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Lin HH, Yu PR, Tseng CY, Lee MS, Chen JH. Protective Effects of Lotus Seedpod Extract on Hepatic Lipid and Glucose Metabolism via AMPK-Associated Mechanisms in a Mouse Model of Metabolic Syndrome and Oleic Acid-Induced HepG2 Cells. Antioxidants (Basel) 2025; 14:595. [PMID: 40427477 PMCID: PMC12108490 DOI: 10.3390/antiox14050595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Revised: 05/07/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025] Open
Abstract
Metabolic syndrome (MetS) poses considerable toxicological risks due to its association with an increased likelihood of metabolic dysfunction-associated steatotic liver disease (MASLD), and is characterized by hypertension, hyperglycemia, dyslipidemia, and obesity. This study aimed to investigate the therapeutic potential of flavonoid-rich lotus seedpod extract (LSE) in alleviating MetS and MASLD-related hepatic disturbances. In vivo, mice subjected to a high-fat diet (HFD) and streptozotocin (STZ) injection were supplemented with LSE or simvastatin for 6 weeks. Obesity indicators included body weight and epididymal fat, while insulin resistance was measured by fasting serum glucose, serum insulin, homeostasis model assessment-insulin resistance index (HOMA-IR), and oral glucose tolerance (OGTT). Also, the levels of serum lipid profiles and blood pressure were evaluated. Adipokines, proinflammatory cytokines, liver fat droplets, and peri-portal fibrosis were analyzed to clarify the mechanism of MetS. LSE significantly reduced the HFD/STZ-induced MetS markers better than simvastatin, as demonstrated by hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory effects. In vitro, LSE improved oleic acid (OA)-triggered phenotypes of MASLD in hepatocyte HepG2 cells by reducing lipid accumulation and enhancing cell viability. This effect might be mediated through proteins involved in lipogenesis that are downregulated by adenosine monophosphate-activated protein kinase (AMPK). In addition, LSE reduced reactive oxygen species (ROS) generation and glycogen levels, as demonstrated by enhancing insulin signaling involving reducing insulin receptor substrate-1 (IRS-1) Ser307 phosphorylation and increasing glycogen synthase kinase 3 beta (GSK3β) and protein kinase B (PKB) expression. These benefits were dependent on AMPK activation, as confirmed by the AMPK inhibitor compound C. These results indicate that LSE exhibits protective effects against MetS-caused toxicological disturbances in hepatic carbohydrate and lipid metabolism, potentially contributing to its efficacy in preventing MASLD or MetS.
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Affiliation(s)
- Hui-Hsuan Lin
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung City 40201, Taiwan;
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung City 40201, Taiwan
| | - Pei-Rong Yu
- Department of Nutrition, Chung Shan Medical University, Taichung City 40201, Taiwan; (P.-R.Y.); (C.-Y.T.)
| | - Chiao-Yun Tseng
- Department of Nutrition, Chung Shan Medical University, Taichung City 40201, Taiwan; (P.-R.Y.); (C.-Y.T.)
| | - Ming-Shih Lee
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung City 40201, Taiwan;
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung City 40201, Taiwan
| | - Jing-Hsien Chen
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung City 40201, Taiwan
- Department of Nutrition, Chung Shan Medical University, Taichung City 40201, Taiwan; (P.-R.Y.); (C.-Y.T.)
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Alpízar Salazar M, Olguín Reyes SE, Medina Estévez A, Saturno Lobos JA, De Aldecoa Castillo JM, Carrera Aguas JC, Alaniz Monreal S, Navarro Rodríguez JA, Alpízar Sánchez DMF. Natural History of Metabolic Dysfunction-Associated Steatotic Liver Disease: From Metabolic Syndrome to Hepatocellular Carcinoma. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:88. [PMID: 39859069 PMCID: PMC11766802 DOI: 10.3390/medicina61010088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 12/30/2024] [Accepted: 01/04/2025] [Indexed: 01/27/2025]
Abstract
Introduction: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) stems from disrupted lipid metabolism in the liver, often linked to obesity, type 2 diabetes, and dyslipidemia. In Mexico, where obesity affects 36.9% of adults, MASLD prevalence has risen, especially with metabolic syndrome affecting 56.31% by 2018. MASLD can progress to Metabolic Dysfunction-Associated Steatohepatitis (MASH), affecting 5.27% globally, leading to severe complications like cirrhosis and hepatocellular carcinoma. Background: Visceral fat distribution varies by gender, impacting MASLD development due to hormonal influences. Insulin resistance plays a central role in MASLD pathogenesis, exacerbated by high-fat diets and specific fatty acids, leading to hepatic steatosis. Lipotoxicity from saturated fatty acids further damages hepatocytes, triggering inflammation and fibrosis progression in MASH. Diagnosing MASLD traditionally involves invasive liver biopsy, but non-invasive methods like ultrasound and transient elastography are preferred due to their safety and availability. These methods detect liver steatosis and fibrosis with reasonable accuracy, offering alternatives to biopsy despite varying sensitivity and specificity. Conclusions: MASLD as a metabolic disorder underscores its impact on public health, necessitating improved awareness and early management strategies to mitigate its progression to severe liver diseases.
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Affiliation(s)
- Melchor Alpízar Salazar
- Endocrinology, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico
| | - Samantha Estefanía Olguín Reyes
- Clinical Research, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico; (S.E.O.R.); (A.M.E.); (J.A.S.L.); (S.A.M.); (J.A.N.R.); (D.M.F.A.S.)
| | - Andrea Medina Estévez
- Clinical Research, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico; (S.E.O.R.); (A.M.E.); (J.A.S.L.); (S.A.M.); (J.A.N.R.); (D.M.F.A.S.)
| | - Julieta Alejandra Saturno Lobos
- Clinical Research, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico; (S.E.O.R.); (A.M.E.); (J.A.S.L.); (S.A.M.); (J.A.N.R.); (D.M.F.A.S.)
| | - Jesús Manuel De Aldecoa Castillo
- Clinical Nutrition, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico;
| | - Juan Carlos Carrera Aguas
- Clinical Nutrition, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico;
| | - Samary Alaniz Monreal
- Clinical Research, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico; (S.E.O.R.); (A.M.E.); (J.A.S.L.); (S.A.M.); (J.A.N.R.); (D.M.F.A.S.)
| | - José Antonio Navarro Rodríguez
- Clinical Research, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico; (S.E.O.R.); (A.M.E.); (J.A.S.L.); (S.A.M.); (J.A.N.R.); (D.M.F.A.S.)
| | - Dulce María Fernanda Alpízar Sánchez
- Clinical Research, Specialized Center for Diabetes, Obesity and Prevention of Cardiovascular Diseases (CEDOPEC), Mexico City 11650, Mexico; (S.E.O.R.); (A.M.E.); (J.A.S.L.); (S.A.M.); (J.A.N.R.); (D.M.F.A.S.)
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Tang S, Borlak J. Genomics of human NAFLD: Lack of data reproducibility and high interpatient variability in drug target expression as major causes of drug failures. Hepatology 2024; 80:901-915. [PMID: 38358517 PMCID: PMC11407777 DOI: 10.1097/hep.0000000000000780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 01/19/2024] [Indexed: 02/16/2024]
Abstract
BACKGROUND AND AIMS NAFLD is a major disease burden and a foremost cause of chronic liver disease. Presently, nearly 300 trials evaluate the therapeutic efficacy of > 20 drugs. Remarkably, the majority of drugs fail. To better comprehend drug failures, we investigated the reproducibility of fatty liver genomic data across 418 liver biopsies and evaluated the interpatient variability of 18 drug targets. APPROACH AND RESULTS Apart from our own data, we retrieved NAFLD biopsy genomic data sets from public repositories and considered patient demographics. We divided the data into test and validation sets, assessed the reproducibility of differentially expressed genes and performed gene enrichment analysis. Patients were stratified by disease activity score, fibrosis grades and sex, and we investigated the regulation of 18 drug targets across 418 NAFLD biopsies of which 278 are NASH cases. We observed poor reproducibility of differentially expressed genes across 9 independent studies. On average, only 4% of differentially expressed genes are commonly regulated based on identical sex and 2% based on identical NAS disease score and fibrosis grade. Furthermore, we observed sex-specific gene regulations, and for females, we noticed induced expression of genes coding for inflammatory response, Ag presentation, and processing. Conversely, extracellular matrix receptor interactions are upregulated in males, and the data agree with clinical findings. Strikingly, and with the exception of stearoyl-CoA desaturase, most drug targets are not regulated in > 80% of patients. CONCLUSIONS Lack of data reproducibility, high interpatient variability, and the absence of disease-dependent drug target regulations are likely causes of NASH drug failures in clinical trials.
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Sharma M, Behera S, Regar RK, Tripathi D, Singh S, Kumar NGV, Gupta P. Acute and Sub-acute Oral Toxicity Assessment of Ferrum phosphoricum in Rats. HOMEOPATHY 2024; 113:86-97. [PMID: 37604183 DOI: 10.1055/s-0043-1770338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2023]
Abstract
BACKGROUND Ferrum phosphoricum (FP) has been used by traditional medicine practitioners for various ailments since ancient times. However, scientific evidence on the safety of FP is still unavailable. Thus, the current study aimed to investigate the acute and sub-acute oral toxicity of homeopathic FP in experimental rats. METHODS In an acute toxicity investigation, a single dose of 2,000 µL/kg of FP 6c, 30c and 200c was administered to female Wistar rats, which were monitored for up to 14 days according to the Organization for Economic Cooperation and Development (OECD) guideline 423. For a sub-acute toxicity study, FP 6c, 30c and 200c (200 µL/kg) were administered to male and female rats for 28 days as per the OECD guideline 407. All the animals were observed for mortality, clinical signs and body weight during the study. At the end of the experiment, hematological, biochemical and histopathological assessments were performed. RESULTS During the acute toxicity study, no mortality was observed in rats administered with FP, and thus the median lethal dose (LD50) was identified as >2,000 µL/kg. In the sub-acute study, no mortality or adverse clinical signs were noticed with FP treatment. Moreover, weekly body weight gain was normal. Hematological and biochemical investigations revealed no abnormalities. Furthermore, histological analysis of FP-treated rats' vital organs revealed no pathological changes. CONCLUSION Overall, our findings imply that FP 6c, 30c and 200c potencies are safe and do not cause toxicity when given orally to Wistar albino rats for an extended period at a dose of 200 µL/kg.
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Affiliation(s)
- Mahima Sharma
- Department of Pharmacology, Drug Standardisation, Dr D P Rastogi Central Research Institute (H), Noida, Uttar Pradesh, India
| | - Sangita Behera
- Department of Pharmacology, Drug Standardisation, Dr D P Rastogi Central Research Institute (H), Noida, Uttar Pradesh, India
| | - Raj Kumar Regar
- Department of Pharmacology, Drug Standardisation, Dr D P Rastogi Central Research Institute (H), Noida, Uttar Pradesh, India
| | - Deepika Tripathi
- Department of Pharmacology, Drug Standardisation, Dr D P Rastogi Central Research Institute (H), Noida, Uttar Pradesh, India
| | - Satvinder Singh
- Department of Biochemistry, Dr D P Rastogi Central Research Institute (H), Noida, Uttar Pradesh, India
| | - Narasimha G V Kumar
- Department of Pharmacology, Drug Standardisation, Dr Anjali Chatterji Regional Research Institute for Homeopathy, Kolkata, West Bengal, India
| | - Pankaj Gupta
- Department of Pharmacology, Drug Standardisation, Dr D P Rastogi Central Research Institute (H), Noida, Uttar Pradesh, India
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Zeng T, Lv J, Liang J, Xie B, Liu L, Tan Y, Zhu J, Jiang J, Xie H. Zebrafish cobll1a regulates lipid homeostasis via the RA signaling pathway. Front Cell Dev Biol 2024; 12:1381362. [PMID: 38699158 PMCID: PMC11063382 DOI: 10.3389/fcell.2024.1381362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 04/04/2024] [Indexed: 05/05/2024] Open
Abstract
Background The COBLL1 gene has been implicated in human central obesity, fasting insulin levels, type 2 diabetes, and blood lipid profiles. However, its molecular mechanisms remain largely unexplored. Methods In this study, we established cobll1a mutant lines using the CRISPR/Cas9-mediated gene knockout technique. To further dissect the molecular underpinnings of cobll1a during early development, transcriptome sequencing and bioinformatics analysis was employed. Results Our study showed that compared to the control, cobll1a -/- zebrafish embryos exhibited impaired development of digestive organs, including the liver, intestine, and pancreas, at 4 days post-fertilization (dpf). Transcriptome sequencing and bioinformatics analysis results showed that in cobll1a knockout group, the expression level of genes in the Retinoic Acid (RA) signaling pathway was affected, and the expression level of lipid metabolism-related genes (fasn, scd, elovl2, elovl6, dgat1a, srebf1 and srebf2) were significantly changed (p < 0.01), leading to increased lipid synthesis and decreased lipid catabolism. The expression level of apolipoprotein genes (apoa1a, apoa1b, apoa2, apoa4a, apoa4b, and apoea) genes were downregulated. Conclusion Our study suggest that the loss of cobll1a resulted in disrupted RA metabolism, reduced lipoprotein expression, and abnormal lipid transport, therefore contributing to lipid accumulation and deleterious effects on early liver development.
