense mechanisms, as well as the proinflammatory state contributes to the development and progression of the diseases. Curcumin (CUR; diferuloylmethane), a well-known polyphenol derived from the rhizomes of turmeric Curcuma longa, has attracted a great deal of attention as a natural compound with beneficial antidiabetic and anticancer properties, partly due to its antioxidative and anti-inflammatory actions. Although this polyphenolic compound is increasingly being recognized for its growing number of protective health effects, the precise molecular mechanisms through which it reduces diabetes- and cancer-related pathological events have not been fully unraveled. Hence, CUR is the subject of intensive research in the fields Diabetology and Oncology as a potential candidate in the treatment of both T2DM and cancer, particularly since current therapeutic options for their treatment are not satisfactory in clinics. In this review, we summarize the recent progress made on the molecular targets and pathways involved in antidiabetic and anticancer activities of CUR that are responsible for its beneficial health effects.
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Guo XY, Sun F, Chen JN, Wang YQ, Pan Q, Fan JG. circRNA_0046366 inhibits hepatocellular steatosis by normalization of PPAR signaling. World J Gastroenterol 2018; 24:323-337. [PMID: 29391755 PMCID: PMC5776394 DOI: 10.3748/wjg.v24.i3.323] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2017] [Revised: 11/15/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate micro (mi)R-34a-antagonizing circular (circ)RNA that underlies hepatocellular steatosis. METHODS The effect of circRNA on miR-34a was recognized by the miRNA response element (MRE), and validated by the dual-luciferase reporter assay. Its association with hepatocellular steatosis was investigated in HepG2-based hepatocellular steatosis induced by free fatty acids (FFAs; 2:1 oleate:palmitate) stimulation. After normalization of the steatosis-related circRNA by expression vector, analysis of miR-34a activity, peroxisome proliferator-activated receptor (PPAR)α level, and expression of downstream genes were carried out so as to reveal its impact on the miR-34a/PPARα regulatory system. Both triglyceride (TG) assessment and cytopathological manifestations uncovered the role of circRNA in miR-34a-dependent hepatosteatogenesis. RESULTS Bioinformatic and functional analysis verified circRNA_0046366 to antagonize the activity of miR-34a via MRE-based complementation. In contrast to its lowered level during FFA-induced hepatocellular steatosis, circRNA_0046366 up-regulation abolished the miR-34a-dependent inhibition of PPARα that played a critical role in metabolic signaling pathways. PPARα restoration exerted transcriptional improvement to multiple genes responsible for lipid metabolism. TG-specific lipolytic genes [carnitine palmitoyltransferase 1A (CPT1A) and solute-carrier family 27A (SLC27A)] among these showed significant increase in their expression levels. The circRNA_0046366-related rebalancing of lipid homeostasis led to dramatic reduction of TG content, and resulted in the ameliorated phenotype of hepatocellular steatosis. CONCLUSION Dysregulation of circRNA_0046366/miR-34a/PPARα signaling may be a novel epigenetic mechanism underlying hepatocellular steatosis. circRNA_0046366 serves as a potential target for the treatment of hepatic steatosis.
