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Yan M, Zhang S, Liang P, Huang H, Li G, A R, Wu H. Research Hotspots and Frontier Trends of Autophagy in Diabetic Cardiomyopathy From 2014 to 2024: A Bibliometric Analysis. J Multidiscip Healthc 2025; 18:837-860. [PMID: 39963325 PMCID: PMC11831922 DOI: 10.2147/jmdh.s507217] [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: 12/04/2024] [Accepted: 02/04/2025] [Indexed: 02/20/2025] Open
Abstract
Objective In recent years, the investigation of autophagy mechanisms has gained prominence as a key focus for understanding the pathogenesis and therapeutic potential of diabetic cardiomyopathy. This study aims to present an overview of the current state, major research areas, and emerging trends in autophagy related to diabetic cardiomyopathy through bibliometric analysis, offering a scientific foundation for future research. Methods The Web of Science Core Collection served as the data source for this study, from which full-text publications were extracted. Using CiteSpace 6.3.R1, VOSviewer v1.6.18, and R-Bibliometrix, the analysis evaluated research output across dimensions such as subjects, countries, institutions, journals, authors, and co-cited references, generating a comprehensive visual map. Results A total of 367 publications met the inclusion criteria. Between 2014 and 2024, the volume of articles demonstrated a consistent upward trajectory. Research on autophagy in diabetic cardiomyopathy predominantly spans the disciplines of biology and medicine. China and the Fourth Military Medical University emerged as leading contributors among 41 countries and 505 institutions. Sun Dongdong was identified as the most prolific author, while Jia GH was the most frequently cited. Key journals in this field include Biochimica et Biophysica Acta - Molecular Basis of Disease and Frontiers in Cardiovascular Medicine, while Circulation Research recorded the highest number of co-citations. The most cited reference was an experimental study by Xie ZL. Current research focuses on autophagy, diabetic cardiomyopathy, oxidative stress, and their underlying mechanisms. Conclusion Research on the role of autophagy in diabetic cardiomyopathy has reached a stable phase of development. Future investigations should prioritize mechanistic studies and emphasize the clinical application of novel pharmacological interventions, thereby advancing therapeutic strategies and contributing to improved human health outcomes.
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Affiliation(s)
- Mei Yan
- Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China
- Shanghai University of Traditional Chinese Medicine Shenzhen Hospital, Shenzhen,People’s Republic of China
| | - Shizhao Zhang
- Shanghai University of Traditional Chinese Medicine Shenzhen Hospital, Shenzhen,People’s Republic of China
- Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Pengpeng Liang
- Shanghai University of Traditional Chinese Medicine Shenzhen Hospital, Shenzhen,People’s Republic of China
- Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Hai Huang
- Shanghai University of Traditional Chinese Medicine Shenzhen Hospital, Shenzhen,People’s Republic of China
| | - Guiyun Li
- Shanghai University of Traditional Chinese Medicine Shenzhen Hospital, Shenzhen,People’s Republic of China
| | - Ruhan A
- Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China
| | - Hongyan Wu
- Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China
- Shanghai University of Traditional Chinese Medicine Shenzhen Hospital, Shenzhen,People’s Republic of China
- Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
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An H, Jang Y, Choi J, Hur J, Kim S, Kwon Y. New Insights into AMPK, as a Potential Therapeutic Target in Metabolic Dysfunction-Associated Steatotic Liver Disease and Hepatic Fibrosis. Biomol Ther (Seoul) 2025; 33:18-38. [PMID: 39702310 PMCID: PMC11704404 DOI: 10.4062/biomolther.2024.188] [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: 10/16/2024] [Revised: 12/08/2024] [Accepted: 12/10/2024] [Indexed: 12/21/2024] Open
Abstract
AMP-activated protein kinase (AMPK) activators have garnered significant attention for their potential to prevent the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) into liver fibrosis and to fundamentally improve liver function. The broad spectrum of pathways regulated by AMPK activators makes them promising alternatives to conventional liver replacement therapies and the limited pharmacological treatments currently available. In this study, we aim to illustrate the newly detailed multiple mechanisms of MASLD progression based on the multiple-hit hypothesis. This model posits that impaired lipid metabolism, combined with insulin resistance and metabolic imbalance, initiates inflammatory cascades, gut dysbiosis, and the accumulation of toxic metabolites, ultimately promoting fibrosis and accelerating MASLD progression to irreversible hepatocellular carcinoma (HCC). AMPK plays a multifaceted protective role against these pathological conditions by regulating several key downstream signaling pathways. It regulates biological effectors critical to metabolic and inflammatory responses, such as SIRT1, Nrf2, mTOR, and TGF-β, through complex and interrelated mechanisms. Due to these intricate connections, AMPK's role is pivotal in managing metabolic and inflammatory disorders. In this review, we demonstrate the specific roles of AMPK and its related pathways. Several agents directly activate AMPK by binding as agonists, while some others indirectly activate AMPK by modulating upstream molecules, including adiponectin, LKB1, and the AMP: ATP ratio. As AMPK activators can target each stage of MASLD progression, the development of AMPK activators offers immense potential to expand therapeutic strategies for liver diseases such as MASH, MASLD, and liver fibrosis.