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Affiliation(s)
- Ting Zeng
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Changsha, Hunan, China
| | - Jinrui Lv
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Changsha, Hunan, China
| | - Jiaxin Liang
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Changsha, Hunan, China
| | - Binling Xie
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Changsha, Hunan, China
| | - Ling Liu
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Changsha, Hunan, China
| | - Yuanyuan Tan
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Changsha, Hunan, China
| | - Junwei Zhu
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Changsha, Hunan, China
| | - Jifan Jiang
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Changsha, Hunan, China
| | - Huaping Xie
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Changsha, Hunan, China
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Mahmoudi A, Hajihasani MM, Majeed M, Jamialahmadi T, Sahebkar A. Effect of Calebin-A on Critical Genes Related to NAFLD: A Protein-Protein Interaction Network and Molecular Docking Study. Curr Genomics 2024; 25:120-139. [PMID: 38751599 PMCID: PMC11092913 DOI: 10.2174/0113892029280454240214072212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 01/12/2024] [Accepted: 02/01/2024] [Indexed: 05/18/2024] Open
Abstract
Background Calebin-A is a minor phytoconstituent of turmeric known for its activity against inflammation, oxidative stress, cancerous, and metabolic disorders like Non-alcoholic fatty liver disease(NAFLD). Based on bioinformatic tools. Subsequently, the details of the interaction of critical proteins with Calebin-A were investigated using the molecular docking technique. Methods We first probed the intersection of genes/ proteins between NAFLD and Calebin-A through online databases. Besides, we performed an enrichment analysis using the ClueGO plugin to investigate signaling pathways and gene ontology. Next, we evaluate the possible interaction of Calebin-A with significant hub proteins involved in NAFLD through a molecular docking study. Results We identified 87 intersection genes Calebin-A targets associated with NAFLD. PPI network analysis introduced 10 hub genes (TP53, TNF, STAT3, HSP90AA1, PTGS2, HDAC6, ABCB1, CCT2, NR1I2, and GUSB). In KEGG enrichment, most were associated with Sphingolipid, vascular endothelial growth factor A (VEGFA), C-type lectin receptor, and mitogen-activated protein kinase (MAPK) signaling pathways. The biological processes described in 87 intersection genes are mostly concerned with regulating the apoptotic process, cytokine production, and intracellular signal transduction. Molecular docking results also directed that Calebin-A had a high affinity to bind hub proteins linked to NAFLD. Conclusion Here, we showed that Calebin-A, through its effect on several critical genes/ proteins and pathways, might repress the progression of NAFLD.
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Affiliation(s)
- Ali Mahmoudi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Mahdi Hajihasani
- Department of Pharmaceutical Control, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Muhammed Majeed
- Department of Chemistry, Sabinsa Corporation, 20 Lake Drive, East Windsor, NJ, 08520, USA
| | - Tannaz Jamialahmadi
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran;
| | - Amirhossein Sahebkar
- Department of Medical Biotechnology, Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Tiniakos DG, Anstee QM, Brunt EM, Burt AD. Fatty Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:330-401. [DOI: 10.1016/b978-0-7020-8228-3.00005-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Omidkhoda N, Mahdiani S, Hayes AW, Karimi G. Natural compounds against nonalcoholic fatty liver disease: A review on the involvement of the LKB1/AMPK signaling pathway. Phytother Res 2023; 37:5769-5786. [PMID: 37748097 DOI: 10.1002/ptr.8020] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 08/18/2023] [Accepted: 09/11/2023] [Indexed: 09/27/2023]
Abstract
Although various therapeutic approaches are used to manage nonalcoholic fatty liver disease (NAFLD), the best approach to NAFLD management is unclear. NAFLD is a liver disorder associated with obesity, metabolic syndrome, and diabetes mellitus. NAFLD progression can lead to cirrhosis and end-stage liver disease. Hepatic kinase B1 (LKB1) is an upstream kinase of 5'-adenosine monophosphate-activated protein kinase (AMPK), a crucial regulator in hepatic lipid metabolism. Activation of LKB1/AMPK inhibits fatty acid synthesis, increases mitochondrial β-oxidation, decreases the expression of genes encoding lipogenic enzymes, improves nonalcoholic steatohepatitis, and suppresses NAFLD progression. One potential opening for new and safe chemicals that can tackle the NAFLD pathogenesis through the LKB1-AMPK pathway includes natural bioactive compounds. Accordingly, we summarized in vitro and in vivo studies regarding the effect of natural bioactive compounds such as a few members of the polyphenols, terpenoids, alkaloids, and some natural extracts on NAFLD through the LKB1/AMPK signaling pathway. This manuscript may shed light on the way to finding a new therapeutic agent for NAFLD management.
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Affiliation(s)
- Navid Omidkhoda
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sina Mahdiani
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - A Wallace Hayes
- College of Public Health, University of South Florida, Tampa, Florida, USA
- Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan, USA
| | - Gholamreza Karimi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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Li Y, Teng M, Zhao L, Sun J, Yan J, Zhu W, Wu F. Vitamin D modulates disordered lipid metabolism in zebrafish (Danio rerio) liver caused by exposure to polystyrene nanoplastics. ENVIRONMENT INTERNATIONAL 2023; 182:108328. [PMID: 37979534 DOI: 10.1016/j.envint.2023.108328] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 11/06/2023] [Accepted: 11/14/2023] [Indexed: 11/20/2023]
Abstract
In this study, zebrafish (Danio rerio) were exposed to polystyrene nanoplastics (PS-NPs, 80 nm) at 0, 15, or 150 μg/L for 21 days and supplied with a low or high vitamin D (VD) diet (280 or 2800 IU/kg, respectively, indicated by - or +) to determine whether and how VD can regulate lipid metabolism disorder induced by PS-NPs. Six groups were created according to the PS-NP concentration and VD diet status: 0-, 0+, 15-, 15+,150-, and 150 +. Transmission electron microscopy showed that PS-NPs accumulated in the livers of zebrafish, which led to large numbers of vacuoles and lipid droplets in liver cell matrices; this accumulation was most prominent in the 150- group, wherein the number of lipid droplets increased significantly by 136.36%. However, the number of lipid droplets decreased significantly by 76.92% in the 150+ group compared with the 150- group. An examination of additional biochemical indicators showed that the high VD diet partially reversed the increases in the triglyceride and total cholesterol contents induced by PS-NPs (e.g., triglycerides decreased by 58.52% in the 150+ group, and total cholesterol decreased by 44.64% in the 15+ group), and regulated lipid metabolism disorder mainly by inhibiting lipid biosynthesis. Untargeted lipidomics analysis showed that exposure to PS-NPs was associated mainly with changes in the lipid molecular content related to cell membrane function and lipid biosynthesis and that the high VD diet reduced the content of lipid molecules related to lipid biosynthesis, effectively alleviating cell membrane damage and lipid accumulation. These findings highlight the potential of VD to alleviate lipid metabolism disorder caused by PS-NP exposure, thereby providing new insights into how the toxic effects of NPs on aquatic organisms could be reduced.
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Affiliation(s)
- Yunxia Li
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China; School of Energy and Environmental Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Miaomiao Teng
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China.
| | - Lihui Zhao
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
| | - Jiaqi Sun
- School of Energy and Environmental Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Jin Yan
- National and Local Joint Engineering Laboratory of Municipal Sewage Resource Utilization Technology, School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou 215009, China
| | - Wentao Zhu
- Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China
| | - Fengchang Wu
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China.
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Zhang C, Ma T, Liu C, Ma D, Wang J, Liu M, Ran J, Wang X, Deng X. PM 2.5 induced liver lipid metabolic disorders in C57BL/6J mice. Front Endocrinol (Lausanne) 2023; 14:1212291. [PMID: 37780625 PMCID: PMC10539470 DOI: 10.3389/fendo.2023.1212291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 08/16/2023] [Indexed: 10/03/2023] Open
Abstract
PM2.5 can cause adverse health effects via several pathways, such as inducing pulmonary and systemic inflammation, penetration into circulation, and activation of the autonomic nervous system. In particular, the impact of PM2.5 exposure on the liver, which plays an important role in metabolism and detoxification to maintain internal environment homeostasis, is getting more attention in recent years. In the present study, C57BL/6J mice were randomly assigned and treated with PM2.5 suspension and PBS solution for 8 weeks. Then, hepatic tissue was prepared and identified by metabolomics analysis and transcriptomics analysis. PM2.5 exposure can cause extensive metabolic disturbances, particularly in lipid and amino acids metabolic dysregulation.128 differential expression metabolites (DEMs) and 502 differently expressed genes (DEGs) between the PM2.5 exposure group and control group were detected. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that DEGs were significantly enriched in two disease pathways, non-alcoholic fatty liver disease (NAFLD) and type II diabetes mellitus (T2DM), and three signaling pathways, which are TGF-beta signaling, AMPK signaling, and mTOR signaling. Besides, further detection of acylcarnitine levels revealed accumulation in liver tissue, which caused restricted lipid consumption. Furthermore, lipid droplet accumulation in the liver was confirmed by Oil Red O staining, suggesting hepatic steatosis. Moreover, the aberrant expression of three key transcription factors revealed the potential regulatory effects in lipid metabolic disorders, the peroxisomal proliferative agent-activated receptors (PPARs) including PPARα and PPARγ is inhibited, and the activated sterol regulator-binding protein 1 (SREBP1) is overexpressed. Our results provide a novel molecular and genetic basis for a better understanding of the mechanisms of PM2.5 exposure-induced hepatic metabolic diseases, especially in lipid metabolism.
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Affiliation(s)
- Chenxiao Zhang
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tengfei Ma
- College of Basic Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chang Liu
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ding Ma
- College of Basic Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian Wang
- College of Basic Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Meng Liu
- College of Basic Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinjun Ran
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueting Wang
- Department of Cardiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaobei Deng
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Chi Z, Teng Y, Liu Y, Gao L, Yang J, Zhang Z. Association between klotho and non-alcoholic fatty liver disease and liver fibrosis based on the NHANES 2007-2016. Ann Hepatol 2023; 28:101125. [PMID: 37286168 DOI: 10.1016/j.aohep.2023.101125] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 05/24/2023] [Accepted: 05/29/2023] [Indexed: 06/09/2023]
Abstract
INTRODUCTION AND OBJECTIVES This study aims to explore the association between Klotho and Non-Alcoholic Fatty Liver Disease (NAFLD), a condition affecting millions worldwide. Klotho may have a protective effect against NAFLD mechanisms like inflammation, oxidative stress, and fibrosis. The study will use FLI and FIB-4 score to diagnose NAFLD in a large population for investigating the link between Klotho and NAFLD. MATERIALS AND METHODS The study aimed to explore the association between Klotho and NAFLD by measuring the α-Klotho protein levels in the participants' blood using ELISA. Patients with underlying chronic liver diseases were excluded. The severity of NAFLD was evaluated using FLI and FIB-4, and logistic regression models were used to analyze the data obtained from NHANES. Subgroup analyses were conducted to study Klotho's effect on hepatic steatosis and fibrosis in diverse subpopulations. RESULTS The study found that low levels of α-Klotho were associated with NAFLD, with ORs ranging from 0.72 to 0.83. However, high levels of α-Klotho were associated with NAFLD-related fibrosis. The Q4 group showed significant results in individuals aged 51 years or younger and in females. Non-Hispanic White ethnicity, education level of high school or above, non-smoking, non-hypertension, and non-diabetic groups showed negative correlations. CONCLUSIONS Our study suggests a potential correlation between α-Klotho levels in the blood and NAFLD in adult patients, especially among younger individuals, females and Non-Hispanic Whites. Elevated α-Klotho levels may have therapeutic benefits in treating NAFLD. Further research is required to validate these findings, but they provide new insights for managing this condition.
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Affiliation(s)
- Zhenfei Chi
- Liaoning University of Traditional Chinese Medicine, PR China
| | - Yun Teng
- Liaoning University of Traditional Chinese Medicine, PR China
| | - Yuting Liu
- Liaoning University of Traditional Chinese Medicine, PR China
| | - Lu Gao
- Liaoning University of Traditional Chinese Medicine, PR China
| | - Junhan Yang
- Liaoning University of Traditional Chinese Medicine, PR China
| | - Zhe Zhang
- Liaoning University of Traditional Chinese Medicine, PR China.
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12
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Delmas D, Cotte AK, Connat JL, Hermetet F, Bouyer F, Aires V. Emergence of Lipid Droplets in the Mechanisms of Carcinogenesis and Therapeutic Responses. Cancers (Basel) 2023; 15:4100. [PMID: 37627128 PMCID: PMC10452604 DOI: 10.3390/cancers15164100] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/04/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Cancer shares common risk factors with cardiovascular diseases such as dyslipidemia, obesity and inflammation. In both cases, dysregulations of lipid metabolism occur, and lipid vesicles emerge as important factors that can influence carcinogenesis. In this review, the role of different lipids known to be involved in cancer and its response to treatments is detailed. In particular, lipid droplets (LDs), initially described for their role in lipid storage, exert multiple functions, from the physiological prevention of LD coalescence and regulation of endoplasmic reticulum homeostasis to pathological involvement in tumor progression and aggressiveness. Analysis of LDs highlights the importance of phosphatidylcholine metabolism and the diversity of lipid synthesis enzymes. In many cancers, the phosphatidylcholine pathways are disrupted, modifying the expression of genes coding for metabolic enzymes. Tumor microenvironment conditions, such as hypoxia, different types of stress or inflammatory conditions, are also important determinants of LD behavior in cancer cells. Therefore, LDs represent therapeutic targets in cancer, and many lipid mediators have emerged as potential biomarkers for cancer onset, progression, and/or resistance.