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Affiliation(s)
- Xing-Ya Guo
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Fang Sun
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Jian-Neng Chen
- Department of Hepatology, Zhengxing Hospital, Zhangzhou 363000, Fujian Province, China
| | - Yu-Qin Wang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Qin Pan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
- Shanghai Key Laboratory of Children’s Digestion and Nutrition, Shanghai 200092, China
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Sugaya Y, Satoh H. Liver-specific G 0 /G 1 switch gene 2 (G0s2) expression promotes hepatic insulin resistance by exacerbating hepatic steatosis in male Wistar rats. J Diabetes 2017; 9:754-763. [PMID: 27624922 DOI: 10.1111/1753-0407.12482] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 08/18/2016] [Accepted: 09/08/2016] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Hepatic steatosis is strongly associated with insulin resistance. It has been reported that G0 /G1 switch gene 2 (G0s2) inhibits the lipolytic activity of adipose triglyceride lipase, which is a major lipase in the liver as well as in adipocytes. Moreover, G0s2 protein content is increased in the livers of high-fat diet (HFD)-fed rats. In the present study, we investigated the effect of hepatic G0s2 on insulin sensitivity in male Wistar rats. METHODS Male Wistar rats were fed a 60% HFD for 4 weeks. After 3 weeks of feeding, rats were injected with adenovirus-expressing green fluorescent protein (Ad-GFP; control) or adenovirus-expressing mouse G0s2 (Ad-G0s2). On Day 7 after injection, a euglycemic-hyperinsulinemic clamp study was performed in rats fasted for 8 h. RESULTS Body weight and fasting glucose levels were not significantly different between the Ad-GFP and Ad-G0s2 groups. During the clamp study, the glucose infusion rate required for euglycemia decreased significantly by 16% in the Ad-G0s2 compared with Ad-GFP group. The insulin-suppressed hepatic glucose output increased significantly in the Ad-G0s2 group, but the insulin-stimulated glucose disposal rate was not significantly different between the two groups. Consistent with the clamp data, insulin-stimulated phosphorylation of Akt decreased significantly in livers of rats injected with Ad-G0s2. Furthermore, Oil Red O-staining indicated that overexpression of G0s2 protein in the liver promoted hepatic steatosis by 2.5-fold in HFD-fed rats. CONCLUSION The results of the present study indicate that hepatic G0s2 protein may promote hepatic insulin resistance by exacerbating hepatic steatosis.
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Affiliation(s)
- Yoshiyuki Sugaya
- Department of Nephrology, Hypertension, Diabetology, Endocrinology, and Metabolism, Fukushima Medical University, Fukushima, Japan
| | - Hiroaki Satoh
- Department of Nephrology, Hypertension, Diabetology, Endocrinology, and Metabolism, Fukushima Medical University, Fukushima, Japan
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Guo XY, He CX, Wang YQ, Sun C, Li GM, Su Q, Pan Q, Fan JG. Circular RNA Profiling and Bioinformatic Modeling Identify Its Regulatory Role in Hepatic Steatosis. BIOMED RESEARCH INTERNATIONAL 2017; 2017:5936171. [PMID: 28717649 PMCID: PMC5499244 DOI: 10.1155/2017/5936171] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Accepted: 03/07/2017] [Indexed: 12/14/2022]
Abstract
Circular RNAs (circRNAs) exhibit a wide range of physiological and pathological activities. To uncover their role in hepatic steatosis, we investigated the expression profile of circRNAs in HepG2-based hepatic steatosis induced by high-fat stimulation. Differentially expressed circRNAs were subjected to validation using QPCR and functional analyses using principal component analysis, hierarchical clustering, target prediction, gene ontology (GO), and pathway annotation, respectively. Bioinformatic integration established the circRNA-miRNA-mRNA regulatory network so as to identify the mechanisms underlying circRNAs' metabolic effect. Here we reported that hepatic steatosis was associated with a total of 357 circRNAs. Enrichment of transcription-related GOs, especially GO: 0006355, GO: 004589, GO: 0045944, GO: 0045892, and GO: 0000122, demonstrated their specific actions in transcriptional regulation. Lipin 1 (LPIN1) was recognized to mediate the transcriptional regulatory effect of circRNAs on metabolic pathways. circRNA-miRNA-mRNA network further identified the signaling cascade of circRNA_021412/miR-1972/LPIN1, which was characterized by decreased level of circRNA_021412 and miR-1972-based inhibition of LPIN1. LPIN1-induced downregulation of long chain acyl-CoA synthetases (ACSLs) expression finally resulted in the hepatosteatosis. These findings identify circRNAs to be important regulators of hepatic steatosis. Transcription-dependent modulation of metabolic pathways may underlie their effects, partially by the circRNA_021412/miR-1972/LPIN1 signaling.