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Affiliation(s)
- Haeun An
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Yerin Jang
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Jungin Choi
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Juhee Hur
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Seojeong Kim
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Youngjoo Kwon
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
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Zhu W, Lusk JA, Pascua V, Djukovic D, Raftery D. Combination of low glucose and SCD1 inhibition impairs cancer metabolic plasticity and growth in MCF-7 cancer cells: a comprehensive metabolomic and lipidomic analysis. Metabolomics 2024; 20:112. [PMID: 39369160 DOI: 10.1007/s11306-024-02179-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 09/19/2024] [Indexed: 10/07/2024]
Abstract
BACKGROUND Cancer cells exhibit remarkable metabolic plasticity, enabling them to adapt to fluctuating nutrient conditions. This study investigates the impact of a combination of low glucose levels and inhibition of stearoyl-CoA desaturase 1 (SCD1) using A939572 on cancer metabolic plasticity and growth. METHODS A comprehensive metabolomic and lipidomic analysis was conducted to unravel the intricate changes in cellular metabolites and lipids. MCF-7 cells were subjected to low glucose conditions, and SCD1 was inhibited using A939572. The resulting alterations in metabolic pathways and lipid profiles were explored to elucidate the synergistic effects on cancer cell physiology. RESULTS The combination of low glucose and A939572-induced SCD1 inhibition significantly impaired cancer cell metabolic plasticity. Metabolomic analysis highlighted shifts in key glycolytic and amino acid pathways, indicating the cells' struggle to adapt to restricted glucose availability. Lipidomic profiling revealed alterations in lipid composition, implying disruptions in membrane integrity and signaling cascades. CONCLUSION Our findings underscore the critical roles of glucose availability and SCD1 activity in sustaining cancer metabolic plasticity and growth. Simultaneously targeting these pathways emerges as a promising strategy to impede cancer progression. The comprehensive metabolomic and lipidomic analysis provides a detailed roadmap of molecular alterations induced by this combination treatment, that may help identify potential therapeutic targets.
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Affiliation(s)
- Wentao Zhu
- Northwest Metabolomics Research Center, Seattle, WA, USA
- Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, USA
| | - John A Lusk
- Northwest Metabolomics Research Center, Seattle, WA, USA
- Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, USA
| | - Vadim Pascua
- Northwest Metabolomics Research Center, Seattle, WA, USA
- Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, USA
| | - Danijel Djukovic
- Northwest Metabolomics Research Center, Seattle, WA, USA
- Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, USA
| | - Daniel Raftery
- Northwest Metabolomics Research Center, Seattle, WA, USA.
- Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, USA.
- Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA.
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Cohen ED, Roethlin K, Yee M, Woeller CF, Brookes PS, Porter GA, O'Reilly MA. PPARγ drives mitochondrial stress signaling and the loss of atrial cardiomyocytes in newborn mice exposed to hyperoxia. Redox Biol 2024; 76:103351. [PMID: 39276392 PMCID: PMC11417530 DOI: 10.1016/j.redox.2024.103351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 08/22/2024] [Accepted: 09/09/2024] [Indexed: 09/17/2024] Open
Abstract
Diastolic dysfunction is increasingly common in preterm infants exposed to supplemental oxygen (hyperoxia). Previous studies in neonatal mice showed hyperoxia suppresses fatty acid synthesis genes required for proliferation and survival of atrial cardiomyocytes. The loss of atrial cardiomyocytes creates a hypoplastic left atrium that inappropriately fills the left ventricle during diastole. Here, we show that hyperoxia stimulates adenosine monophosphate-activated kinase (AMPK) and peroxisome proliferator activated receptor-gamma (PPARγ) signaling in atrial cardiomyocytes. While both pathways can regulate lipid homeostasis, PPARγ was the primary pathway by which hyperoxia inhibits fatty acid gene expression and inhibits proliferation of mouse atrial HL-1 cells. It also enhanced the toxicity of hyperoxia by increasing expression of activating transcription factor (ATF) 5 and other mitochondrial stress response genes. Silencing PPARγ signaling restored proliferation and survival of HL-1 cells as well as atrial cardiomyocytes in neonatal mice exposed to hyperoxia. Our findings reveal PPARγ enhances the toxicity of hyperoxia on atrial cardiomyocytes, thus suggesting inhibitors of PPARγ signaling may prevent diastolic dysfunction in preterm infants.
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Affiliation(s)
- E David Cohen
- Department of Pediatrics, School of Medicine and Dentistry, The University of Rochester, Rochester, NY 14642, USA.
| | - Kyle Roethlin
- Department of Pediatrics, School of Medicine and Dentistry, The University of Rochester, Rochester, NY 14642, USA
| | - Min Yee
- Department of Pediatrics, School of Medicine and Dentistry, The University of Rochester, Rochester, NY 14642, USA
| | - Collynn F Woeller
- Department of Ophthalmology, School of Medicine and Dentistry, The University of Rochester, Rochester, NY 14642, USA
| | - Paul S Brookes
- Department of Anesthesiology, School of Medicine and Dentistry, The University of Rochester, Rochester, NY 14642, USA
| | - George A Porter
- Department of Pediatrics, School of Medicine and Dentistry, The University of Rochester, Rochester, NY 14642, USA
| | - Michael A O'Reilly
- Department of Pediatrics, School of Medicine and Dentistry, The University of Rochester, Rochester, NY 14642, USA.
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Feng X, Zhang R, Yang Z, Zhang K, Xing J. Mechanism of Metabolic Dysfunction-associated Steatotic Liver Disease: Important role of lipid metabolism. J Clin Transl Hepatol 2024; 12:815-826. [PMID: 39280069 PMCID: PMC11393839 DOI: 10.14218/jcth.2024.00019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 08/02/2024] [Accepted: 08/08/2024] [Indexed: 09/18/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, has a high global prevalence and can progress to metabolic dysfunction-associated steatohepatitis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of MASLD is primarily driven by disturbances in hepatic lipid metabolism, involving six key processes: increased hepatic fatty acid uptake, enhanced fatty acid synthesis, reduced oxidative degradation of fatty acids, increased cholesterol uptake, elevated cholesterol synthesis, and increased bile acid synthesis. Consequently, maintaining hepatic lipid metabolic homeostasis is essential for effective MASLD management. Numerous novel molecules and Chinese proprietary medicines have demonstrated promising therapeutic potential in treating MASLD, primarily by inhibiting lipid synthesis and promoting lipid oxidation. In this review, we summarized recent research on MASLD, elucidated the molecular mechanisms by which lipid metabolism disorders contribute to MASLD pathogenesis, and discussed various lipid metabolism-targeted therapeutic approaches for MASLD.