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Affiliation(s)
- Dominique Delmas
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
- Centre de Lutte Contre le Cancer Georges François Leclerc, 21000 Dijon, France
| | - Alexia K. Cotte
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
| | - Jean-Louis Connat
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
| | - François Hermetet
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
| | - Florence Bouyer
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
| | - Virginie Aires
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
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Lin W, Song H, Shen J, Wang J, Yang Y, Yang Y, Cao J, Xue L, Zhao F, Xiao T, Lin R. Functional role of skeletal muscle-derived interleukin-6 and its effects on lipid metabolism. Front Physiol 2023; 14:1110926. [PMID: 37555019 PMCID: PMC10405179 DOI: 10.3389/fphys.2023.1110926] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 07/06/2023] [Indexed: 08/10/2023] Open
Abstract
The detrimental impact of obesity on human health is increasingly evident with the rise in obesity-related diseases. Skeletal muscle, the crucial organ responsible for energy balance metabolism, plays a significant role as a secretory organ by releasing various myokines. Among these myokines, interleukin 6 (IL-6) is closely associated with skeletal muscle contraction. IL-6 triggers the process of lipolysis by mobilizing energy-storing adipose tissue, thereby providing energy for physical exercise. This phenomenon also elucidates the health benefits of regular exercise. However, skeletal muscle and adipose tissue maintain a constant interaction, both directly and indirectly. Direct interaction occurs through the accumulation of excess fat within skeletal muscle, known as ectopic fat deposition. Indirect interaction takes place when adipose tissue is mobilized to supply the energy for skeletal muscle during exercise. Consequently, maintaining a functional balance between skeletal muscle and adipose tissue becomes paramount in regulating energy metabolism and promoting overall health. IL-6, as a representative cytokine, participates in various inflammatory responses, including non-classical inflammatory responses such as adipogenesis. Skeletal muscle influences adipogenesis through paracrine mechanisms, primarily by secreting IL-6. In this research paper, we aim to review the role of skeletal muscle-derived IL-6 in lipid metabolism and other physiological activities, such as insulin resistance and glucose tolerance. By doing so, we provide valuable insights into the regulatory function of skeletal muscle-derived myokines in lipid metabolism.
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Affiliation(s)
- Weimin Lin
- *Correspondence: Weimin Lin, ; Ruiyi Lin,
| | | | | | | | | | | | | | | | | | | | - Ruiyi Lin
- College of Animal Sciences (College of Bee Science), Fujian Agriculture and Forestry University, Fuzhou, China
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14
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Ghadami S, Dellinger K. The lipid composition of extracellular vesicles: applications in diagnostics and therapeutic delivery. Front Mol Biosci 2023; 10:1198044. [PMID: 37520326 PMCID: PMC10381967 DOI: 10.3389/fmolb.2023.1198044] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 07/03/2023] [Indexed: 08/01/2023] Open
Abstract
Extracellular vesicles (EVs), including exosomes, with nanoscale sizes, biological origins, various functions, and unique lipid and protein compositions have been introduced as versatile tools for diagnostic and therapeutic medical applications. Numerous studies have reported the importance of the lipid composition of EVs and its influence on their mechanism of action. For example, changes in the lipidomic profile of EVs have been shown to influence the progression of various diseases, including ovarian malignancies and prostate cancer. In this review, we endeavored to examine differences in the lipid content of EV membranes derived from different cell types to characterize their capabilities as diagnostic tools and treatments for diseases like cancer and Alzheimer's disease. We additionally discuss designing functionalized vesicles, whether synthetically by hybrid methods or by changing the lipid composition of natural EVs. Lastly, we provide an overview of current and potential biomedical applications and perspectives on the future of this growing field.
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Affiliation(s)
| | - Kristen Dellinger
- Department of Nanoengineering, Joint School of Nanoscience and Nanoengineering, North Carolina A&T State University, Greensboro, NC, United States
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15
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Becerril-Campos AA, Ramos-Gómez M, De Los Ríos-Arellano EA, Ocampo-Anguiano PV, González-Gallardo A, Macotela Y, García-Gasca T, Ahumada-Solórzano SM. Bean Leaves Ameliorate Lipotoxicity in Fatty Liver Disease. Nutrients 2023; 15:2928. [PMID: 37447254 DOI: 10.3390/nu15132928] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 06/26/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Bioactive compounds in plant-based food have protective effects against metabolic alterations, including non-alcoholic fatty liver disease (NAFLD). Bean leaves are widely cultivated in the world and are a source of dietary fiber and polyphenols. High fat/high fructose diet animal models promote deleterious effects in adipose and non-adipose tissues (lipotoxicity), leading to obesity and its comorbidities. Short-term supplementation of bean leaves exhibited anti-diabetic, anti-hyperlipidemic, and anti-obesity effects in high-fat/high-fructose diet animal models. This study aimed to evaluate the effect of bean leaves supplementation in the prevention of lipotoxicity in NAFLD and contribute to elucidating the possible mechanism involved for a longer period of time. During thirteen weeks, male Wistar rats (n = 9/group) were fed with: (1) S: Rodent Laboratory Chow 5001® (RLC); (2) SBL: 90% RLC+ 10% dry bean leaves; (3) H: high-fat/high-fructose diet; (4) HBL: H+ 10% of dry bean leaves. Overall, a HBL diet enhanced impaired glucose tolerance and ameliorated obesity, risk factors in NAFLD development. Additionally, bean leaves exerted antioxidant (↑serum GSH) and anti-inflammatory (↓mRNA TNFα in the liver) effects, prevented hepatic fat accumulation by enhanced ↑mRNA PPARα (β oxidation), and enhanced lipid peroxidation (↓liver MDA). These findings suggest that bean leaves ameliorated hepatic lipotoxicity derived from the consumption of a deleterious diet.
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Affiliation(s)
- Adriana Araceli Becerril-Campos
- Laboratory of Cellular and Molecular Biology, Faculty of Natural Sciences, Autonomous University of Queretaro, Campus Juriquilla, Av. De las Ciencias S/N, Queretaro 76230, Mexico
| | - Minerva Ramos-Gómez
- Food Research and Graduate Department, School of Chemistry, Autonomous University of Queretaro, Centro Universitario, Cerro de las Campanas S/N, Queretaro 76010, Mexico
| | | | - Perla Viridiana Ocampo-Anguiano
- Laboratory of Cellular and Molecular Biology, Faculty of Natural Sciences, Autonomous University of Queretaro, Campus Juriquilla, Av. De las Ciencias S/N, Queretaro 76230, Mexico
- Food Research and Graduate Department, School of Chemistry, Autonomous University of Queretaro, Centro Universitario, Cerro de las Campanas S/N, Queretaro 76010, Mexico
| | - Adriana González-Gallardo
- Proteogenomic Unit, Neurobiology Institute, National Autonomous University of Mexico, Campus UNAM-Juriquilla, Queretaro 76230, Mexico
| | - Yazmín Macotela
- Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Queretaro 76237, Mexico
| | - Teresa García-Gasca
- Laboratory of Cellular and Molecular Biology, Faculty of Natural Sciences, Autonomous University of Queretaro, Campus Juriquilla, Av. De las Ciencias S/N, Queretaro 76230, Mexico
| | - Santiaga Marisela Ahumada-Solórzano
- Interdisciplinary Research in Biomedicine, Faculty of Natural Sciences, Autonomous University of Queretaro, Campus Juriquilla, Av. De las Ciencias S/N, Queretaro 76230, Mexico
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Tong J, Lan XT, Zhang Z, Liu Y, Sun DY, Wang XJ, Ou-Yang SX, Zhuang CL, Shen FM, Wang P, Li DJ. Ferroptosis inhibitor liproxstatin-1 alleviates metabolic dysfunction-associated fatty liver disease in mice: potential involvement of PANoptosis. Acta Pharmacol Sin 2023; 44:1014-1028. [PMID: 36323829 PMCID: PMC10104837 DOI: 10.1038/s41401-022-01010-5] [Citation(s) in RCA: 98] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 09/25/2022] [Indexed: 11/07/2022]
Abstract
Ferroptosis is a new form of regulated cell death characterized by excessive iron accumulation and uncontrollable lipid peroxidation. The role of ferroptosis in metabolic dysfunction-associated fatty liver disease (MAFLD) is not fully elucidated. In this study we compared the therapeutic effects of ferroptosis inhibitor liproxstatin-1 (LPT1) and iron chelator deferiprone (DFP) in MAFLD mouse models. This model was established in mice by feeding a high-fat diet with 30% fructose in water (HFHF) for 16 weeks. The mice then received LPT1 (10 mg·kg-1·d-1, ip) or DFP (100 mg·kg-1·d-1, ig) for another 2 weeks. We showed that both LPT1 and DFP treatment blocked the ferroptosis markers ACSL4 and ALOX15 in MAFLD mice. Furthermore, LPT1 treatment significantly reduced the liver levels of triglycerides and cholesterol, lipid peroxidation markers 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), and ameliorated the expression of lipid synthesis/oxidation genes (Pparα, Scd1, Fasn, Hmgcr and Cpt1a), insulin resistance, mitochondrial ROS content and liver fibrosis. Importantly, LPT1 treatment potently inhibited hepatic apoptosis (Bax/Bcl-xL ratio and TUNEL+ cell number), pyroptosis (cleavages of Caspase-1 and GSDMD) and necroptosis (phosphorylation of MLKL). Moreover, LPT1 treatment markedly inhibited cleavages of PANoptosis-related caspase-8 and caspase-6 in MAFLD mouse liver. In an in vitro MAFLD model, treatment with LPT1 (100 nM) prevented cultured hepatocyte against cell death induced by pro-PANoptosis molecules (TNF-α, LPS and nigericin) upon lipid stress. On the contrary, DFP treatment only mildly attenuated hepatic inflammation but failed to alleviate lipid deposition, insulin resistance, apoptosis, pyroptosis and necroptosis in MAFLD mice. We conclude that ferroptosis inhibitor LPT1 protects against steatosis and steatohepatitis in MAFLD mice, which may involve regulation of PANoptosis, a coordinated cell death pathway that involves apoptosis, pyroptosis and necroptosis. These results suggest a potential link between ferroptosis and PANoptosis.
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Affiliation(s)
- Jie Tong
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Xiu-Ting Lan
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Zhen Zhang
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Yi Liu
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Di-Yang Sun
- School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, 200433, China
| | - Xu-Jie Wang
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Shen-Xi Ou-Yang
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Chun-Lin Zhuang
- School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, 200433, China
| | - Fu-Ming Shen
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Pei Wang
- School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, 200433, China.
| | - Dong-Jie Li
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
- Institute of Nuclear Medicine, Tongji University School of Medicine, Shanghai, 200072, China.
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17
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Ma DW, Ha J, Yoon KS, Kang I, Choi TG, Kim SS. Innate Immune System in the Pathogenesis of Non-Alcoholic Fatty Liver Disease. Nutrients 2023; 15:2068. [PMID: 37432213 DOI: 10.3390/nu15092068] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/17/2023] [Accepted: 04/21/2023] [Indexed: 07/12/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition characterized by lipid accumulation in hepatocytes with low alcohol consumption. The development of sterile inflammation, which occurs in response to a range of cellular stressors or injuries, has been identified as a major contributor to the pathogenesis of NAFLD. Recent studies of the pathogenesis of NAFLD reported the newly developed roles of damage-associated molecular patterns (DAMPs). These molecules activate pattern recognition receptors (PRRs), which are placed in the infiltrated neutrophils, dendritic cells, monocytes, or Kupffer cells. DAMPs cause the activation of PRRs, which triggers a number of immunological responses, including the generation of cytokines that promote inflammation and the localization of immune cells to the site of the damage. This review provides a comprehensive overview of the impact of DAMPs and PRRs on the development of NAFLD.
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Affiliation(s)
- Dae Won Ma
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Joohun Ha
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Kyung Sik Yoon
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Insug Kang
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Tae Gyu Choi
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sung Soo Kim
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
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Zhou X, Ma L, Dong L, Li D, Chen F, Hu X. Bamboo shoot dietary fiber alleviates gut microbiota dysbiosis and modulates liver fatty acid metabolism in mice with high-fat diet-induced obesity. Front Nutr 2023; 10:1161698. [PMID: 36969828 PMCID: PMC10035599 DOI: 10.3389/fnut.2023.1161698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 02/20/2023] [Indexed: 03/11/2023] Open
Abstract
IntroductionObesity is a common nutritional disorder characterized by an excessive fat accumulation. In view of the critical role of gut microbiota in the development of obesity and metabolic diseases, novel dietary therapies have been developed to manage obesity by targeting the gut microbiome. In this study, we investigated anti-obesity effects of bamboo shoot dietary fiber (BSDF) and the potential mechanisms.MethodsAfter 12 weeks of intervention with BSDF in high-fat mice, we detected obesity-related phenotypic indicators, and made transcriptomic analysis of liver tissue. Then we analyzed the changes of gut microbiota using 16S rRNA gene sequencing, explored the effect of BSDF on gut microbiota metabolites, and finally verified the importance of gut microbiota through antibiotic animal model.Results and discussionWe found that BSDF was effective in reducing lipid accumulation in liver and adipose tissue and alleviating dyslipidemia and insulin resistance. Liver transcriptome analysis results showed that BSDF could improve lipid metabolism and liver injury by modulating peroxisome proliferator-activated receptor (PPAR) and fatty acid metabolic pathways. The 16S rRNA gene sequencing analysis of gut microbiota composition showed that BSDF significantly enriched beneficial bacteria such as Bifidobacterium, Akkermansia, Dubosiella, and Alloprevotella. Analysis of fecal metabolomics and gut microbiota metabolites revealed that BSDF increased the levels of several short-chain fatty acids and enriched bile acids, which may be important for improving lipid metabolism. Notably, the obesity-related metabolic disorders were abrogated after the abrogation of gut microbiota, suggesting that gut microbiota is a key factor in the beneficial effects of BSDF.ConclusionOur study suggests that BSDF as a prebiotic supplement has the potential to improve obesity by improving gut microbiota and modulating host PPAR and fatty acid metabolic pathways.