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Affiliation(s)
- Xing-Ya Guo
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Chong-Xin He
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Yu-Qin Wang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Chao Sun
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Guang-Ming Li
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Qing Su
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Qin Pan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
- Shanghai Key Laboratory of Children's Digestion and Nutrition, Shanghai 200092, China
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Bakulin IG, Sandler YG, Vinnitskaya EV, Keiyan VA, Rodionova SV, Rotin DL. [Diabetes mellitus and nonalcoholic fatty liver disease: The verges of contingency]. TERAPEVT ARKH 2017; 89:59-65. [PMID: 28281517 DOI: 10.17116/terarkh201789259-65] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
AIM To estimate the incidence of hepatic steatosis (HS) and liver fibrosis (LF) in patients with diabetes mellitus (DM), by applying the noninvasive techniques of liver fibroelastometry (LFE) and a battery of fibrotests (FTs); to determine their diagnostic value and to identify factors influencing the development of LF. SUBJECTS AND METHODS A comprehensive examination was made in 82 diabetic patients (mean age, 56.7±12.7 years; p=0.033). The data were statistically evaluated using ROC curve analysis, correlation and single-factor analyses of variance, and multiple logistic regression analysis. RESULTS FTs and LFE revealed that the DM patients had liver cirrhosis (LC) (METAVIR F4) in 12 (14.6%) and 15 (18.2%) patients, respectively. Those showed clinically significant fibrosis (METAVIR fibrosis stages F2-3) in 19 (23.1%) and 23 (28%) patients, respectively. Varying degrees of HS were present in 79 (96.3%) patients. LFE and FTs demonstrated comparable results in detecting LC (the area under the receiver operating characteristics curve (AUROC), 0.83 and 0.81, respectively). The development of LF is influenced by factors, such as the degree of HS, obesity, the activity of an inflammatory process, and the level of alanine aminotransferase and α2-macroglobulin. CONCLUSION Diabetic patients are at high risk for NAFLD to develop LF and LC. LFE and FTs showed a comparably high accuracy in the diagnosis of LC in patients with DM and these may be used for screening. With allowance made for the existing risk factors of LF and LC, it is necessary to identify groups of patients with DM for further examination and follow-up. Patients who are diagnosed with stage F4 should be examined carefully to evaluate concurrent diseases and to make liver biopsy.
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Affiliation(s)
- I G Bakulin
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
| | - Yu G Sandler
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
| | - E V Vinnitskaya
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
| | - V A Keiyan
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
| | - S V Rodionova
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
| | - D L Rotin
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
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Alleviation of hepatic fat accumulation by betaine involves reduction of homocysteine via up-regulation of betaine-homocysteine methyltransferase (BHMT). Biochem Biophys Res Commun 2016; 477:440-7. [DOI: 10.1016/j.bbrc.2016.06.080] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Accepted: 06/15/2016] [Indexed: 01/08/2023]
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Hong J, Kim S, Kim HS. Hepatoprotective Effects of Soybean Embryo by Enhancing Adiponectin-Mediated AMP-Activated Protein Kinase α Pathway in High-Fat and High-Cholesterol Diet-Induced Nonalcoholic Fatty Liver Disease. J Med Food 2016; 19:549-59. [PMID: 27266339 DOI: 10.1089/jmf.2015.3604] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), which is characterized by >5% deposition of triglycerides in hepatocytes, is often referred as a major risk factor for obesity, type 2 diabetes, and hypertension. We investigated the hepatoprotective effect of whole soybean embryos containing bioactive substances such as isoflavones and soyasaponins. For this study, mice were randomly allocated into four groups that were fed different diets for 10 weeks: normal diets and high-fat and high-cholesterol diets (HD), and HD with 10% or 20% soybean embryo powder (10SE-HD and 20SE-HD). Hepatic superoxide dismutase and glutathione peroxidase activity of the experimental groups increased during the period of the study (P < .05). Hepatic mRNA expressions of tumor necrosis factor α, nuclear factor (erythroid-derived 2)-like 2, and Caspase 3 were decreased when soybean embryos were increased in the mice's diets. Both of the soybean embryo-treated groups showed significantly decreased serum and liver triglyceride and total cholesterol. Adiponectin, AMP-activated protein kinase (AMPK) α, hydroxymethylglutaryl-CoA reductase, sterol regulatory element-binding protein-1c, fatty acid synthase, and apolipoprotein B mRNA expressions were decreased in the mice that were fed soybean embryos. We suggest that the regular supplementation of soybean embryos might be a useful treatment for preventing NAFLD and associated complications through upregulation of adiponectin-mediated AMPKα pathway parameters, which are implicated in antioxidant, anti-inflammatory, and lipid metabolism activities.