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Affiliation(s)
- Xiaoxi Feng
- Department of Digestive Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Rutong Zhang
- Department of Digestive Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Zhenye Yang
- Department of Digestive Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Kaiguang Zhang
- Department of Digestive Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Jun Xing
- Department of Digestive Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
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Bjørndal B, Tungland SL, Bohov P, Sydnes MO, Dankel SN, Madsen L, Berge RK. Meldonium-induced steatosis is associated with increased delta 6 desaturation and reduced elongation of n-6 polyunsaturated fatty acids. LIVER RESEARCH 2024; 8:152-164. [PMID: 39957749 PMCID: PMC11771272 DOI: 10.1016/j.livres.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 06/24/2024] [Accepted: 09/03/2024] [Indexed: 02/18/2025]
Abstract
Background and objective Metabolic associated fatty liver disease (MAFLD) is associated with abnormal lipid metabolism. Mitochondrial dysfunction is considered an important factor in the onset of MAFLD, whereas altered fatty acid composition has been linked to the severity of the disease. Tetradecylthioacetic acid (TTA), shown to induce mitochondrial proliferation and alter the fatty acid composition, was used to delay the accumulation of hepatic triacylglycerol. This study aimed to evaluate how impaired mitochondrial fatty acid beta-oxidation affects fatty acid composition by incorporating meldonium into a high-carbohydrate diet. Methods C57BL/6 mice (n = 40) were fed high-carbohydrate diets supplemented with meldonium, TTA, or a combination of meldonium and TTA for 21 days. Lipid levels were determined in liver samples, and fatty acid composition was measured in both liver and plasma samples. Additionally, desaturase and elongase activities were estimated. The hepatic activities and gene expression levels of enzymes involved in fatty acid metabolism were measured in liver samples, whereas carnitines, their precursors, and acylcarnitines were measured in plasma samples. Results The meldonium-induced depletion of L-carnitine and mitochondrial fatty acid oxidation was confirmed by reduced plasma levels of L-carnitine and acylcarnitines. Principal component analyses of the hepatic fatty acid composition revealed clustering dependent on meldonium and TTA. The meldonium-induced increase in hepatic triacylglycerol levels correlated negatively with estimated activities of elongases and was associated with higher estimated activities of delta-6 desaturase (D6D; C18:4n-3/C18:3n-3 and C18:3n-6/C18:2n-6), and increased circulating levels of C18:4n-3 and C18:3n-6 (gamma-linolenic acid). TTA mitigated meldonium-induced triacylglycerol levels by 80% and attenuated the estimated D6D activities, and elongation of n-6 polyunsaturated fatty acids (PUFAs). TTA also attenuated the meldonium-mediated reduction of C24:1n-9 (nervonic acid), possibly by stimulating Elovl 5 and increased elongation of erucic acid (C22:1n-9) to nervonic acid. The hepatic levels of nervonic acid and the estimated activity of n-6 PUFA elongation correlated negatively with the hepatic triacylglycerol levels, while the estimated activities of D6D correlated positively. Conclusion Circulating levels of gamma-linolenic acid, along with reduced estimated elongation of n-6 PUFAs and D6D desaturation activities, were associated with hepatic triacylglycerol levels.
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Affiliation(s)
- Bodil Bjørndal
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Sports, Physical Activity and Food, Western Norway University of Applied Sciences, Bergen, Norway
| | - Siri Lunde Tungland
- Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway
| | - Pavol Bohov
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Magne O. Sydnes
- Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway
| | - Simon N. Dankel
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Lise Madsen
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Rolf K Berge
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
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Mahmoudi A, Jalili A, Butler AE, Aghaee-Bakhtiari SH, Jamialahmadi T, Sahebkar A. Exploration of the Key Genes Involved in Non-alcoholic Fatty Liver Disease and Possible MicroRNA Therapeutic Targets. J Clin Exp Hepatol 2024; 14:101365. [PMID: 38433957 PMCID: PMC10904918 DOI: 10.1016/j.jceh.2024.101365] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 02/11/2024] [Indexed: 03/05/2024] Open
Abstract
Background MicroRNAs (miRNAs) are promising therapeutic agents for non-alcoholic fatty liver disease (NAFLD). This study aimed to identify key genes/proteins involved in NAFLD pathogenesis and progression and to evaluate miRNAs influencing their expression. Methods Gene expression profiles from datasets GSE151158, GSE163211, GSE135251, GSE167523, GSE46300, and online databases were analyzed to identify significant NAFLD-related genes. Then, protein-protein interaction networks and module analysis identified hub genes/proteins, which were validated using real-time PCR in oleic acid-treated HepG2 cells. Functional enrichment analysis evaluated signaling pathways and biological processes. Gene-miRNA interaction networks identified miRNAs targeting critical NAFLD genes. Results The most critical overexpressed hub genes/proteins included: TNF, VEGFA, TLR4, CYP2E1, ACE, SCD, FASN, SREBF2, and TGFB1 based on PPI network analysis, of which TNF, TLR4, SCD, FASN, SREBF2, and TGFB1 were up-regulated in oleic acid-treated HepG2 cells. Functional enrichment analysis for biological processes highlighted programmed necrotic cell death, lipid metabolic process response to reactive oxygen species, and inflammation. In the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, the highest adjusted P-value signaling pathways encompassed AGE-RAGE in diabetic complications, TNF, and HIF-1 signaling pathways. In gene-miRNA network analysis, miR-16 and miR-124 were highlighted as the miRNAs exerting the most influence on important NAFLD-related genes. Conclusion In silico analyses identified NAFLD therapeutic targets and miRNA candidates to guide further experimental investigation.