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Canh Pham E, Van LV, Nguyen CV, Duong NTN, Le Thi TV, Truong TN. Acute and sub-acute toxicity evaluation of Merremia tridentata (L.) stem extract on mice. Toxicon 2023; 227:107093. [PMID: 36972838 DOI: 10.1016/j.toxicon.2023.107093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 03/09/2023] [Accepted: 03/22/2023] [Indexed: 03/28/2023]
Abstract
The acute and sub-acute toxicity studies were performed in male and female Swiss albino mice as per the guidelines mentioned in OECD. The oral administration of M. tridentata stem extract (MSE) showed no treatment-related mortality and body weight change in mice up to the single dose of 30,000 mg/kg body weight in the acute toxicity study and up to a dose of 30,000 mg/kg/day body weight in the sub-acute toxicity study. Moreover, the clinical signs, body weight, gross pathology, organ weight, hematology (except for platelet count), biochemical analysis, and histopathology did not show significant variation at a medium dose of 15,000 mg/kg/day body weight compared to the control group. However, toxicological signs in behavior, very mild interstitial nephritis, as well as significant variation in platelet count and total protein parameters were observed at a dose of 30,000 mg/kg/day in the 28-day oral toxicity study. Thus, the no-observed-adverse-effect level was determined at a dose of 15,000 mg/kg/day body weight. Based on study results, it is concluded that MSE showed LD50 of greater than 5000 mg/kg/day body weight. Hence, this could be a potential candidature as a future safe pharmaceutical product.
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20
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Hepatitis C Virus-Lipid Interplay: Pathogenesis and Clinical Impact. Biomedicines 2023; 11:biomedicines11020271. [PMID: 36830808 PMCID: PMC9953247 DOI: 10.3390/biomedicines11020271] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Hepatitis C virus (HCV) infection represents the major cause of chronic liver disease, leading to a wide range of hepatic diseases, including cirrhosis and hepatocellular carcinoma. It is the leading indication for liver transplantation worldwide. In addition, there is a growing body of evidence concerning the role of HCV in extrahepatic manifestations, including immune-related disorders and metabolic abnormalities, such as insulin resistance and steatosis. HCV depends on its host cells to propagate successfully, and every aspect of the HCV life cycle is closely related to human lipid metabolism. The virus circulates as a lipid-rich particle, entering the hepatocyte via lipoprotein cell receptors. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation (steatosis) and circulating hypocholesterolemia. Patients with chronic HCV are at increased risk for hepatic steatosis, dyslipidemia, and cardiovascular disease, including accelerated atherosclerosis. This review aims to describe different aspects of the HCV viral life cycle as it impacts host lipoproteins and lipid metabolism. It then discusses the mechanisms of HCV-related hepatic steatosis, hypocholesterolemia, and accelerated atherosclerosis.
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Hepatic Transporters Alternations Associated with Non-alcoholic Fatty Liver Disease (NAFLD): A Systematic Review. Eur J Drug Metab Pharmacokinet 2023; 48:1-10. [PMID: 36319903 DOI: 10.1007/s13318-022-00802-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND AND OBJECTIVES Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disorder and is usually accompanied by obesity, metabolic syndrome, and diabetes mellitus. NAFLD progression can lead to impaired functions of hepatocytes such as alternations in expression and function of hepatic transporters. The present study aimed to summarize and discuss the results of clinical and preclinical human studies that investigate the effect of NAFLD on hepatic transporters. METHODS The databases of PubMed, Scopus, Embase, and Web of Science were searched systematically up to 1 March 2022. The risk of bias was assessed for cross-sectional studies through the Newcastle-Ottawa Scale score. RESULTS Our review included ten cross-sectional studies consisting of 485 participants. Substantial alternations in hepatic transporters were seen during NAFLD progression to non-alcoholic steatohepatitis (NASH) in comparison with control groups. A significant reduction in expression and function of several hepatic uptake transporters, upregulation of many efflux transporters, downregulation of cholesterol efflux transporters, and mislocalization of canalicular transporter ABCC2 are associated with NAFLD progression. CONCLUSION Since extensive changes in hepatic transporters could alter the pharmacokinetics of the drugs and potentially affect the safety and efficacy of drugs, close monitoring of drug administration is highly suggested in patients with NASH.
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22
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Gieseler RK, Schreiter T, Canbay A. The Aging Human Liver: The Weal and Woe of Evolutionary Legacy. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2023; 61:83-94. [PMID: 36623546 DOI: 10.1055/a-1955-5297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Aging is characterized by the progressive decline of biological integrity and its compensatory mechanisms as well as immunological dysregulation. This goes along with an increasing risk of frailty and disease. Against this background, we here specifically focus on the aging of the human liver. For the first time, we shed light on the intertwining evolutionary underpinnings of the liver's declining regenerative capacity, the phenomenon of inflammaging, and the biotransformation capacity in the process of aging. In addition, we discuss how aging influences the risk for developing nonalcoholic fatty liver disease, hepatocellular carcinoma, and/or autoimmune hepatitis, and we describe chronic diseases as accelerators of biological aging.
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Affiliation(s)
- Robert K Gieseler
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Bochum, Germany
| | - Thomas Schreiter
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Bochum, Germany
| | - Ali Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Bochum, Germany
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Promising hepatoprotective effects of lycopene in different liver diseases. Life Sci 2022; 310:121131. [PMID: 36306869 DOI: 10.1016/j.lfs.2022.121131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 10/13/2022] [Accepted: 10/23/2022] [Indexed: 11/07/2022]
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24
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Regulatory Networks, Management Approaches, and Emerging Treatments of Nonalcoholic Fatty Liver Disease. Can J Gastroenterol Hepatol 2022; 2022:6799414. [PMID: 36397950 PMCID: PMC9666027 DOI: 10.1155/2022/6799414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/05/2022] [Indexed: 11/09/2022] Open
Abstract
The pathogenesis of NAFLD is complex and diverse, involving multiple signaling pathways and cytokines from various organs. Hepatokines, stellakines, adipokines, and myokines secreted by hepatocytes, hepatic stellate cells, adipose tissue, and myocytes play an important role in the occurrence and development of nonalcoholic fatty liver disease (NAFLD). The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) contributes to the progression of NAFLD by mediating liver inflammation, immune response, hepatocyte death, and later compensatory proliferation. In this review, we first discuss the crosstalk and interaction between hepatokines, stellakines, adipokines, and myokines and NF-κB in NAFLD. The characterization of the crosstalk of NF-κB with these factors will provide a better understanding of the molecular mechanisms involved in the progression of NAFLD. In addition, we examine new expert management opinions for NAFLD and explore the therapeutic potential of silymarin in NAFLD/NASH.
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25
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Clare K, Dillon JF, Brennan PN. Reactive Oxygen Species and Oxidative Stress in the Pathogenesis of MAFLD. J Clin Transl Hepatol 2022; 10:939-946. [PMID: 36304513 PMCID: PMC9547261 DOI: 10.14218/jcth.2022.00067] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 05/22/2022] [Accepted: 06/06/2022] [Indexed: 12/04/2022] Open
Abstract
The pathogenesis of metabolic-associated fatty liver disease (MAFLD) is complex and thought to be dependent on multiple parallel hits on a background of genetic susceptibility. The evidence suggests that MAFLD progression is a dynamic two-way process relating to repetitive bouts of metabolic stress and inflammation interspersed with endogenous anti-inflammatory reparative responses. In MAFLD, excessive hepatic lipid accumulation causes the production of lipotoxins that induce mitochondrial dysfunction, endoplasmic reticular stress, and over production of reactive oxygen species (ROS). Models of MAFLD show marked disruption of mitochondrial function and reduced oxidative capacitance with impact on cellular processes including mitophagy, oxidative phosphorylation, and mitochondrial biogenesis. In excess, ROS modify insulin and innate immune signaling and alter the expression and activity of essential enzymes involved in lipid homeostasis. ROS can also cause direct damage to intracellular structures causing hepatocyte injury and death. In select cases, the use of anti-oxidants and ROS scavengers have been shown to diminish the pro-apoptopic effects of fatty acids. Given this link, endogenous anti-oxidant pathways have been a target of interest, with Nrf2 activation showing a reduction in oxidative stress and inflammation in models of MAFLD. Thyroid hormone receptor β (THRβ) agonists and nuclear peroxisome proliferation-activated receptor (PPAR) family have also gained interest in reducing hepatic lipotoxicity and restoring hepatic function in models of MAFLD. Unfortunately, the true interplay between the clinical and molecular components of MAFLD progression remain only partly understood. Most recently, multiomics-based strategies are being adopted for hypothesis-free analysis of the molecular changes in MAFLD. Transcriptome profiling maps the unique genotype-phenotype associations in MAFLD and with various single-cell transcriptome-based projects underway, there is hope of novel physiological insights to MAFLD progression and uncover therapeutic targets.
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Affiliation(s)
- Kathleen Clare
- Royal Alexandra Hospital, Paisley, NHS Greater Glasgow and Clyde, PA2 9PN, UK
| | - John F. Dillon
- University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK
| | - Paul N. Brennan
- University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK
- University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, EH16 4UU, UK
- Correspondence to: Paul N. Brennan, University of Dundee, Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK. ORCID: https://orcid.org/0000-0001-8368-1478. Tel: +44-7445308786, E-mail:
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26
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Yang B, Luo W, Wang M, Tang Y, Zhu W, Jin L, Wang M, Wang Y, Zhang Y, Zuo W, Huang LJ, Zhao Y, Liang G. Macrophage-specific MyD88 deletion and pharmacological inhibition prevents liver damage in non-alcoholic fatty liver disease via reducing inflammatory response. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166480. [PMID: 35811033 DOI: 10.1016/j.bbadis.2022.166480] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/14/2022] [Accepted: 06/28/2022] [Indexed: 02/06/2023]
Abstract
Activation of the innate immune system through toll-like receptors (TLRs) has been repeatedly demonstrated in non-alcoholic fatty liver disease (NAFLD) and several TLRs have been shown to contribute. Myeloid differentiation primary response 88 (MyD88) is as an adapter protein for the activation of TLRs and bridges TLRs to NF-κB-mediated inflammation in macrophages. However, whether myeloid cell MyD88 contributes to NAFLD are largely unknown. To test this approach, we generated macrophage-specific MyD88 knockout mice and show that these mice are protected against high-fat diet (HFD)-induced hepatic injury, lipid accumulation, and fibrosis. These protective effects were associated with reduced macrophage numbers in liver tissues and surpassed inflammatory responses. In cultured macrophages, saturated fatty acid palmitate utilizes MyD88 to activate NF-κB and induce inflammatory and fibrogenic factors. In hepatocytes, these factors may cause lipid accumulation and a further elaboration of inflammatory cytokines. In hepatic stellate cells, macrophage-derived factors, especially TGF-β, cause activation and hepatic fibrosis. We further show that pharmacological inhibition of MyD88 is also able to reduce NAFLD injury in HFD-fed mice. Therefore, our study has provided empirical evidence that macrophage MyD88 participates in HFD-induced NAFLD and could be targeted to prevent the development and progression of NAFLD/NASH.
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Affiliation(s)
- Bin Yang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Wu Luo
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Medical Research Center, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Minxiu Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yelin Tang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Weiwei Zhu
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Leiming Jin
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Meihong Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yi Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yi Zhang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China
| | - Wei Zuo
- Affiliated Xiangshan Hospital of Wenzhou Medial University (Xiangshan First People's Hospital Medical and Health Group), Xiangshan, Zhejiang 315799, China
| | - Li-Jiang Huang
- Affiliated Xiangshan Hospital of Wenzhou Medial University (Xiangshan First People's Hospital Medical and Health Group), Xiangshan, Zhejiang 315799, China
| | - Yunjie Zhao
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China.
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27
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Kołakowski A, Dziemitko S, Chmielecka A, Żywno H, Bzdęga W, Charytoniuk T, Chabowski A, Konstantynowicz-Nowicka K. Molecular Advances in MAFLD—A Link between Sphingolipids and Extracellular Matrix in Development and Progression to Fibrosis. Int J Mol Sci 2022; 23:ijms231911380. [PMID: 36232681 PMCID: PMC9569877 DOI: 10.3390/ijms231911380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/18/2022] [Accepted: 09/23/2022] [Indexed: 11/25/2022] Open
Abstract
Metabolic-Associated Fatty Liver Disease (MAFLD) is a major cause of liver diseases globally and its prevalence is expected to grow in the coming decades. The main cause of MAFLD development is changed in the composition of the extracellular matrix (ECM). Increased production of matrix molecules and inflammatory processes lead to progressive fibrosis, cirrhosis, and ultimately liver failure. In addition, increased accumulation of sphingolipids accompanied by increased expression of pro-inflammatory cytokines in the ECM is closely related to lipogenesis, MAFLD development, and its progression to fibrosis. In our work, we will summarize all information regarding the role of sphingolipids e.g., ceramide and S1P in MAFLD development. These sphingolipids seem to have the most significant effect on macrophages and, consequently, HSCs which trigger the entire cascade of overproduction matrix molecules, especially type I and III collagen, proteoglycans, elastin, and also tissue inhibitors of metalloproteinases, which as a result cause the development of liver fibrosis.