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Affiliation(s)
- Jihye Hong
- Major in Food and Nutrition, College of Human Ecology, Sookmyung Women's University , Seoul, Korea
| | - Sera Kim
- Major in Food and Nutrition, College of Human Ecology, Sookmyung Women's University , Seoul, Korea
| | - Hyun-Sook Kim
- Major in Food and Nutrition, College of Human Ecology, Sookmyung Women's University , Seoul, Korea
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Effect of canagliflozin on liver function tests in patients with type 2 diabetes. DIABETES & METABOLISM 2015; 42:25-32. [PMID: 26575250 DOI: 10.1016/j.diabet.2015.10.003] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 09/24/2015] [Accepted: 10/05/2015] [Indexed: 12/29/2022]
Abstract
AIMS To report changes in liver function tests observed with canagliflozin, a sodium glucose co-transporter 2 inhibitor, across phase 3 studies in patients with type 2 diabetes, and to examine the relationship between changes in liver function tests and the weight loss and glycaemic improvements observed with canagliflozin. METHODS Data were pooled from four 26-week, placebo-controlled studies of canagliflozin 100 and 300mg (n=2313) and two 52-week, active-controlled studies of canagliflozin 300mg versus sitagliptin 100mg (n=1488). Analysis of covariance was performed to determine the contribution of changes in body weight and HbA1c to the changes in liver function tests. RESULTS Reductions in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma-glutamyl transferase, and increases in bilirubin were seen with canagliflozin 100 and 300mg versus placebo (nominal P<0.001 for alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase [both doses]; P<0.001 for alkaline phosphatase and P=0.015 for bilirubin [canagliflozin 300mg only]) at week 26 and with canagliflozin 300mg versus sitagliptin 100mg (nominal P<0.001 for alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase and bilirubin, and P<0.01 for alkaline phosphatase) at week 52. Few patients met predefined limits of change criteria for liver function tests, and none met Hy's law criteria. In both populations, alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase reductions were fully explained by HbA1c and body weight reductions. CONCLUSIONS Canagliflozin provided improvements in liver function tests versus either placebo or sitagliptin treatments that were fully explained by the combined effects of HbA1c and body weight reductions with canagliflozin.
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Lee JH, Jung JY, Jang EJ, Jegal KH, Moon SY, Ku SK, Kang SH, Cho IJ, Park SJ, Lee JR, Zhao RJ, Kim SC, Kim YW. Combination of honokiol and magnolol inhibits hepatic steatosis through AMPK-SREBP-1 c pathway. Exp Biol Med (Maywood) 2014; 240:508-18. [PMID: 25125496 DOI: 10.1177/1535370214547123] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 07/03/2014] [Indexed: 12/14/2022] Open
Abstract
Honokiol and magnolol, as pharmacological biphenolic compounds of Magnolia officinalis, have been reported to have antioxidant and anti-inflammatory properties. Sterol regulatory element binding protein-1 c (SREBP-1 c) plays an important role in the development and processing of steatosis in the liver. In the present study, we investigated the effects of a combination of honokiol and magnolol on SREBP-1 c-dependent lipogenesis in hepatocytes as well as in mice with fatty liver due to consumption of high-fat diet (HFD). Liver X receptor α (LXRα) agonists induced activation of SREBP-1 c and expression of lipogenic genes, which were blocked by co-treatment of honokiol and magnolol (HM). Moreover, a combination of HM potently increased mRNA of fatty acid oxidation genes. HM induced AMP-activated protein kinase (AMPK), an inhibitory kinase of the LXRα-SREBP-1 c pathway. The role of AMPK activation induced by HM was confirmed using an inhibitor of AMPK, Compound C, which reversed the ability of HM to both inhibit SREBP-1 c induction as well as induce genes for fatty acid oxidation. In mice, HM administration for four weeks ameliorated HFD-induced hepatic steatosis and liver dysfunction, as indicated by plasma parameters and Oil Red O staining. Taken together, our results demonstrated that a combination of HM has beneficial effects on inhibition of fatty liver and SREBP-1 c-mediated hepatic lipogenesis, and these events may be mediated by AMPK activation.