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Affiliation(s)
- Ali Mahmoudi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Iran
| | - Amin Jalili
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Iran
| | | | - Seyed H. Aghaee-Bakhtiari
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Iran
- Bioinformatics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Tannaz Jamialahmadi
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Cui Y, Man S, Tao J, Liu Y, Ma L, Guo L, Huang L, Liu C, Gao W. The lipid droplet in cancer: From being a tumor-supporting hallmark to clinical therapy. Acta Physiol (Oxf) 2024; 240:e14087. [PMID: 38247395 DOI: 10.1111/apha.14087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 10/18/2023] [Accepted: 01/01/2024] [Indexed: 01/23/2024]
Abstract
INTRODUCTION Abnormal lipid metabolism, one of the hallmarks in cancer, has gradually emerged as a novel target for cancer treatment. As organelles that store and release excess lipids, lipid droplets (LDs) resemble "gears" and facilitate cancer development in the body. AIM This review discusses the life cycle of LDs, the relationship between abnormal LDs and cancer hallmarks, and the application of LDs in theragnostic and clinical contexts to provide a contemporary understanding of the role of LDs in cancer. METHODS A systematic literature search was conducted in PubMed and SPORTDiscus. Retrieve and summarize clinical trials of drugs that target proteins associated with LD formation using the Clinical Trials website. Create a schematic diagram of lipid droplets in the tumor microenvironment using Adobe Illustrator. CONCLUSION As one of the top ten hallmarks of cancer, abnormal lipid metabolism caused by excessive generation of LDs interrelates with other hallmarks. The crosstalk between excessive LDs and intracellular free fatty acids (FFAs) promotes an inflammatory environment that supports tumor growth. Moreover, LDs contribute to cancer metastasis and cell death resistance in vivo. Statins, as HMGCR inhibitors, are promising to be the pioneering commercially available anti-cancer drugs that target LD formation.
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Affiliation(s)
- Yingfang Cui
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
| | - Shuli Man
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
| | - Jiejing Tao
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
| | - Yu Liu
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
| | - Long Ma
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
| | - Lanping Guo
- National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Luqi Huang
- National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Changxiao Liu
- State Key Laboratory of Drug Release Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research Co and Ltd., Tianjin, China
| | - Wenyuan Gao
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
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Wu Y, Pu X, Wang X, Xu M. Reprogramming of lipid metabolism in the tumor microenvironment: a strategy for tumor immunotherapy. Lipids Health Dis 2024; 23:35. [PMID: 38302980 PMCID: PMC10832245 DOI: 10.1186/s12944-024-02024-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 01/18/2024] [Indexed: 02/03/2024] Open
Abstract
Lipid metabolism in cancer cells has garnered increasing attention in recent decades. Cancer cells thrive in hypoxic conditions, nutrient deficiency, and oxidative stress and cannot be separated from alterations in lipid metabolism. Therefore, cancer cells exhibit increased lipid metabolism, lipid uptake, lipogenesis and storage to adapt to a progressively challenging environment, which contribute to their rapid growth. Lipids aid cancer cell activation. Cancer cells absorb lipids with the help of transporter and translocase proteins to obtain energy. Abnormal levels of a series of lipid synthases contribute to the over-accumulation of lipids in the tumor microenvironment (TME). Lipid reprogramming plays an essential role in the TME. Lipids are closely linked to several immune cells and their phenotypic transformation. The reprogramming of tumor lipid metabolism further promotes immunosuppression, which leads to immune escape. This event significantly affects the progression, treatment, recurrence, and metastasis of cancer. Therefore, the present review describes alterations in the lipid metabolism of immune cells in the TME and examines the connection between lipid metabolism and immunotherapy.
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Affiliation(s)
- Yuting Wu
- Department of Gastroenterology, Jiangsu University Cancer Institute, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Jingkou, Zhenjiang, Jiangsu, 212001, P. R. China
- Digestive Disease Research Institute of Jiangsu University, Zhenjiang, 212001, Jiangsu, China
| | - Xi Pu
- Department of Gastroenterology, Jiangsu University Cancer Institute, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Jingkou, Zhenjiang, Jiangsu, 212001, P. R. China
- Digestive Disease Research Institute of Jiangsu University, Zhenjiang, 212001, Jiangsu, China
| | - Xu Wang
- Department of Radiation Oncology, Institute of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China.
- Department of Radiation Oncology, Jiangsu University Cancer Institute, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Jingkou, Zhenjiang, Jiangsu, 212001, P. R. China.
| | - Min Xu
- Department of Gastroenterology, Jiangsu University Cancer Institute, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Jingkou, Zhenjiang, Jiangsu, 212001, P. R. China.
- Digestive Disease Research Institute of Jiangsu University, Zhenjiang, 212001, Jiangsu, China.
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Ren Q, Sun Q, Fu J. Dysfunction of autophagy in high-fat diet-induced non-alcoholic fatty liver disease. Autophagy 2024; 20:221-241. [PMID: 37700498 PMCID: PMC10813589 DOI: 10.1080/15548627.2023.2254191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 08/24/2023] [Indexed: 09/14/2023] Open
Abstract
ABBREVIATIONS ACOX1: acyl-CoA oxidase 1; ADH5: alcohol dehydrogenase 5 (class III), chi polypeptide; ADIPOQ: adiponectin, C1Q and collagen domain containing; ATG: autophagy related; BECN1: beclin 1; CRTC2: CREB regulated transcription coactivator 2; ER: endoplasmic reticulum; F2RL1: F2R like trypsin receptor 1; FA: fatty acid; FOXO1: forkhead box O1; GLP1R: glucagon like peptide 1 receptor; GRK2: G protein-coupled receptor kinase 2; GTPase: guanosine triphosphatase; HFD: high-fat diet; HSCs: hepatic stellate cells; HTRA2: HtrA serine peptidase 2; IRGM: immunity related GTPase M; KD: knockdown; KDM6B: lysine demethylase 6B; KO: knockout; LAMP2: lysosomal associated membrane protein 2; LAP: LC3-associated phagocytosis; LDs: lipid droplets; Li KO: liver-specific knockout; LSECs: liver sinusoidal endothelial cells; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP3K5: mitogen-activated protein kinase kinase kinase 5; MED1: mediator complex subunit 1; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin complex 1; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; NFE2L2: NFE2 like bZIP transcription factor 2; NOS3: nitric oxide synthase 3; NR1H3: nuclear receptor subfamily 1 group H member 3; OA: oleic acid; OE: overexpression; OSBPL8: oxysterol binding protein like 8; PA: palmitic acid; RUBCNL: rubicon like autophagy enhancer; PLIN2: perilipin 2; PLIN3: perilipin 3; PPARA: peroxisome proliferator activated receptor alpha; PRKAA2/AMPK: protein kinase AMP-activated catalytic subunit alpha 2; RAB: member RAS oncogene family; RPTOR: regulatory associated protein of MTOR complex 1; SCD: stearoyl-CoA desaturase; SIRT1: sirtuin 1; SIRT3: sirtuin 3; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1;SREBF2: sterol regulatory element binding transcription factor 2; STING1: stimulator of interferon response cGAMP interactor 1; STX17: syntaxin 17; TAGs: triacylglycerols; TFEB: transcription factor EB; TP53/p53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; VMP1: vacuole membrane protein 1.