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Affiliation(s)
- Adrian Kołakowski
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Sylwia Dziemitko
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
| | | | - Hubert Żywno
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Wiktor Bzdęga
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Tomasz Charytoniuk
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
- Department of Ophthalmology, Antoni Jurasz University Hospital No. 1, 85-094 Bydgoszcz, Poland
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
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28
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Tan P, Jin L, Qin X, He B. Natural flavonoids: Potential therapeutic strategies for non-alcoholic fatty liver disease. Front Pharmacol 2022; 13:1005312. [PMID: 36188561 PMCID: PMC9524541 DOI: 10.3389/fphar.2022.1005312] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 08/26/2022] [Indexed: 01/30/2023] Open
Abstract
The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly worldwide; however, there are currently limited treatments for NAFLD. The disease spectrum includes simple fatty liver, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and progression to hepatocellular carcinoma (NASH-HCC). The therapeutic effects of NAFLD remain controversial. Although researchers have conducted studies on the pathogenesis of NAFLD, its pathogenesis and anti-NAFLD mechanisms have not been fully elucidated. Previous studies have found that flavonoids, as natural substances with extensive pharmacological activity and good therapeutic effects, have excellent antioxidant, anti-inflammatory, metabolic disease improvement, anti-tumor, and other properties and can significantly alleviate NAFLD. Flavonoids could be further developed as therapeutic drugs for NAFLD. In this paper, the pathogenesis of NAFLD and the mechanisms of flavonoids against NAFLD are summarized to provide a theoretical basis for screening flavonoids against non-alcoholic liver injury.
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Affiliation(s)
- Panli Tan
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Li Jin
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiang Qin
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Beihui He
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
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29
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Qiao P, Jia Y, Ma A, He J, Shao C, Li X, Wang S, Yang B, Zhou H. Dapagliflozin protects against nonalcoholic steatohepatitis in db/db mice. Front Pharmacol 2022; 13:934136. [PMID: 36059948 PMCID: PMC9437261 DOI: 10.3389/fphar.2022.934136] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/18/2022] [Indexed: 01/18/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), which is the most common liver disease, is associated with type 2 diabetes mellitus and metabolic syndrome. Although there is no consensus on the treatment of NAFLD, growing evidence suggests that tight glycemic control would contribute to the improvement of NAFLD. However, some insulin sensitizers cannot improve NAFLD, especially nonalcoholic steatohepatitis (NASH). Whether insulin-independent hypoglycemic drug dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, may improve NAFLD keeps unclear. Therefore, 12-week-old male C57BL/6 wild-type and db/db mice were treated with 1 mg/kg dapagliflozin or vehicle for 12 weeks. Dapagliflozin alleviated NASH, manifesting as decreased alanine aminotransferase and NAFLD activity score in db/db mice. Also, dapagliflozin reduced de novo lipogenesis by the upregulation of FXR/SHP and downregulation of LXRα/SREBP-1c in the liver of db/db mice. Moreover, dapagliflozin treatment reduced inflammatory response by inhibiting the NF-κB pathway and alleviated fibrosis by restoring the balance between fibrogenesis and fibrolysis in the liver of db/db mice. In summary, dapagliflozin alleviates NASH mostly by reducing lipid accumulation, inflammation, and fibrosis. These findings provide new insights for understanding the protective effect of dapagliflozin in NASH and suggest that dapagliflozin may be used to treat NASH.
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Affiliation(s)
- Panshuang Qiao
- Department of Pharmacology and Department of the Integration of Chinese and Western Medicine and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yingli Jia
- Department of Pharmacology and Department of the Integration of Chinese and Western Medicine and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Ang Ma
- Department of Pharmacology and Department of the Integration of Chinese and Western Medicine and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Jinzhao He
- Department of Pharmacology and Department of the Integration of Chinese and Western Medicine and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Chen Shao
- The Department of Pathology, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Xiaowei Li
- Department of Pharmacology and Department of the Integration of Chinese and Western Medicine and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Shuyuan Wang
- Department of Pharmacology and Department of the Integration of Chinese and Western Medicine and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Baoxue Yang
- Department of Pharmacology and Department of the Integration of Chinese and Western Medicine and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
- *Correspondence: Baoxue Yang, ; Hong Zhou,
| | - Hong Zhou
- Department of Pharmacology and Department of the Integration of Chinese and Western Medicine and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
- *Correspondence: Baoxue Yang, ; Hong Zhou,
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30
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Qian J, Xu Z, Meng C, Liu Y, Wu H, Wang Y, Yang J, Zheng H, Ran F, Liu GQ, Ling Y. Redox-Activatable Theranostic Co-Prodrug for Precise Tumor Diagnosis and Selective Combination Chemotherapy. J Med Chem 2022; 65:10393-10407. [PMID: 35877176 DOI: 10.1021/acs.jmedchem.2c00130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
A novel theranostic co-prodrug SCB has been designed by combining a co-prodrug from CDDO-Me and SAHA with a biotin-coupled near-infrared (NIR) probe hemicyanine via redox-responsive linker thiolactate to enhance the tumor theranostic efficacy and reduce the toxic side effects using both active and passive targeting strategies. SCB displayed reactive oxygen species (ROS)- and glutathione (GSH)-dependent release of NIR fluorescence and two parent drugs. Furthermore, the administration of SCB caused selective illumination of the tumor tissues for >24 h, thereby guiding precise removal of a tumor from intraoperative mice. Importantly, SCB exhibited highly efficient tumor inhibition, exerted selective combination therapy through prodrug mode, and minimized the adverse effects. Finally, SCB induced mitochondrial depolarization, DNA damage, and cell apoptosis through ROS generation and downregulation of HDAC6 protein, as verified by H2AX, Bax, cleaved-PARP, and Mcl-1 proteins. Thus, we suggest that SCB can provide a new platform for both precise diagnosis-guided tumor removal and selective combination therapy with high safety.
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Affiliation(s)
- Jianqiang Qian
- School of Pharmacy, Nantong University, Nantong 226001, P. R. China.,Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, P. R. China
| | - Zhongyuan Xu
- School of Pharmacy, Nantong University, Nantong 226001, P. R. China.,Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, P. R. China
| | - Chi Meng
- School of Pharmacy, Nantong University, Nantong 226001, P. R. China
| | - Yun Liu
- School of Pharmacy, Nantong University, Nantong 226001, P. R. China
| | - Hongmei Wu
- School of Pharmacy, Nantong University, Nantong 226001, P. R. China
| | - Yunyun Wang
- School of Pharmacy, Nantong University, Nantong 226001, P. R. China
| | - Jinxian Yang
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, P. R. China
| | - Hongwei Zheng
- School of Pharmacy, Nantong University, Nantong 226001, P. R. China
| | - Fansheng Ran
- School of Pharmacy, Nantong University, Nantong 226001, P. R. China.,Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, P. R. China
| | - Gong-Qing Liu
- School of Pharmacy, Nantong University, Nantong 226001, P. R. China.,Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, P. R. China
| | - Yong Ling
- School of Pharmacy, Nantong University, Nantong 226001, P. R. China.,Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, P. R. China
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31
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Driessen M, van der Plas-Duivesteijn S, Kienhuis AS, van den Brandhof EJ, Roodbergen M, van de Water B, Spaink HP, Palmblad M, van der Ven LTM, Pennings JLA. Identification of proteome markers for drug-induced liver injury in zebrafish embryos. Toxicology 2022; 477:153262. [PMID: 35868597 DOI: 10.1016/j.tox.2022.153262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/26/2022] [Accepted: 07/18/2022] [Indexed: 10/17/2022]
Abstract
The zebrafish embryo (ZFE) is a promising alternative non-rodent model in toxicology, and initial studies suggested its applicability in detecting hepatic responses related to drug-induced liver injury (DILI). Here, we hypothesize that detailed analysis of underlying mechanisms of hepatotoxicity in ZFE contributes to the improved identification of hepatotoxic properties of compounds and to the reduction of rodents used for hepatotoxicity assessment. ZFEs were exposed to nine reference hepatotoxicants, targeted at induction of steatosis, cholestasis, and necrosis, and effects compared with negative controls. Protein profiles of the individual compounds were generated using LC-MS/MS. We identified differentially expressed proteins and pathways, but as these showed considerable overlap, phenotype-specific responses could not be distinguished. This led us to identify a set of common hepatotoxicity marker proteins. At the pathway level, these were mainly associated with cellular adaptive stress-responses, whereas single proteins could be linked to common hepatotoxicity-associated processes. Applying several stringency criteria to our proteomics data as well as information from other data sources resulted in a set of potential robust protein markers, notably Igf2bp1, Cox5ba, Ahnak, Itih3b.2, Psma6b, Srsf3a, Ces2b, Ces2a, Tdo2b, and Anxa1c, for the detection of adverse responses.
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Affiliation(s)
- Marja Driessen
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O.Box 1, 3720 BA Bilthoven, the Netherlands; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, the Netherlands
| | | | - Anne S Kienhuis
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O.Box 1, 3720 BA Bilthoven, the Netherlands
| | - Evert-Jan van den Brandhof
- Centre for Environmental Quality, National Institute for Public Health and the Environment (RIVM), P.O.Box 1, 3720 BA Bilthoven, the Netherlands
| | - Marianne Roodbergen
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O.Box 1, 3720 BA Bilthoven, the Netherlands; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, the Netherlands
| | - Bob van de Water
- Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, the Netherlands
| | - Herman P Spaink
- Institute of Biology, Leiden University, Einsteinweg 55, 2333 CC Leiden, the Netherlands
| | - Magnus Palmblad
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
| | - Leo T M van der Ven
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O.Box 1, 3720 BA Bilthoven, the Netherlands
| | - Jeroen L A Pennings
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O.Box 1, 3720 BA Bilthoven, the Netherlands.
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32
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Leslie J, Geh D, Elsharkawy AM, Mann DA, Vacca M. Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions. J Hepatol 2022; 77:219-236. [PMID: 35157957 DOI: 10.1016/j.jhep.2022.01.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/12/2022] [Accepted: 01/31/2022] [Indexed: 12/16/2022]
Abstract
HCV hijacks many host metabolic processes in an effort to aid viral replication. The resulting hepatic metabolic dysfunction underpins many of the hepatic and extrahepatic manifestations of chronic hepatitis C (CHC). However, the natural history of CHC is also substantially influenced by the host metabolic status: obesity, insulin resistance and hepatic steatosis are major determinants of CHC progression toward hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed the treatment and natural history of CHC. While DAA therapy effectively eradicates the virus, the long-lasting overlapping metabolic disease can persist, especially in the presence of obesity, increasing the risk of liver disease progression. This review covers the mechanisms by which HCV tunes hepatic and systemic metabolism, highlighting how systemic metabolic disturbance, lipotoxicity and chronic inflammation favour disease progression and a precancerous niche. We also highlight the therapeutic implications of sustained metabolic dysfunction following sustained virologic response as well as considerations for patients who develop HCC on the background of metabolic dysfunction.
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Affiliation(s)
- Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Daniel Geh
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Ahmed M Elsharkawy
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, B15 2TH UK; National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey.
| | - Michele Vacca
- Interdisciplinary Department of Medicine, Università degli Studi di Bari "Aldo Moro", Bari, Italy.
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33
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Calpain-mediated proteolytic production of free amino acids in vascular endothelial cells augments obesity-induced hepatic steatosis. J Biol Chem 2022; 298:101953. [PMID: 35447117 PMCID: PMC9110893 DOI: 10.1016/j.jbc.2022.101953] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 04/02/2022] [Accepted: 04/04/2022] [Indexed: 10/25/2022] Open
Abstract
Free amino acids that accumulate in the plasma of diabetes and obesity patients influence lipid metabolism and protein synthesis in the liver. The stress-inducible intracellular protease calpain proteolyzes various substrates in vascular endothelial cells (ECs), although its contribution to the supply of free amino acids in the liver microenvironment remains enigmatic. In the present study, we showed that calpains are associated with free amino acid production in cultured ECs. Furthermore, conditioned media derived from calpain-activated ECs facilitated the phosphorylation of ribosomal protein S6 kinase (S6K) and de novo lipogenesis in hepatocytes, which were abolished by the amino acid transporter inhibitor, JPH203, and the mTORC1 inhibitor, rapamycin. Meanwhile, calpain-overexpressing capillary-like ECs were observed in the livers of high-fat diet-fed mice. Conditional knockout of EC/hematopoietic Capns1, which encodes a calpain regulatory subunit, diminished levels of branched chain amino acids in the hepatic microenvironment without altering plasma amino acid levels. Concomitantly, conditional knockout of Capns1 mitigated hepatic steatosis without normalizing body weight and the plasma lipoprotein profile in an amino acid transporter-dependent manner. Mice with targeted Capns1 knockout exhibited reduced phosphorylation of S6K and maturation of lipid homeostasis transcription factor SREBP1 in hepatocytes. Finally, we show that bone marrow transplantation negated the contribution of hematopoietic calpain systems; therefore, calpains are likely responsible for the observed phenotypes of ECs. We conclude that overactivation of calpain systems may be responsible for the production of free amino acid in ECs, which may be sufficient to potentiate S6K/SREBP1-induced lipogenesis in surrounding hepatocytes.