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Affiliation(s)
- Ju-Hee Lee
- Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Korea
| | - Ji Yun Jung
- Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Korea
| | - Eun Jeong Jang
- Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Korea
| | - Kyung Hwan Jegal
- Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Korea
| | - Soo Young Moon
- Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Korea
| | - Sae Kwang Ku
- Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Korea
| | - Seung Ho Kang
- Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Korea
| | - Il Je Cho
- Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Korea
| | - Sook Jahr Park
- Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Korea
| | - Jong Rok Lee
- Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Korea
| | - Rong Jie Zhao
- Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Korea Department of Pharmacology, Mudanjiang Medical University, Mudanjiang 157011, China
| | - Sang Chan Kim
- Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Korea
| | - Young Woo Kim
- Medical Research Center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Korea
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Xiong J, Yang H, Wu L, Shang W, Shan E, Liu W, Hu G, Xi T, Yang J. Fluoxetine suppresses AMP-activated protein kinase signaling pathway to promote hepatic lipid accumulation in primary mouse hepatocytes. Int J Biochem Cell Biol 2014; 54:236-44. [PMID: 25102273 DOI: 10.1016/j.biocel.2014.07.019] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 07/07/2014] [Accepted: 07/25/2014] [Indexed: 12/11/2022]
Abstract
In the previous study, we demonstrated that fluoxetine (FLX) regulated lipogenic and lipolytic genes to promote hepatic lipid accumulation. On this basis, underlying mechanisms were investigated by focusing on the intracellular signaling transduction in the present study using primary mouse hepatocytes. The expression of lipogenesis- and lipolysis-related genes was evaluated with the application of specific activators and inhibitors. Activation status of respective signaling pathway and the lipid accumulation in hepatocytes were analyzed. We provided evidence that AMP-activated protein kinase (AMPK) activator AICAR (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside) significantly suppressed the increased expression of representative lipogenesis-related genes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) by FLX, while increased the repressed expression of lipolysis-related genes, carboxylesterases. In the meanwhile, FLX regulated the above genes in the same way as AMPK inhibitor Compound C did. Furthermore, AICAR inhibited the proteolytic activation of SREBP1c induced by FLX, resulting in the decreased level of nuclear SREBP1c. Further studies demonstrated that FLX significantly suppressed the phosphorylation of AMPK and subsequent phosphorylation of ACC, following the inhibited phosphorylation and nuclear export of liver kinase B1 (LKB1). As a functional analysis, FLX-induced lipid accumulation in hepatocytes was repeatedly abolished by AICAR. In conclusion, FLX-induced hepatic lipid accumulation is mediated by the suppression of AMPK signaling pathway. The findings not only provide new insight into the understanding of the mechanisms for selective serotonin reuptake inhibitors-mediated dyslipidemia effects, but also suggest a novel therapeutic target to interfere.
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Affiliation(s)
- Jing Xiong
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Huan Yang
- Research Center of Biotechnology, School of Life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu 210009, China
| | - Lili Wu
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Wei Shang
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Enfang Shan
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Wei Liu
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Gang Hu
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Tao Xi
- Research Center of Biotechnology, School of Life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu 210009, China
| | - Jian Yang
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
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Modeling progressive non-alcoholic fatty liver disease in the laboratory mouse. Mamm Genome 2014; 25:473-86. [PMID: 24802098 PMCID: PMC4164843 DOI: 10.1007/s00335-014-9521-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Accepted: 04/14/2014] [Indexed: 12/19/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world and its prevalence is rising. In the absence of disease progression, fatty liver poses minimal risk of detrimental health outcomes. However, advancement to non-alcoholic steatohepatitis (NASH) confers a markedly increased likelihood of developing severe liver pathologies, including fibrosis, cirrhosis, organ failure, and cancer. Although a substantial percentage of NAFLD patients develop NASH, the genetic and molecular mechanisms driving this progression are poorly understood, making it difficult to predict which patients will ultimately develop advanced liver disease. Deficiencies in mechanistic understanding preclude the identification of beneficial prognostic indicators and the development of effective therapies. Mouse models of progressive NAFLD serve as a complementary approach to the direct analysis of human patients. By providing an easily manipulated experimental system that can be rigorously controlled, they facilitate an improved understanding of disease development and progression. In this review, we discuss genetically- and chemically-induced models of NAFLD that progress to NASH, fibrosis, and liver cancer in the context of the major signaling pathways whose disruption has been implicated as a driving force for their development. Additionally, an overview of nutritional models of progressive NAFLD is provided.