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Affiliation(s)
- Qiannan Ren
- Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Qiming Sun
- International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China
- Department of Biochemistry, and Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Junfen Fu
- Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
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11
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Zamanian MY, Sadeghi Ivraghi M, Khachatryan LG, Vadiyan DE, Bali HY, Golmohammadi M. A review of experimental and clinical studies on the therapeutic effects of pomegranate ( Punica granatum) on non-alcoholic fatty liver disease: Focus on oxidative stress and inflammation. Food Sci Nutr 2023; 11:7485-7503. [PMID: 38107091 PMCID: PMC10724645 DOI: 10.1002/fsn3.3713] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 09/06/2023] [Accepted: 09/12/2023] [Indexed: 12/19/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is frequently linked to metabolic disorders and is prevalent in obese and diabetic patients. The pathophysiology of NAFLD involves multiple factors, including insulin resistance (IR), oxidative stress (OS), inflammation, and genetic predisposition. Recently, there has been an emphasis on the use of herbal remedies with many people around the world resorting to phytonutrients or nutraceuticals for treatment of numerous health challenges in various national healthcare settings. Pomegranate (Punica granatum) parts, such as juice, peel, seed and flower, have high polyphenol content and is well known for its antioxidant capabilities. Pomegranate polyphenols, such as hydrolyzable tannins, anthocyanins, and flavonoids, have high antioxidant capabilities that can help lower the OS and inflammation associated with NAFLD. The study aimed to investigate whether pomegranate parts could attenuate OS, inflammation, and other risk factors associated with NAFLD, and ultimately prevent the development of the disease. The findings of this study revealed that: 1. pomegranate juice contains hypoglycemic qualities that can assist manage blood sugar levels, which is vital for avoiding and treating NAFLD. 2. Polyphenols from pomegranate flowers increase paraoxonase 1 (PON1) mRNA and protein levels in the liver, which can help protect liver enzymes and prevent NAFLD. 3. Punicalagin (PU) is one of the major ellagitannins found in pomegranate, and PU-enriched pomegranate extract (PE) has been shown to inhibit HFD-induced hyperlipidemia and hepatic lipid deposition in rats. 4. Pomegranate fruit consumption, which is high in antioxidants, can decrease the activity of AST and ALT (markers of liver damage), lower TNF-α (a marker of inflammation), and improve overall antioxidant capacity in NAFLD patients. Overall, the polyphenols in pomegranate extracts have antioxidant, anti-inflammatory, hypoglycemic, and protective effects on liver enzymes, which can help prevent and manage NAFLD effects on liver enzymes, which can help prevent and manage NAFLD.
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Affiliation(s)
- Mohammad Yassin Zamanian
- Department of Physiology, School of MedicineHamadan University of Medical SciencesHamadanIran
- Department of Pharmacology and Toxicology, School of PharmacyHamadan University of Medical SciencesHamadanIran
| | | | - Lusine G. Khachatryan
- Department of Pediatric Diseases, N.F. Filatov Clinical Institute of Children's HealthI.M. Sechenov First Moscow State Medical University (Sechenov University)MoscowRussia
| | - Diana E. Vadiyan
- Institute of Dentistry, Department of Pediatric, Preventive Dentistry and OrthodonticsI.M. Sechenov First Moscow State Medical University (Sechenov University)MoscowRussia
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12
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Zhang Y, Xu J, Zhou D, Ye T, Zhou P, Liu Z, Liu X, Wang Z, Hua T, Zhang Z, Sun Q. Swimming exercise ameliorates insulin resistance and nonalcoholic fatty liver by negatively regulating PPARγ transcriptional network in mice fed high fat diet. Mol Med 2023; 29:150. [PMID: 37907845 PMCID: PMC10617119 DOI: 10.1186/s10020-023-00740-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 10/16/2023] [Indexed: 11/02/2023] Open
Abstract
BACKGROUND Recent findings elucidated hepatic PPARγ functions as a steatogenic-inducer gene that activates de novo lipogenesis, and is involved in regulation of glucose homeostasis, lipid accumulation, and inflammation response. This study delved into a comprehensive analysis of how PPARγ signaling affects the exercise-induced improvement of insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD), along with its underlying mechanism. METHODS Chronic and acute swimming exercise intervention were conducted in each group mice. IR status was assessed by GTT and ITT assays. Serum inflammatory cytokines were detected by Elisa assays. PPARγ and its target genes expression were detected by qPCR assay. Relative protein levels were quantified via Western blotting. ChIP-qPCR assays were used to detect the enrichment of PPARγ on its target genes promoter. RESULTS Through an exploration of a high-fat diet (HFD)-induced IR and NAFLD model, both chronic and acute swimming exercise training led to significant reductions in body weight and visceral fat mass, as well as hepatic lipid accumulation. The exercise interventions also demonstrated a significant amelioration in IR and the inflammatory response. Meanwhile, swimming exercise significantly inhibited PPARγ and its target genes expression induced by HFD, containing CD36, SCD1 and PLIN2. Furthermore, swimming exercise presented significant modulation on regulatory factors of PPARγ expression and transcriptional activity. CONCLUSION The findings suggest that swimming exercise can improve lipid metabolism in IR and NAFLD, possibly through PPARγ signaling in the liver of mice.