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34
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Sphingolipid control of cognitive functions in health and disease. Prog Lipid Res 2022; 86:101162. [DOI: 10.1016/j.plipres.2022.101162] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 03/10/2022] [Accepted: 03/12/2022] [Indexed: 12/14/2022]
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Li Y, Yang M, Lin H, Yan W, Deng G, Ye H, Shi H, Wu C, Ma G, Xu S, Tan Q, Gao Z, Gao L. Limonin Alleviates Non-alcoholic Fatty Liver Disease by Reducing Lipid Accumulation, Suppressing Inflammation and Oxidative Stress. Front Pharmacol 2022; 12:801730. [PMID: 35046824 PMCID: PMC8762292 DOI: 10.3389/fphar.2021.801730] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 11/26/2021] [Indexed: 12/30/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and continues to rise in the worldwide. Limonin is a triterpenoid compound widely found in the fruits of citrus plants with a wide range of pharmacological effects, including anti-cancer, anti-inflammation, anti-viral, anti-oxidation and liver protection properties. However, the potential molecular mechanism of limonin on NAFLD in zebrafish remains unknown. In this study, zebrafish larvae were exposed to thioacetamide to establish an NAFLD model and the larvae were treated with limonin for 72 h simultaneously. The human liver cell line was stimulated with lipid mixture and meanwhile incubated with limonin for 24 h. The results showed that Limonin significantly reduced the accumulation of lipid droplets in the liver and down-regulated the levels of lipogenic transcription factors FASN and SREBP1 in NAFLD. Limonin suppressed macrophages infiltration and the down-regulated the relative expression levels of the pro-inflammatory factors IL-6, IL-1β and TNF-α secreted by macrophages. Besides, limonin could reversed the reduction of glutathione and the accumulation of reactive oxygen species through up-regulating NRF2/HO-1 signaling pathway in the liver. In conclusion, this study revealed that limonin has a protective effect on NAFLD due to its resistance to lipid deposition as well as antioxidant and anti-inflammatory actions.
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Affiliation(s)
- Yunjia Li
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Menghan Yang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Haiyan Lin
- Shenzhen Hospital, University of Chinese Academy of Sciences, Shenzhen, China
| | - Weixin Yan
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Guanghui Deng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Haixin Ye
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Hao Shi
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Chaofeng Wu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Guoliang Ma
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Shu Xu
- Shenzhen Hospital, University of Chinese Academy of Sciences, Shenzhen, China
| | - Qinxiang Tan
- Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Zhuowei Gao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.,Shunde Hospital, Guangzhou University of Chinese Medicine, Foshan, China
| | - Lei Gao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, China.,Zhujiang Hospital, Southern Medical University, Guangzhou, China
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Combined Metabolomics and Network Toxicology to Explore the Molecular Mechanism of Phytolacca acinose Roxb-Induced Hepatotoxicity in Zebrafish Larvae in Vivo. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:3303014. [PMID: 34876912 PMCID: PMC8645354 DOI: 10.1155/2021/3303014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/17/2021] [Accepted: 10/21/2021] [Indexed: 11/18/2022]
Abstract
Phytolacca acinosa Roxb (PAR), a traditional Chinese medicine, has been widely used as a diuretic drug for a long period of time for the treatment edema, swelling, and sores. However, it has been reported that PAR might induce hepatotoxicity, while the mechanisms of its toxic effect are still unclear. In this study, network toxicology and metabolomic technique were applied to explore PAR-induced hepatotoxicity on zebrafish larvae. We evaluated the effect of PAR on the ultrastructure and the function of the liver, predictive targets, and pathways in network toxicology, apoptosis of liver cells by PCR and western blot, and metabolic profile by GC-MS. PAR causes liver injury, abnormal liver function, and apoptosis in zebrafish. The level of arachidonic acid in endogenous metabolites treated with PAR was significantly increased, leading to oxidative stress in vivo. Excessive ROS further activated the p53 signal pathway and caspase family, which were obtained from KEGG enrichment analysis of network toxicology. The gene levels of caspase-3, caspase-8, and caspase-9 were significantly increased by RT-PCR, and the level of Caps3 protein was also significantly up-regulated through western blot. PAR exposure results in the liver function abnormal amino acid metabolism disturbance and motivates hepatocyte apoptosis, furthermore leading to liver injury.
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Seifeldein GS, Hassan EA, Imam HM, Makboul R, Idriss NK, Gaber MA, Elkady RM. Quantitative MDCT and MRI assessment of hepatic steatosis in genotype 4 chronic hepatitis C patients with fibrosis. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2021. [DOI: 10.1186/s43055-021-00590-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Hepatic steatosis has been shown to worsen the course of liver disease in chronic hepatitis C (CHC) patients, and it may reduce the efficacy of antiviral therapy and accelerate disease progression. In this cross-sectional study, we aimed to evaluate the role of multidetector computed tomography and magnetic resonance imaging (MRI) in the quantitative assessment and grading of hepatic steatosis to evaluate the association between hepatic steatosis and fibrosis in Egyptian genotype 4-CHC (G4-CHC) patients.
Results
Histopathological hepatic steatosis was found in 70.3% of 155 patients. No correlation was found between the CT ratio and pathological hepatic steatosis. Proton density fat fraction, T1-fat fraction, and fat percentage correlated with histological steatosis grading (r = 0.953, p < 0.001; r = 0.380, p = 0.027 and r = 0.384, p = 0.025, respectively). An agreement between steatosis grading by histology and 1H-MRS was found in 74.2% of patients. Compared to other MRI modalities, proton density fat fraction had the highest area under the receiver operating characteristic curve (AUC), with 0.910, 0.931, and 0.975 for mild, moderate, and severe steatosis, respectively. The cutoff with the best ability to predict steatosis was > 4.95 for a proton density fat fraction (AUC = 0.958) with 95.8% sensitivity, 90% specificity, 78.5% positive predictive value, and 96.1% negative predictive value.
Conclusion
1H-MRS had good diagnostic performance in predicting hepatic steatosis in G4-CHC patients, and hence, it may offer a useful noninvasive quantitative modality for grading steatosis with clinical applicability, especially in those where a liver biopsy cannot be done.
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Ishaq A, Gulzar H, Hassan A, Kamran M, Riaz M, Parveen A, Chattha MS, Walayat N, Fatima S, Afzal S, Fahad S. Ameliorative mechanisms of turmeric-extracted curcumin on arsenic (As)-induced biochemical alterations, oxidative damage, and impaired organ functions in rats. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:66313-66326. [PMID: 34331650 DOI: 10.1007/s11356-021-15695-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 07/23/2021] [Indexed: 06/13/2023]
Abstract
Arsenic (As) is known for its carcinogenic and hepatorenal toxic effects causing serious health problems in human beings. Turmeric (Curcuma longa L.) extracted curcumin (Cur) is a polyphenolic antioxidant which has ability to combat hazardous environmental toxicants. This study (28 days) was carried out to investigate the therapeutic efficacy of different doses of Cur (Cur: 80, 160, 240 mg kg-1) against the oxidative damage in the liver and kidney of male rats caused by sodium arsenate (Na3AsO4) (10 mg L-1). As exposure significantly elevated the values of organ index, markers of hepatic injury (i.e., alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP)) and renal functions (i.e., total bilirubin, urea and creatinine, total cholesterol, total triglycerides, and lipid peroxidation malondialdehyde (MDA)). Moreover, different antioxidant markers such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) activities in the liver and kidney tissues were reduced after As-induced toxicity. However, Na3AsO4 induced histopathological changes in various organs were minimized after the treatment with Cur. The alleviation effect of Cur was dosage dependent with an order of 240>160>80 mg kg-1. The oral administration of Cur prominently alleviated the As-induced toxicity in liver and kidney tissues by reducing lipid peroxidation, ALT, AST, ALP, total bilirubin, urea, creatinine, total cholesterol, total triglycerides, and low-density lipoproteins (LDL). In addition, Cur being an antioxidant improved defense system by enhancing activities of SOD, CAT, GPx, and GR. Overall, the findings explain the capability of Cur to counteract the oxidative alterations as well as hepatorenal injuries due to As intoxication.
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Affiliation(s)
- Anam Ishaq
- National Institute of Food Science & Technology, Faculty of Food, Nutrition & Home Sciences, University of Agriculture, Faisalabad, 3800, Pakistan
| | - Huma Gulzar
- College of Life Sciences, China Agricultural University, Beijing, 100083, People's Republic of China
| | - Ali Hassan
- National Institute of Food Science & Technology, Faculty of Food, Nutrition & Home Sciences, University of Agriculture, Faisalabad, 3800, Pakistan.
| | - Muhammad Kamran
- University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
| | - Muhammad Riaz
- College of Natural Resources and Environment, South China Agricultural University, Guangzhou, 510642, People's Republic of China
| | - Aasma Parveen
- Faculty of Agriculture & Environmental Sciences, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan
| | - Muhammad Sohaib Chattha
- College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, 430070, Hubei, People's Republic of China
| | - Noman Walayat
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China
| | - Sana Fatima
- Faculty of Sciences, University of Agriculture, Faisalabad, 3800, Pakistan
| | - Sobia Afzal
- Faculty of Agriculture & Environmental Sciences, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan
| | - Shah Fahad
- Hainan Key Laboratory for Sustainable Utilization of Tropical Bioresource, College of Tropical Crops, Hainan University, Haikou, Hainan, 570228, People's Republic of China.
- Department of Agronomy, The University of Haripur, Haripur, Khyber Pakhtunkhwa, 22620, Pakistan.
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Rao Y, Li C, Hu YT, Xu YH, Song BB, Guo SY, Jiang Z, Zhao DD, Chen SB, Tan JH, Huang SL, Li QJ, Wang XJ, Zhang YJ, Ye JM, Huang ZS. A novel HSF1 activator ameliorates nonalcoholic steatohepatitis by stimulating mitochondrial adaptive oxidation. Br J Pharmacol 2021; 179:1411-1432. [PMID: 34783017 DOI: 10.1111/bph.15727] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 10/09/2021] [Accepted: 10/12/2021] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND AND PURPOSE Nonalcoholic steatohepatitis (NASH) is the more severe form of metabolic associated fatty liver disease (MAFLD), and no pharmacologic treatment approved as yet. Identification of novel therapeutic targets and their agents are critical to overcome the current inadequacy of drug treatment for NASH. EXPERIMENTAL APPROACH The correlation between heat shock factor 1 (HSF1) levels and the development of NASH and the target genes of HSF1 in hepatocyte were revealed by chromatin-immunoprecipitation sequencing. The effects and mechanisms of SYSU-3d in alleviating NASH were examined in relevant cell models and mouse models (the Ob/Ob mice, high-fat and high-cholesterol diet, the methionine-choline deficient diet fed mice). The drug-like properties of SYSU-3d in vivo were evaluated. KEY RESULTS HSF1 is progressively reduced with mitochondrial dysfunction in NASH pathogenesis and activation of this transcription factor by its newly-identified activator SYSU-3d efficiently ameliorated all manifestations of NASH in mice. When activated, the phosphorylated HSF1 (Ser326) translocated to nucleus and bound to the promoter of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) to induce mitochondrial biogenesis, thus increasing mitochondrial adaptive oxidation and inhibiting oxidative stress. The deletion of HSF1 and PGC-1α or recovery of HSF1 in HSF1-deficiency cells revealed the HSF1/PGC-1α metabolic axis mainly responsible for the anti-NASH effects of SYSU-3d independent of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). CONCLUSION AND IMPLICATIONS Activation of HSF1 is a practicable therapeutic approach for NASH treatment via the HSF1/PGC-1α/mitochondrial axis, and SYSU-3d would take into consideration as a potential candidate for the treatment of NASH.
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Affiliation(s)
- Yong Rao
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Chan Li
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yu-Tao Hu
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yao-Hao Xu
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Bing-Bing Song
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Shi-Yao Guo
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zhi Jiang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Dan-Dan Zhao
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Shuo-Bin Chen
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jia-Heng Tan
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Shi-Liang Huang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Qing-Jiang Li
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xiao-Jun Wang
- Sunshine Lake Pharma Co., Ltd, Dongguan, Guangdong, China
| | - Ying-Jun Zhang
- Sunshine Lake Pharma Co., Ltd, Dongguan, Guangdong, China
| | - Ji-Ming Ye
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, Guangdong, China
| | - Zhi-Shu Huang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, Guangdong, China
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40
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Negi CK, Bajard L, Kohoutek J, Blaha L. An adverse outcome pathway based in vitro characterization of novel flame retardants-induced hepatic steatosis. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2021; 289:117855. [PMID: 34340181 DOI: 10.1016/j.envpol.2021.117855] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/16/2021] [Accepted: 07/25/2021] [Indexed: 05/22/2023]
Abstract
A wide range of novel replacement flame retardants (nFRs) is consistently detected in increasing concentrations in the environment and human matrices. Evidence suggests that nFRs exposure may be associated with disruption of the endocrine system, which has been linked with the etiology of various metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). NAFLD is a multifactorial disease characterized by the uncontrolled accumulation of fats (lipids) in the hepatocytes and involves multiple-hit pathogenesis, including exposure to occupational and environmental chemicals such as organophosphate flame retardants (OPFRs). In the present study we aimed to investigate the potential mechanisms of the nFRs-induced hepatic steatosis in the human liver cells. In this study, we employed an in vitro bioassay toolbox to assess the key events (KEs) in the proposed adverse outcome pathways (AOP) (s) for hepatic steatosis. We examined nine nFRs using AOP- based in vitro assays measuring KEs such as lipid accumulation, mitochondrial dysfunction, gene expression, and in silico approach to identify the putative molecular initiating events (MIEs). Our findings suggest that several tested OPFRs induced lipid accumulation in human liver cell culture. Tricresyl phosphate (TMPP), triphenyl phosphate (TPHP), tris(1,3-dichloropropyl) phosphate (TDCIPP), and 2-ethylhexyl diphenyl phosphate (EHDPP) induced the highest lipid accumulation by altering the expression of genes encoding hepatic de novo lipogenesis and mitochondrial dysfunction depicted by decreased cellular ATP production. Available in vitro data from ToxCast and in silico molecular docking suggests that pregnane X receptor (PXR) and peroxisome proliferator-activated receptor gamma (PPARγ) could be the molecular targets for the tested nFRs. The study identifies several nFRs, such as TMPP and EHDPP, TPHP, and TDCIPP, as potential risk factor for NAFLD and advances our understanding of the mechanisms involved, demonstrating the utility of an AOP-based strategy for screening and prioritizing chemicals and elucidating the molecular mechanisms of toxicity.