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Xu E, Forest MP, Schwab M, Avramoglu RK, St-Amand E, Caron AZ, Bellmann K, Shum M, Voisin G, Paquet M, Montoudis A, Lévy E, Siminovitch KA, Neel BG, Beauchemin N, Marette A. Hepatocyte-specific Ptpn6 deletion promotes hepatic lipid accretion, but reduces NAFLD in diet-induced obesity: potential role of PPARγ. Hepatology 2014; 59:1803-15. [PMID: 24327268 DOI: 10.1002/hep.26957] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Accepted: 11/27/2013] [Indexed: 01/04/2023]
Abstract
UNLABELLED Hepatocyte-specific Shp1 knockout mice (Ptpn6(H-KO)) are protected from hepatic insulin resistance evoked by high-fat diet (HFD) feeding for 8 weeks. Unexpectedly, we report herein that Ptpn6(H-KO) mice fed an HFD for up to 16 weeks are still protected from insulin resistance, but are more prone to hepatic steatosis, as compared with their HFD-fed Ptpn6(f/f) counterparts. The livers from HFD-fed Ptpn6(H-KO) mice displayed 1) augmented lipogenesis, marked by increased expression of several hepatic genes involved in fatty acid biosynthesis, 2) elevated postprandial fatty acid uptake, and 3) significantly reduced lipid export with enhanced degradation of apolipoprotein B (ApoB). Despite more extensive hepatic steatosis, the inflammatory profile of the HFD-fed Ptpn6(H-KO) liver was similar (8 weeks) or even improved (16 weeks) as compared to their HFD-fed Ptpn6(f/f) littermates, along with reduced hepatocellular damage as revealed by serum levels of hepatic enzymes. Interestingly, comparative microarray analysis revealed a significant up-regulation of peroxisome proliferator-activated receptor gamma (PPARγ) gene expression, confirmed by quantitative polymerase chain reaction. Elevated PPARγ nuclear activity also was observed and found to be directly regulated by Shp1 in a cell-autonomous manner. CONCLUSION These findings highlight a novel role for hepatocyte Shp1 in the regulation of PPARγ and hepatic lipid metabolism. Shp1 deficiency prevents the development of severe hepatic inflammation and hepatocellular damage in steatotic livers, presenting hepatocyte Shp1 as a potential novel mediator of nonalcoholic fatty liver diseases in obesity.
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Affiliation(s)
- Elaine Xu
- Department of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Ste-Foy, Québec, Canada
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Ruiz R, Jideonwo V, Ahn M, Surendran S, Tagliabracci VS, Hou Y, Gamble A, Kerner J, Irimia-Dominguez JM, Puchowicz MA, DePaoli-Roach A, Hoppel C, Roach P, Morral N. Sterol regulatory element-binding protein-1 (SREBP-1) is required to regulate glycogen synthesis and gluconeogenic gene expression in mouse liver. J Biol Chem 2014; 289:5510-7. [PMID: 24398675 DOI: 10.1074/jbc.m113.541110] [Citation(s) in RCA: 112] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Sterol regulatory element-binding protein-1 (SREBP-1) is a key transcription factor that regulates genes in the de novo lipogenesis and glycolysis pathways. The levels of SREBP-1 are significantly elevated in obese patients and in animal models of obesity and type 2 diabetes, and a vast number of studies have implicated this transcription factor as a contributor to hepatic lipid accumulation and insulin resistance. However, its role in regulating carbohydrate metabolism is poorly understood. Here we have addressed whether SREBP-1 is needed for regulating glucose homeostasis. Using RNAi and a new generation of adenoviral vector, we have silenced hepatic SREBP-1 in normal and obese mice. In normal animals, SREBP-1 deficiency increased Pck1 and reduced glycogen deposition during fed conditions, providing evidence that SREBP-1 is necessary to regulate carbohydrate metabolism during the fed state. Knocking SREBP-1 down in db/db mice resulted in a significant reduction in triglyceride accumulation, as anticipated. However, mice remained hyperglycemic, which was associated with up-regulation of gluconeogenesis gene expression as well as decreased glycolysis and glycogen synthesis gene expression. Furthermore, glycogen synthase activity and glycogen accumulation were significantly reduced. In conclusion, silencing both isoforms of SREBP-1 leads to significant changes in carbohydrate metabolism and does not improve insulin resistance despite reducing steatosis in an animal model of obesity and type 2 diabetes.