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Affiliation(s)
- Yong Zhang
- Physiology laboratory of College of Life Sciences, Anhui Normal University, Wuhu, China
- the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Jie Xu
- Department of Hepatology, Affiliated Hospital of Panzhihua University, Panzhihua, China
| | - Di Zhou
- Physiology laboratory of College of Life Sciences, Anhui Normal University, Wuhu, China
| | - Tingting Ye
- Physiology laboratory of College of Life Sciences, Anhui Normal University, Wuhu, China
| | - Puqing Zhou
- Physiology laboratory of College of Life Sciences, Anhui Normal University, Wuhu, China
| | - Zuofeng Liu
- Department of Hepatology, Affiliated Hospital of Panzhihua University, Panzhihua, China
| | - Xinyuan Liu
- the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Zinan Wang
- the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Tianmiao Hua
- Physiology laboratory of College of Life Sciences, Anhui Normal University, Wuhu, China
| | - Zhenghao Zhang
- Department of Hematology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China.
| | - Qingyan Sun
- Physiology laboratory of College of Life Sciences, Anhui Normal University, Wuhu, China.
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13
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Luo C, Chen Y, Yin D, Yuan J. Effects of Different Dietary Starch Sources and Digestible Lysine Levels on Carcass Traits, Serum Metabolites, Liver Lipid and Breast Muscle Protein Metabolism in Broiler Chickens. Animals (Basel) 2023; 13:2104. [PMID: 37443902 DOI: 10.3390/ani13132104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 06/19/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
This study investigated the effects of digestible lysine (dLys) in different dietary starch sources on liver lipid metabolism and breast muscle protein metabolism in broiler chickens. The experimental design was a 3 × 3 two-factor completely randomized design. A total of 702 one-day-old male Arbor Acres Plus broilers were randomly divided into nine treatments of six replicate cages with thirteen birds each. The treatments consisted of three different starch sources (corn, cassava and waxy corn) with three different dLys levels (1.08%, 1.20% and 1.32%). The trial lasted from 1 to 21 days. Carcass traits, serum metabolites, breast muscle protein and liver lipid metabolism were evaluated. A significant interaction effect (p < 0.05) for dietary starch sources and dLys levels was noted in the percentage of abdominal fat and gene expression related to breast muscle protein metabolism throughout the experimental period. The waxy corn starch diet and a 1.08% dLys level in the diet increased both the percentage of abdominal fat (p < 0.01) and blood total cholesterol (p < 0.05) in the broilers. The waxy corn starch diet significantly upregulated the mRNA expressions of Eif4E, AMPK, FABP1, ACC and CPT1 (p < 0.05). The 1.32% dLys level significantly upregulated the mRNA expressions of mTOR, S6K1, Eif4E, AMPK and PPARα (p < 0.05) and significantly downregulated the mRNA expressions of MuRF and Atrogin-1 (p < 0.05). In summary, the waxy corn starch diet resulted in significantly higher expression levels of fat-synthesis-related genes than lipolysis-related genes, leading to abdominal fat deposition in broilers. Increasing the level of dLys in the diet increased the protein content in muscle by promoting protein synthesis and inhibiting protein degradation and also promoted the expression of lipolysis-related genes, thereby degrading the generation of abdominal fat in broilers. Our findings signify that increasing the dLys level to 1.32% when using the waxy corn starch diet could improve carcass traits.
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Affiliation(s)
- Caiwei Luo
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Yanhong Chen
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Dafei Yin
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
- College of Animal Husbandry and Veterinary Medicine, Shenyang Agricultural University, Shenyang 110866, China
| | - Jianmin Yuan
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
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14
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Mondal SA, Mann SN, van der Linden C, Sathiaseelan R, Kamal M, Das S, Bubak MP, Logan S, Miller BF, Stout MB. Metabolic benefits of 17α-estradiol in liver are partially mediated by ERβ in male mice. Sci Rep 2023; 13:9841. [PMID: 37330610 PMCID: PMC10276872 DOI: 10.1038/s41598-023-37007-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 06/14/2023] [Indexed: 06/19/2023] Open
Abstract
Metabolic dysfunction underlies several chronic diseases. Dietary interventions can reverse metabolic declines and slow aging but remaining compliant is difficult. 17α-estradiol (17α-E2) treatment improves metabolic parameters and slows aging in male mice without inducing significant feminization. We recently reported that estrogen receptor α is required for the majority of 17α-E2-mediated benefits in male mice, but that 17α-E2 also attenuates fibrogenesis in liver, which is regulated by estrogen receptor β (ERβ)-expressing hepatic stellate cells (HSC). The current studies sought to determine if 17α-E2-mediated benefits on systemic and hepatic metabolism are ERβ-dependent. We found that 17α-E2 treatment reversed obesity and related systemic metabolic sequela in both male and female mice, but this was partially blocked in female, but not male, ERβKO mice. ERβ ablation in male mice attenuated 17α-E2-mediated benefits on hepatic stearoyl-coenyzme A desaturase 1 (SCD1) and transforming growth factor β1 (TGF-β1) production, which play critical roles in HSC activation and liver fibrosis. We also found that 17α-E2 treatment suppresses SCD1 production in cultured hepatocytes and hepatic stellate cells, indicating that 17α-E2 directly signals in both cell-types to suppress drivers of steatosis and fibrosis. We conclude that ERβ partially controls 17α-E2-mediated benefits on systemic metabolic regulation in female, but not male, mice, and that 17α-E2 likely signals through ERβ in HSCs to attenuate pro-fibrotic mechanisms.
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Affiliation(s)
- Samim Ali Mondal
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Chapman S212, Oklahoma City, OK, 73104, USA
| | - Shivani N Mann
- Department of Neuroscience, University of Arizona, Tucson, AZ, USA
| | - Carl van der Linden
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Chapman S212, Oklahoma City, OK, 73104, USA
| | - Roshini Sathiaseelan
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Chapman S212, Oklahoma City, OK, 73104, USA
- Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Maria Kamal
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Snehasis Das
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Matthew P Bubak
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Chapman S212, Oklahoma City, OK, 73104, USA
| | - Sreemathi Logan
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Benjamin F Miller
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Chapman S212, Oklahoma City, OK, 73104, USA
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK, USA
| | - Michael B Stout
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Chapman S212, Oklahoma City, OK, 73104, USA.
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK, USA.