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Affiliation(s)
- Chander K Negi
- Faculty of Science, RECETOX, Masaryk University, Kamenice 5, CZ62500, Brno, Czech Republic
| | - Lola Bajard
- Faculty of Science, RECETOX, Masaryk University, Kamenice 5, CZ62500, Brno, Czech Republic
| | - Jiri Kohoutek
- Faculty of Science, RECETOX, Masaryk University, Kamenice 5, CZ62500, Brno, Czech Republic
| | - Ludek Blaha
- Faculty of Science, RECETOX, Masaryk University, Kamenice 5, CZ62500, Brno, Czech Republic.
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Mitra S, Anand U, Sanyal R, Jha NK, Behl T, Mundhra A, Ghosh A, Radha, Kumar M, Proćków J, Dey A. Neoechinulins: Molecular, cellular, and functional attributes as promising therapeutics against cancer and other human diseases. Biomed Pharmacother 2021; 145:112378. [PMID: 34741824 DOI: 10.1016/j.biopha.2021.112378] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 10/23/2021] [Accepted: 10/25/2021] [Indexed: 12/21/2022] Open
Abstract
Neoechinulins are fungal and plant-derived chemicals extracted from Microsporum sp., Eurotium rubrum, Aspergillus sp., etc. Two analogues of neoechinulin, i.e., A and B, exerted extensive pharmacological properties described in this review. Neoechinulin is an indole alkaloid and has a double bond between C8/C9, which tends to contribute to its cytoprotective nature. Neoechinulin A exhibits protection to PC12 cells against nitrosative stress via increasing NAD(P)H reserve capacity and decreasing cellular GSH levels. It also confers protection via rescuing PC12 cells from rotenone-induced stress by lowering LDH leakage. This compound has great positive potential against neurodegenerative diseases by inhibiting SIN-1 induced cell death in neuronal cells. Together with these, neoechinulin A tends to inhibit Aβ42-induced microglial activation and confers protection against neuroinflammation. Alongside, it also inhibits cervical cancer cells by caspase-dependent apoptosis and via upregulation of apoptosis inducing genes like Bax, it suppresses LPS-induced inflammation in RAW264.7 macrophages and acts as an antidepressant. Whereas, another analogue, Neoechinulin B tends to interfere with the cellular mechanism thereby, inhibiting the entry of influenza A virus and it targets Liver X receptor (LXR) and decreases the infection rate of Hepatitis C. The present review describes the pharmaceutical properties of neoechinulins with notes on their molecular, cellular, and functional basis and their therapeutic properties.
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Affiliation(s)
- Sicon Mitra
- Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
| | - Uttpal Anand
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Rupa Sanyal
- Department of Botany, Bhairab Ganguly College (affiliated to West Bengal State University), Feeder Road, Belghoria, Kolkata 700056, West Bengal, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India
| | - Avinash Mundhra
- Department of Botany, Rishi Bankim Chandra College (Affiliated to the West Bengal State University), East Kantalpara, North 24 Parganas, Naihati 743165, West Bengal, India
| | - Arabinda Ghosh
- Department of Botany, Gauhati University, Guwahati, Assam 781014, India
| | - Radha
- School of Biological and Environmental Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, Himachal Pradesh 173229, India
| | - Manoj Kumar
- Chemical and Biochemical Processing Division, ICAR - Central Institute for Research on Cotton Technology, Mumbai 400019, Maharashtra, India
| | - Jarosław Proćków
- Department of Plant Biology, Institute of Environmental Biology, Wrocław University of Environmental and Life Sciences, Kożuchowska 5b, 51-631 Wrocław, Poland.
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, West Bengal, India.
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Song Z, Zhong X, Li M, Gao P, Ning Z, Sun Z, Song X. 1-MNA Ameliorates High Fat Diet-Induced Heart Injury by Upregulating Nrf2 Expression and Inhibiting NF-κB in vivo and in vitro. Front Cardiovasc Med 2021; 8:721814. [PMID: 34712707 PMCID: PMC8545986 DOI: 10.3389/fcvm.2021.721814] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 09/17/2021] [Indexed: 12/05/2022] Open
Abstract
High levels of free fatty acids (FFA) are closely associated with obesity and the development of cardiovascular diseases. Recently, nicotinamide adenine dinucleotide (NAD) metabolism has emerged as a potential target for several modern diseases including diabetes. Herein, we explored the underlying mechanisms of NAD metabolism associated with the risk of cardiovascular disease. Our study found that nicotinamide N-methyltransferase (NNMT) mRNA levels were significantly increased in the hearts of FFA-bound-albumin-overloaded mice and in H9C2 cells treated with palmitic acid (PA). We studied the mechanisms underlining the anti-inflammatory and anti-oxidant activities of 1-methylnicotinamide (1-MNA), a metabolite of NNMT. We found a significantly higher level of reactive oxygen species, inflammation, apoptosis, and cell hypertrophy in PA-treated H9C2 cells and this effect was inhibited by 1-MNA treatment. in vivo, 1-MNA improved inflammation, apoptosis, and fibrosis damage in mice and this inhibition was associated with inhibited NF-κB activity. In conclusion, our study revealed that 1-MNA may prevent high fatty diet and PA-induced heart injury by regulating Nrf2 and NF-κB pathways.
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Affiliation(s)
- Ziguang Song
- Cardiovascular Center, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Xiao Zhong
- Cardiovascular Center, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Mingyang Li
- Cardiovascular Center, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Pingping Gao
- Cardiovascular Center, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Zhongping Ning
- Department of Cardiovascular Medicine, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Zhiqi Sun
- Department of Cardiovascular Medicine, DaQing Oilfield General Hospital, Daqing, China
| | - Xiang Song
- Cardiovascular Center, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
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Guerra JVS, Dias MMG, Brilhante AJVC, Terra MF, García-Arévalo M, Figueira ACM. Multifactorial Basis and Therapeutic Strategies in Metabolism-Related Diseases. Nutrients 2021; 13:nu13082830. [PMID: 34444990 PMCID: PMC8398524 DOI: 10.3390/nu13082830] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/09/2021] [Accepted: 08/11/2021] [Indexed: 12/11/2022] Open
Abstract
Throughout the 20th and 21st centuries, the incidence of non-communicable diseases (NCDs), also known as chronic diseases, has been increasing worldwide. Changes in dietary and physical activity patterns, along with genetic conditions, are the main factors that modulate the metabolism of individuals, leading to the development of NCDs. Obesity, diabetes, metabolic associated fatty liver disease (MAFLD), and cardiovascular diseases (CVDs) are classified in this group of chronic diseases. Therefore, understanding the underlying molecular mechanisms of these diseases leads us to develop more accurate and effective treatments to reduce or mitigate their prevalence in the population. Given the global relevance of NCDs and ongoing research progress, this article reviews the current understanding about NCDs and their related risk factors, with a focus on obesity, diabetes, MAFLD, and CVDs, summarizing the knowledge about their pathophysiology and highlighting the currently available and emerging therapeutic strategies, especially pharmacological interventions. All of these diseases play an important role in the contamination by the SARS-CoV-2 virus, as well as in the progression and severity of the symptoms of the coronavirus disease 2019 (COVID-19). Therefore, we briefly explore the relationship between NCDs and COVID-19.
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Affiliation(s)
- João V. S. Guerra
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Graduate Program in Pharmaceutical Sciences, Faculty Pharmaceutical Sciences, University of Campinas, Campinas 13083-970, Brazil
| | - Marieli M. G. Dias
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Graduate Program in Functional and Molecular Biology, Institute of Biology, State University of Campinas (Unicamp), Campinas 13083-970, Brazil;
| | - Anna J. V. C. Brilhante
- Graduate Program in Functional and Molecular Biology, Institute of Biology, State University of Campinas (Unicamp), Campinas 13083-970, Brazil;
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biorenewables National Laboratory (LNBR), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil
| | - Maiara F. Terra
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Graduate Program in Functional and Molecular Biology, Institute of Biology, State University of Campinas (Unicamp), Campinas 13083-970, Brazil;
| | - Marta García-Arévalo
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Correspondence: or (M.G.-A.); (A.C.M.F.)
| | - Ana Carolina M. Figueira
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Correspondence: or (M.G.-A.); (A.C.M.F.)
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Choi Y, Song MJ, Jung WJ, Jeong H, Park S, Yang B, Lee EC, Joo JS, Choi D, Koo SH, Kim EK, Nam KT, Kim HP. Liver-Specific Deletion of Mouse CTCF Leads to Hepatic Steatosis via Augmented PPARγ Signaling. Cell Mol Gastroenterol Hepatol 2021; 12:1761-1787. [PMID: 34358714 PMCID: PMC8551791 DOI: 10.1016/j.jcmgh.2021.07.016] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The liver is the major organ for metabolizing lipids, and malfunction of the liver leads to various diseases. Nonalcoholic fatty liver disease is rapidly becoming a major health concern worldwide and is characterized by abnormal retention of excess lipids in the liver. CCCTC-binding factor (CTCF) is a highly conserved zinc finger protein that regulates higher-order chromatin organization and is involved in various gene regulation processes. Here, we sought to determine the physiological role of CTCF in hepatic lipid metabolism. METHODS We generated liver-specific, CTCF-ablated and/or CD36 whole-body knockout mice. Overexpression or knockdown of peroxisome proliferator-activated receptor (PPAR)γ in the liver was achieved using adenovirus. Mice were examined for development of hepatic steatosis and inflammation. RNA sequencing was performed to identify genes affected by CTCF depletion. Genome-wide occupancy of H3K27 acetylation, PPARγ, and CTCF were analyzed by chromatin immunoprecipitation sequencing. Genome-wide chromatin interactions were analyzed by in situ Hi-C. RESULTS Liver-specific, CTCF-deficient mice developed hepatic steatosis and inflammation when fed a standard chow diet. Global analysis of the transcriptome and enhancer landscape revealed that CTCF-depleted liver showed enhanced accumulation of PPARγ in the nucleus, which leads to increased expression of its downstream target genes, including fat storage-related gene CD36, which is involved in the lipid metabolic process. Hepatic steatosis developed in liver-specific, CTCF-deficient mice was ameliorated by repression of PPARγ via pharmacologic blockade or adenovirus-mediated knockdown, but hardly rescued by additional knockout of CD36. CONCLUSIONS Our data indicate that liver-specific deletion of CTCF leads to hepatosteatosis through augmented PPARγ DNA-binding activity, which up-regulates its downstream target genes associated with the lipid metabolic process.
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Affiliation(s)
- Yeeun Choi
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Seoul, Korea
| | - Min-Ji Song
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Seoul, Korea
| | - Woong-Jae Jung
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Seoul, Korea; Department of Bioinformatics, Graduate School of Soongsil University, Seoul, Korea
| | - Haengdueng Jeong
- Brain Korea 21 Plus Project for Medical Science, Seoul, Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Seokjae Park
- Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea; Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea
| | - Bobae Yang
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Seoul, Korea
| | - Eun-Chong Lee
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Seoul, Korea
| | - Jung-Sik Joo
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Seoul, Korea
| | - Dahee Choi
- Division of Life Sciences, Korea University, Seoul, Korea
| | - Seung-Hoi Koo
- Division of Life Sciences, Korea University, Seoul, Korea
| | - Eun-Kyoung Kim
- Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea; Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea
| | - Ki Taek Nam
- Brain Korea 21 Plus Project for Medical Science, Seoul, Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Hyoung-Pyo Kim
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Seoul, Korea.
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Yefimenko T, Mykytyuk M. Non-alcoholic fatty liver disease: time for changes. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (UKRAINE) 2021; 17:334-345. [DOI: 10.22141/2224-0721.17.4.2021.237350] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The review contains updated information on the epidemiology, etiology, pathogenesis, diagnosis, treatment and prevention of non-alcoholic fatty liver disease (NAFLD). We searched for terms including NAFLD, non-alcoholic steatohepatitis (NASH), metabolic syndrome and type 2 diabetes mellitus in literature published over the past 5 years using the Scopus, Web of Science, CyberLeninka, PubMed databases. The concept of NAFLD includes two morphological forms of the disease with different prognosis: non-alcoholic fatty hepatosis and NASH. The severity of NASH is quite variable, including fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD, a spectrum of fatty liver disorders of viral, autoimmune, drug-induced, and genetic origin, which are not caused by alcohol abuse, has recently been renamed as metabolic (dysfunction) associated fatty liver disease (MAFLD). The average prevalence of NAFLD is approximately 25% among the adult population worldwide, and in some regions exceeds 30%. An increase in the prevalence of this pathology is in parallel with the global epidemic of obesity and type 2 diabetes mellitus in the world. It is time to reach a general consensus in the scientific community on changing the nomenclature and moving from a negative to a positive definition of NAFLD/NASH. The new nomenclature points to the “positive” determinants of the disease, namely the close relationship with metabolic disorders, instead of defining it as what it is not (ie. non-alcoholic). The MAFLD abbreviation more accurately discloses existing knowledge about fatty liver diseases associated with metabolic dysfunction and should replace NAFLD/NASH, as this will stimulate the research community’s efforts to update the disease nomenclature and subphenotype and accelerate the transition to new treatments. It is important that primary care physicians, endocrinologists, and other specialists are aware of the extent and long-term consequences of NAFLD. Early identification of patients with NASH can help improve treatment outcomes, avoid liver transplantation in patients with decompensated cirrhosis. There are currently no effective treatments for NAFLD, so it is important to follow a multidisciplinary approach, which means using measures to improve prognosis, reduce the risk of death associated with NAFLD, the development of cirrhosis or hepatocellular carcinoma. Epidemiological data suggest a close relationship between unhealthy lifestyles and NAFLD, so lifestyle adjustments are needed to all patients. Insulin sensitizers, statins, ezetimibe, a cholesterol absorption inhibitor, hepatoprotectors, antioxidants, incretin analogues, dipeptidyl peptidase 4 inhibitors, pentoxifylline, probiotics, angiotensin-converting enzyme inhibitors, and endocannabinoid antagonists are used in the treatment of NAFLD.