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Affiliation(s)
- Rafaela Ruiz
- From the Departments of Medical and Molecular Genetics and
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Wang Y, Zhang Y, Qian H, Lu J, Zhang Z, Min X, Lang M, Yang H, Wang N, Zhang P. The g0/g1 switch gene 2 is an important regulator of hepatic triglyceride metabolism. PLoS One 2013; 8:e72315. [PMID: 23951308 PMCID: PMC3741160 DOI: 10.1371/journal.pone.0072315] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Accepted: 07/10/2013] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease is associated with obesity and insulin resistance. Factors that regulate the disposal of hepatic triglycerides contribute to the development of hepatic steatosis. G0/G1 switch gene 2 (G0S2) is a target of peroxisome proliferator-activated receptors and plays an important role in regulating lipolysis in adipocytes. Therefore, we investigated whether G0S2 plays a role in hepatic lipid metabolism. Adenovirus-mediated expression of G0S2 (Ad-G0S2) potently induced fatty liver in mice. The liver mass of Ad-G0S2-infected mice was markedly increased with excess triglyceride content compared to the control mice. G0S2 did not change cellular cholesterol levels in hepatocytes. G0S2 was found to be co-localized with adipose triglyceride lipase at the surface of lipid droplets. Hepatic G0S2 overexpression resulted in an increase in plasma Low-density lipoprotein (LDL)/Very-Low-density (VLDL) lipoprotein cholesterol level. Plasma High-density lipoprotein (HDL) cholesterol and ketone body levels were slightly decreased in Ad-G0S2 injected mice. G0S2 also increased the accumulation of neutral lipids in cultured HepG2 and L02 cells. However, G0S2 overexpression in the liver significantly improved glucose tolerance in mice. Livers expressing G0S2 exhibited increased 6-(N-(7-nitrobenz-2-oxa-1-3-diazol-4-yl) amino)-6-deoxyglucose uptake compared with livers transfected with control adenovirus. Taken together, our results provide evidence supporting an important role for G0S2 as a regulator of triglyceride content in the liver and suggest that G0S2 may be a molecular target for the treatment of insulin resistance and other obesity-related metabolic disorders.
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Affiliation(s)
- Yinfang Wang
- Cardiovascular Research Center, Hubei University of Medicine, Hubei, China
- Department of Physiology, Hubei University of Medicine, Hubei, China
| | - Yahui Zhang
- Department of Pathophysiology, Hubei University of Medicine, Hubei, China
| | - Hang Qian
- Cardiovascular Research Center, Hubei University of Medicine, Hubei, China
| | - Juan Lu
- Cardiovascular Research Center, Hubei University of Medicine, Hubei, China
- Department of Physiology, Hubei University of Medicine, Hubei, China
| | - Zhifeng Zhang
- Cardiovascular Research Center, Hubei University of Medicine, Hubei, China
- Department of Physiology, Hubei University of Medicine, Hubei, China
| | - Xinwen Min
- Cardiovascular Research Center, Hubei University of Medicine, Hubei, China
| | - Mingjian Lang
- Cardiovascular Research Center, Hubei University of Medicine, Hubei, China
| | - Handong Yang
- Cardiovascular Research Center, Hubei University of Medicine, Hubei, China
| | - Nanping Wang
- Cardiovascular Research Center, Xi’an Jiaotong University School of Medicine, Xi’an, China
| | - Peng Zhang
- Cardiovascular Research Center, Hubei University of Medicine, Hubei, China
- Department of Physiology, Hubei University of Medicine, Hubei, China
- * E-mail:
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De Ceuninck F, Kargar C, Ilic C, Caliez A, Rolin JO, Umbdenstock T, Vinson C, Combettes M, de Fanti B, Harley E, Sadlo M, Lefèvre AL, Broux O, Wierzbicki M, Fourquez JM, Perron-Sierra F, Kotschy A, Ktorza A. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans. Br J Pharmacol 2013; 168:339-53. [PMID: 22925001 DOI: 10.1111/j.1476-5381.2012.02184.