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15
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Feng G, Zhang X, Zhang L, Liu WY, Geng S, Yuan HY, Sha JC, Wang XD, Sun DQ, Targher G, Byrne CD, Zheng TL, Ye F, Zheng MH, Chai J. Novel urinary protein panels for the non-invasive diagnosis of non-alcoholic fatty liver disease and fibrosis stages. Liver Int 2023; 43:1234-1246. [PMID: 36924436 DOI: 10.1111/liv.15565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 03/18/2023]
Abstract
BACKGROUND & AIMS There is an unmet clinical need for non-invasive tests to diagnose non-alcoholic fatty liver disease (NAFLD) and individual fibrosis stages. We aimed to test whether urine protein panels could be used to identify NAFLD, NAFLD with fibrosis (stage F ≥ 1) and NAFLD with significant fibrosis (stage F ≥ 2). METHODS We collected urine samples from 100 patients with biopsy-confirmed NAFLD and 40 healthy volunteers, and proteomics and bioinformatics analyses were performed in this derivation cohort. Diagnostic models were developed for detecting NAFLD (UPNAFLD model), NAFLD with fibrosis (UPfibrosis model), or NAFLD with significant fibrosis (UPsignificant fibrosis model). Subsequently, the derivation cohort was divided into training and testing sets to evaluate the efficacy of these diagnostic models. Finally, in a separate independent validation cohort of 100 patients with biopsy-confirmed NAFLD and 45 healthy controls, urinary enzyme-linked immunosorbent assay analyses were undertaken to validate the accuracy of these new diagnostic models. RESULTS The UPfibrosis model and the UPsignificant fibrosis model showed an AUROC of .863 (95% CI: .725-1.000) and 0.858 (95% CI: .712-1.000) in the training set; and .837 (95% CI: .711-.963) and .916 (95% CI: .825-1.000) in the testing set respectively. The UPNAFLD model showed an excellent diagnostic performance and the area under the receiver operator characteristic curve (AUROC) exceeded .90 in the derivation cohort. In the independent validation cohort, the AUROC for all three of the above diagnostic models exceeded .80. CONCLUSIONS Our newly developed models constructed from urine protein biomarkers have good accuracy for non-invasively diagnosing liver fibrosis in NAFLD.
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Affiliation(s)
- Gong Feng
- Department of Infectious Disease, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, China
- Institute of General Practice, Xi'an Medical University, 710021, Xi'an, China
| | - Xiaoxun Zhang
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Institute of Digestive Diseases of PLA, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), 400038, Chongqing, China
- Center for Metabolic Associated Fatty Liver Disease and Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), 400038, Chongqing, China
| | - Liangjun Zhang
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Institute of Digestive Diseases of PLA, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), 400038, Chongqing, China
- Center for Metabolic Associated Fatty Liver Disease and Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), 400038, Chongqing, China
| | - Wen-Yue Liu
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Shi Geng
- Artificial Intelligence Unit, Department of Medical Equipment Management, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221004, China
| | - Hai-Yang Yuan
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, China
| | - Jun-Cheng Sha
- Interventional Radiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221004, China
| | - Xiao-Dong Wang
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, 325000, China
| | - Dan-Qin Sun
- Department of Nephrology, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, 214001, Jiangsu, China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Christopher D Byrne
- Southampton National Institute for Health and Care Research Biomedical Research Centre, University Hospital Southampton, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Tian-Lei Zheng
- Artificial Intelligence Unit, Department of Medical Equipment Management, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221004, China
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou, 221116, China
| | - Feng Ye
- Department of Infectious Disease, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, China
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, 325000, China
| | - Jin Chai
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Institute of Digestive Diseases of PLA, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), 400038, Chongqing, China
- Center for Metabolic Associated Fatty Liver Disease and Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), 400038, Chongqing, China
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16
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Mondal SA, Mann SN, van der Linden C, Sathiaseelan R, Kamal M, Das S, Bubak MP, Logan S, Miller BF, Stout MB. Metabolic benefits of 17α-estradiol in liver are partially mediated by ERβ in male mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.25.534216. [PMID: 36993459 PMCID: PMC10055366 DOI: 10.1101/2023.03.25.534216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/13/2023]
Abstract
Metabolic dysfunction underlies several chronic diseases. Dietary interventions can reverse metabolic declines and slow aging but remaining compliant is difficult. 17α-estradiol (17α-E2) treatment improves metabolic parameters and slows aging in male mice without inducing significant feminization. We recently reported that estrogen receptor α is required for the majority of 17α-E2-mediated benefits in male mice, but that 17α-E2 also attenuates fibrogenesis in liver, which is regulated by estrogen receptor β (ERβ)-expressing hepatic stellate cells (HSC). The current studies sought to determine if 17α-E2-mediated benefits on systemic and hepatic metabolism are ERβ-dependent. We found that 17α-E2 treatment reversed obesity and related systemic metabolic sequela in both male and female mice, but this was partially blocked in female, but not male, ERβKO mice. ERβ ablation in male mice attenuated 17α-E2-mediated benefits on hepatic stearoyl-coenyzme A desaturase 1 (SCD1) and transforming growth factor β1 (TGF-β1) production, which play critical roles in HSC activation and liver fibrosis. We also found that 17α-E2 treatment suppresses SCD1 production in cultured hepatocytes and hepatic stellate cells, indicating that 17α-E2 directly signals in both cell-types to suppress drivers of steatosis and fibrosis. We conclude that ERβ partially controls 17α-E2-mediated benefits on systemic metabolic regulation in female, but not male, mice, and that 17α-E2 likely signals through ERβ in HSCs to attenuate pro-fibrotic mechanisms.