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Juanola O, Martínez-López S, Francés R, Gómez-Hurtado I. Non-Alcoholic Fatty Liver Disease: Metabolic, Genetic, Epigenetic and Environmental Risk Factors. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18105227. [PMID: 34069012 PMCID: PMC8155932 DOI: 10.3390/ijerph18105227] [Citation(s) in RCA: 167] [Impact Index Per Article: 41.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/29/2021] [Accepted: 05/09/2021] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of chronic liver disease in the Western world, probably due to the growing prevalence of obesity, metabolic diseases, and exposure to some environmental agents. In certain patients, simple hepatic steatosis can progress to non-alcoholic steatohepatitis (NASH), which can sometimes lead to liver cirrhosis and its complications including hepatocellular carcinoma. Understanding the mechanisms that cause the progression of NAFLD to NASH is crucial to be able to control the advancement of the disease. The main hypothesis considers that it is due to multiple factors that act together on genetically predisposed subjects to suffer from NAFLD including insulin resistance, nutritional factors, gut microbiota, and genetic and epigenetic factors. In this article, we will discuss the epidemiology of NAFLD, and we overview several topics that influence the development of the disease from simple steatosis to liver cirrhosis and its possible complications.
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Affiliation(s)
- Oriol Juanola
- Gastroenterology and Hepatology, Translational Research Laboratory, Ente Ospedaliero Cantonale, Università della Svizzera Italiana, 6900 Lugano, Switzerland
| | - Sebastián Martínez-López
- Clinical Medicine Department, Miguel Hernández University, 03550 San Juan de Alicante, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Hospital General Universitario de Alicante, 03010 Alicante, Spain
| | - Rubén Francés
- Clinical Medicine Department, Miguel Hernández University, 03550 San Juan de Alicante, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Hospital General Universitario de Alicante, 03010 Alicante, Spain
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, 28029 Madrid, Spain
| | - Isabel Gómez-Hurtado
- Alicante Institute for Health and Biomedical Research (ISABIAL), Hospital General Universitario de Alicante, 03010 Alicante, Spain
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, 28029 Madrid, Spain
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Mazilescu LI, Selzner M, Selzner N. Defatting strategies in the current era of liver steatosis. JHEP Rep 2021; 3:100265. [PMID: 34027337 PMCID: PMC8121960 DOI: 10.1016/j.jhepr.2021.100265] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 02/14/2021] [Accepted: 02/19/2021] [Indexed: 12/25/2022] Open
Abstract
Liver steatosis is emerging as a major cause of chronic liver disease worldwide, mainly due to the increasing rate of obesity, type 2 diabetes, and metabolic syndrome. Because of the increased incidence of liver steatosis, many organs are currently declined for transplantation despite high demand and waiting list mortality. Defatting strategies have recently emerged as a means of rapidly reducing liver steatosis to expand the pool of available organs. This review summarises advances in defatting strategies in experimental and human models of liver steatosis over the last 20 years.
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Key Words
- GDNF, glial cell-line derived neurotrophic factor
- HFD, high-fat diet
- HIEC, hepatic endothelial cells
- HOPE, hypothermic machine perfusion
- LDs, lipid droplets
- Macrosteatosis
- NAFL, non-alcoholic fatty liver
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- NEsLP, normothermic ex situ machine perfusion
- PHHs, primary human hepatocytes
- PPAR, peroxisome proliferator-activated receptor
- PXR, pregnane X receptor
- SCS, static cold storage
- SRS, steatosis reduction supplements
- TG, triglyceride
- ischemia-reperfusion injury
- liver transplantation
- machine perfusion
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Affiliation(s)
- Laura Ioana Mazilescu
- Ajmera Transplant Program, Toronto General Hospital, Ontario, Canada
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of General, Visceral, and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Markus Selzner
- Ajmera Transplant Program, Toronto General Hospital, Ontario, Canada
| | - Nazia Selzner
- Ajmera Transplant Program, Toronto General Hospital, Ontario, Canada
- Corresponding author. Address: Multi-Organ Transplant Program, Toronto General Hospital, 585 University Avenue, 11 PMB-178 Toronto, ON, Canada M5G 2N2.
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Zhao M, Chen S, Ji X, Shen X, You J, Liang X, Yin H, Zhao L. Current innovations in nutraceuticals and functional foods for intervention of non-alcoholic fatty liver disease. Pharmacol Res 2021; 166:105517. [PMID: 33636349 DOI: 10.1016/j.phrs.2021.105517] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 01/27/2021] [Accepted: 02/21/2021] [Indexed: 02/07/2023]
Abstract
As innovations in global agricultural production and food trading systems lead to major dietary shifts, high morbidity rates from non-alcoholic fatty liver disease (NAFLD), accompanied by elevated risk of lipid metabolism-related complications, has emerged as a growing problem worldwide. Treatment and prevention of NAFLD and chronic liver disease depends on the availability of safe, effective, and diverse therapeutic agents, the development of which is urgently needed. Supported by a growing body of evidence, considerable attention is now focused on interventional approaches that combines nutraceuticals and functional foods. In this review, we summarize the pathological progression of NAFLD and discuss the beneficial effects of nutraceuticals and the active ingredients in functional foods. We also describe the underlying mechanisms of these compounds in the intervention of NAFLD, including their effects on regulation of lipid homeostasis, activation of signaling pathways, and their role in gut microbial community dynamics and the gut-liver axis. In order to identify novel targets for treatment of lipid metabolism-related diseases, this work broadly explores the molecular mechanism linking nutraceuticals and functional foods, host physiology, and gut microbiota. Additionally, the limitations in existing knowledge and promising research areas for development of active interventions and treatments against NAFLD are discussed.
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Affiliation(s)
- Mengyao Zhao
- School of Biotechnology, State Key Laboratory of Bioreactor Engineering, R&D Center of Separation and Extraction Technology in Fermentation Industry, East China University of Science and Technology, Shanghai 200237, China; Shanghai Collaborative Innovation Center for Biomanufacturing Technology (SCICBT), Shanghai 200237, China
| | - Shumin Chen
- School of Biotechnology, State Key Laboratory of Bioreactor Engineering, R&D Center of Separation and Extraction Technology in Fermentation Industry, East China University of Science and Technology, Shanghai 200237, China
| | - Xiaoguo Ji
- School of Biotechnology, State Key Laboratory of Bioreactor Engineering, R&D Center of Separation and Extraction Technology in Fermentation Industry, East China University of Science and Technology, Shanghai 200237, China
| | - Xin Shen
- School of Biotechnology, State Key Laboratory of Bioreactor Engineering, R&D Center of Separation and Extraction Technology in Fermentation Industry, East China University of Science and Technology, Shanghai 200237, China
| | - Jiangshan You
- School of Biotechnology, State Key Laboratory of Bioreactor Engineering, R&D Center of Separation and Extraction Technology in Fermentation Industry, East China University of Science and Technology, Shanghai 200237, China
| | - Xinyi Liang
- School of Biotechnology, State Key Laboratory of Bioreactor Engineering, R&D Center of Separation and Extraction Technology in Fermentation Industry, East China University of Science and Technology, Shanghai 200237, China
| | - Hao Yin
- Organ Transplant Center, Shanghai Changzheng Hospital, Shanghai 200003, China.
| | - Liming Zhao
- School of Biotechnology, State Key Laboratory of Bioreactor Engineering, R&D Center of Separation and Extraction Technology in Fermentation Industry, East China University of Science and Technology, Shanghai 200237, China; School of Life Science, Shandong University of Technology, Zibo, Shandong 255000, China; Shanghai Collaborative Innovation Center for Biomanufacturing Technology (SCICBT), Shanghai 200237, China.
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The influence of PM 2.5 exposure on non-alcoholic fatty liver disease. Life Sci 2021; 270:119135. [PMID: 33513397 DOI: 10.1016/j.lfs.2021.119135] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/11/2021] [Accepted: 01/20/2021] [Indexed: 02/07/2023]
Abstract
Emerging studies have pointed to a significant relationship between exposure to ambient fine particulate matter (aerodynamic diameter < 2.5 μm, PM2.5) and the incidence of non-alcoholic fatty liver disease (NAFLD). By referring to previous studies on the pathogenesis of NAFLD and PM2.5 exposure-induced metabolic damage, we summarized the possible mediating pathways through which PM2.5 exposure can cause the phenotype and progression of NAFLD. Crucially, PM2.5 exposure is considered to have an impact on the classic hypothesis "multiple hits" of NAFLD. In addition, we also concluded that exposure to PM2.5 can promote the development of NAFLD by destroying the intestinal epithelium and microbiotic homeostasis, triggering endoplasmic reticulum stress, inducing abnormal expression of specific microRNA or inflammatory factors.
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50
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Mueller AM, Kleemann R, Gart E, van Duyvenvoorde W, Verschuren L, Caspers M, Menke A, Krömmelbein N, Salic K, Burmeister Y, Seilheimer B, Morrison MC. Cholesterol Accumulation as a Driver of Hepatic Inflammation Under Translational Dietary Conditions Can Be Attenuated by a Multicomponent Medicine. Front Endocrinol (Lausanne) 2021; 12:601160. [PMID: 33815271 PMCID: PMC8014004 DOI: 10.3389/fendo.2021.601160] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 02/04/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is characterised by dysfunctional lipid metabolism and cholesterol homeostasis, and a related chronic inflammatory response. NAFLD has become the most common cause of chronic liver disease in many countries, and its prevalence continues to rise in parallel with increasing rates of obesity. Here, we evaluated the putative NAFLD-attenuating effects of a multicomponent medicine consisting of 24 natural ingredients: Hepar compositum (HC-24). METHODS Ldlr-/-.Leiden mice were fed a high-fat diet (HFD) with a macronutrient composition and cholesterol content comparable to human diets for 24 weeks to induce obesity-associated metabolic dysfunction, including hepatic steatosis and inflammation. HC-24 or vehicle control was administered intraperitoneally 3 times/week (1.5 ml/kg) for the last 18 weeks of the study. Histological analyses of liver and adipose tissue were combined with extensive hepatic transcriptomics analysis. Transcriptomics results were further substantiated with ELISA, immunohistochemical and liver lipid analyses. RESULTS HFD feeding induced obesity and metabolic dysfunction including adipose tissue inflammation and increased gut permeability. In the liver, HFD-feeding resulted in a disturbance of cholesterol homeostasis and an associated inflammatory response. HC-24 did not affect body weight, metabolic risk factors, adipose tissue inflammation or gut permeability. While HC-24 did not alter total liver steatosis, there was a pronounced reduction in lobular inflammation in HC-24-treated animals, which was associated with modulation of genes and proteins involved in inflammation (e.g., neutrophil chemokine Cxcl1) and cholesterol homeostasis (i.e., predicted effect on 'cholesterol' as an upstream regulator, based on gene expression changes associated with cholesterol handling). These effects were confirmed by CXCL1 ELISA, immunohistochemical staining of neutrophils and biochemical analysis of hepatic free cholesterol content. Intrahepatic free cholesterol levels were found to correlate significantly with the number of inflammatory aggregates in the liver, thereby providing a potential rationale for the observed anti-inflammatory effects of HC-24. CONCLUSIONS Free cholesterol accumulates in the liver of Ldlr-/-.Leiden mice under physiologically translational dietary conditions, and this is associated with the development of hepatic inflammation. The multicomponent medicine HC-24 reduces accumulation of free cholesterol and has molecular and cellular anti-inflammatory effects in the liver.
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Affiliation(s)
| | - Robert Kleemann
- Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), Leiden, Netherlands
- Department of Vascular Surgery, Leiden University Medical Center, Leiden, Netherlands
| | - Eveline Gart
- Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), Leiden, Netherlands
- Human and Animal Physiology, Wageningen University, Wageningen, Netherlands
| | - Wim van Duyvenvoorde
- Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), Leiden, Netherlands
| | - Lars Verschuren
- Department of Microbiology and Systems Biology, The Netherlands Organisation for Applied Scientific Research (TNO), Leiden, Netherlands
| | - Martien Caspers
- Department of Microbiology and Systems Biology, The Netherlands Organisation for Applied Scientific Research (TNO), Leiden, Netherlands
| | - Aswin Menke
- Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), Leiden, Netherlands
| | | | - Kanita Salic
- Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), Leiden, Netherlands
| | | | - Bernd Seilheimer
- Systems Research and Development, Heel GmbH, Baden-Baden, Germany
| | - Martine C. Morrison
- Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), Leiden, Netherlands
- Human and Animal Physiology, Wageningen University, Wageningen, Netherlands
- *Correspondence: Martine C. Morrison,
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