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Revised: 07/23/2012] [Accepted: 08/03/2012] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND AND PURPOSE Small-molecule glucokinase activators (GKAs) are currently being investigated as therapeutic options for the treatment of type 2 diabetes (T2D). Because liver overexpression of glucokinase is thought to be associated with altered lipid profiles, this study aimed at assessing the potential lipogenic risks linked to oral GKA administration. EXPERIMENTAL APPROACH Nine GKA candidates were qualified for their ability to activate recombinant glucokinase and to stimulate glycogen synthesis in rat hepatocytes and insulin secretion in rat INS-1E cells. In vivo activity was monitored by plasma glucose and HbA1c measurements after oral administration in rodents. Risk-associated effects were assessed by measuring hepatic and plasma triglycerides and free fatty acids, as well as plasma aminotransferases, and alkaline phosphatase. KEY RESULTS GKAs, while efficiently decreasing glycaemia in acute conditions and HbA1c levels after chronic administration in hyperglycemic db/db mice, were potent inducers of hepatic steatosis. This adverse outcome appeared as soon as 4 days after daily oral administration at pharmacological doses and was not transient. GKA treatment similarly increased hepatic triglycerides in diabetic and normoglycaemic rats, together with a pattern of metabolic phenotypes including different combinations of increased plasma triglycerides, free fatty acids, alanine and aspartyl aminotransferases, and alkaline phosphatase. GKAs belonging to three distinct structural families induced hepatic steatosis in db/db mice, arguing in favour of a target-mediated, rather than a chemical class-mediated, effect. CONCLUSION AND IMPLICATIONS Given the risks associated with fatty liver disease in the general population and furthermore in patients with T2D, these findings represent a serious warning for the use of GKAs in humans. LINKED ARTICLE This article is commented on by Rees and Gloyn, pp. 335-338 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02201.x.
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Affiliation(s)
- Frédéric De Ceuninck
- Division of Metabolic Diseases, Institut de Recherches Servier, Suresnes, France.
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Krarup NT, Grarup N, Banasik K, Friedrichsen M, Færch K, Sandholt CH, Jørgensen T, Poulsen P, Witte DR, Vaag A, Sørensen T, Pedersen O, Hansen T. The PNPLA3 rs738409 G-allele associates with reduced fasting serum triglyceride and serum cholesterol in Danes with impaired glucose regulation. PLoS One 2012; 7:e40376. [PMID: 22792295 PMCID: PMC3390392 DOI: 10.1371/journal.pone.0040376] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2012] [Accepted: 06/04/2012] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND AND AIM Non-alcoholic fatty liver disease (NAFLD) is a common condition, associated with hepatic insulin resistance and the metabolic syndrome including hyperglycaemia and dyslipidemia. We aimed at studying the potential impact of the NAFLD-associated PNPLA3 rs738409 G-allele on NAFLD-related metabolic traits in hyperglycaemic individuals. METHODS The rs738409 variant was genotyped in the population-based Inter99 cohort examined by an oral glucose-tolerance test, and a combined study-sample consisting of 192 twins (96 twin pairs) and a sub-set of the Inter99 population (n = 63) examined by a hyperinsulinemic euglycemic clamp (n(total) = 255). In Inter99, we analyzed associations of rs738409 with components of the WHO-defined metabolic syndrome (n = 5,847) and traits related to metabolic disease (n = 5,663). In the combined study sample we elucidated whether the rs738409 G-allele altered hepatic or peripheral insulin sensitivity. Study populations were divided into individuals with normal glucose-tolerance (NGT) and with impaired glucose regulation (IGR). RESULTS The case-control study showed no associations with components of the metabolic syndrome or the metabolic syndrome. Among 1,357 IGR individuals, the rs738409 G-allele associated with decreased fasting serum triglyceride levels (per allele effect(β) = -9.9% [-14.4%;-4.0% (95% CI)], p = 5.1×10(-5)) and fasting total cholesterol (β = -0.2 mmol/l [-0.3;-0.01 mmol/l(95% CI)], p = 1.5×10(-4)). Meta-analyses showed no impact on hepatic or peripheral insulin resistance in carriers of the rs738409 G-allele. CONCLUSION Our findings suggest that the G-allele of PNPLA3 rs738409 associates with reduced fasting levels of cholesterol and triglyceride in individuals with IGR.
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Affiliation(s)
- Nikolaj Thure Krarup
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
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