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Affiliation(s)
- Samim Ali Mondal
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Shivani N. Mann
- Department of Neuroscience, University of Arizona, Tucson, AZ, USA
| | - Carl van der Linden
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Roshini Sathiaseelan
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
- Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Maria Kamal
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Snehasis Das
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Matthew P. Bubak
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Sreemathi Logan
- Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
| | - Benjamin F. Miller
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK, USA
| | - Michael B. Stout
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK, USA
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17
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Ali Mondal S, Sathiaseelan R, Mann SN, Kamal M, Luo W, Saccon TD, Isola JVV, Peelor FF, Li T, Freeman WM, Miller BF, Stout MB. 17α-estradiol, a lifespan-extending compound, attenuates liver fibrosis by modulating collagen turnover rates in male mice. Am J Physiol Endocrinol Metab 2023; 324:E120-E134. [PMID: 36516471 PMCID: PMC9902223 DOI: 10.1152/ajpendo.00256.2022] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/13/2022] [Accepted: 12/13/2022] [Indexed: 12/15/2022]
Abstract
Estrogen signaling is protective against chronic liver diseases, although men and a subset of women are contraindicated for chronic treatment with 17β-estradiol (17β-E2) or combination hormone replacement therapies. We sought to determine if 17α-estradiol (17α-E2), a naturally occurring diastereomer of 17β-E2, could attenuate liver fibrosis. We evaluated the effects of 17α-E2 treatment on collagen synthesis and degradation rates using tracer-based labeling approaches in male mice subjected to carbon tetrachloride (CCl4)-induced liver fibrosis. We also assessed the effects of 17α-E2 on markers of hepatic stellate cell (HSC) activation, collagen cross-linking, collagen degradation, and liver macrophage content and polarity. We found that 17α-E2 significantly reduced collagen synthesis rates and increased collagen degradation rates, which was mirrored by declines in transforming growth factor β1 (TGF-β1) and lysyl oxidase-like 2 (LOXL2) protein content in liver. These improvements were associated with increased matrix metalloproteinase 2 (MMP2) activity and suppressed stearoyl-coenzyme A desaturase 1 (SCD1) protein levels, the latter of which has been linked to the resolution of liver fibrosis. We also found that 17α-E2 increased liver fetuin-A protein, a strong inhibitor of TGF-β1 signaling, and reduced proinflammatory macrophage activation and cytokines expression in the liver. We conclude that 17α-E2 reduces fibrotic burden by suppressing HSC activation and enhancing collagen degradation mechanisms. Future studies will be needed to determine if 17α-E2 acts directly in hepatocytes, HSCs, and/or immune cells to elicit these benefits.
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Affiliation(s)
- Samim Ali Mondal
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - Roshini Sathiaseelan
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
- Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Shivani N Mann
- Department of Neuroscience, University of Arizona, Tucson, Arizona
| | - Maria Kamal
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Wenyi Luo
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Tatiana D Saccon
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - José V V Isola
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - Frederick F Peelor
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - Tiangang Li
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Willard M Freeman
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma
| | - Benjamin F Miller
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma
| | - Michael B Stout
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma
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Wang J, Wang L, Zhang XJ, Zhang P, Cai J, She ZG, Li H. Recent updates on targeting the molecular mediators of NAFLD. J Mol Med (Berl) 2023; 101:101-124. [PMID: 36792729 DOI: 10.1007/s00109-022-02282-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 11/29/2022] [Accepted: 12/21/2022] [Indexed: 02/17/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common disease worldwide in an era of rapid economic growth. NAFLD is a multifactorial disease, involving multiple genetic, metabolic, and environmental factors, and is closely associated with metabolic syndrome, obesity, and cardiovascular disease. NAFLD can be classified into nonalcoholic fatty liver disease (NAFL) and nonalcoholic steatohepatitis (NASH), which can both progress to cirrhosis and even hepatocellular carcinoma (HCC). Due to the enormous burden of NAFLD and its complications, no FDA-approved drugs for the treatment of NAFLD are on the market, and therapeutic targets and drug therapies are being actively investigated. In view of the various pathological mechanisms of NAFLD, numbers of preclinical studies and clinical trials have made rapid progress. This review mainly summarizes the most recently characterized mechanisms and therapeutic targets in each mechanism of NAFLD, focusing on the mechanism and application potential.
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Affiliation(s)
- Jia Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Luojia Mount Wuchang, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
| | - Lei Wang
- Department of Neurosurgery, Huanggang Central Hospital of Yangtze University, Huanggang, China
- Translation Medicine Research Center, Yangtze University, Huanggang, China
| | - Xiao-Jing Zhang
- Institute of Model Animal, Wuhan University, Wuhan, China
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Peng Zhang
- Institute of Model Animal, Wuhan University, Wuhan, China
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Jingjing Cai
- Institute of Model Animal, Wuhan University, Wuhan, China
- Department of Cardiology, The Third Xiangya Hospital, Central South University, The Third Xiangya Hospital, Changsha, China
| | - Zhi-Gang She
- Department of Cardiology, Renmin Hospital of Wuhan University, Luojia Mount Wuchang, Wuhan, China.
- Institute of Model Animal, Wuhan University, Wuhan, China.
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Luojia Mount Wuchang, Wuhan, China.
- Institute of Model Animal, Wuhan University, Wuhan, China.
- Translation Medicine Research Center, Yangtze University, Huanggang, China.
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Diosgenin Ameliorated Type II Diabetes-Associated Nonalcoholic Fatty Liver Disease through Inhibiting De Novo Lipogenesis and Improving Fatty Acid Oxidation and Mitochondrial Function in Rats. Nutrients 2022; 14:nu14234994. [PMID: 36501024 PMCID: PMC9738614 DOI: 10.3390/nu14234994] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/11/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022] Open
Abstract
Diosgenin (DIO) is a dietary and phytochemical steroidal saponin representing multiple activities. The present study investigated the protective effect of DIO on type II diabetes-associated nonalcoholic fatty liver disease (D-NAFLD). The rat model was established by high-fat diet and streptozotocin injection and then administered DIO for 8 weeks. The results showed that DIO reduced insulin resistance index, improved dyslipidemia, and relieved pancreatic damage. DIO decreased hepatic injury markers, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT). H&E staining showed that DIO relieved hepatic lipid deposition. Mechanistically, DIO inhibited hepatic de novo lipogenesis (DNL) and increased fatty acid β-oxidation (FAO) through regulation of the AMPK-ACC/SREBP1 pathway. Endoplasmic reticulum (ER) stress was inhibited by DIO through regulation of PERK and IRE1 arms, which may then inhibit DNL. DIO also decreased reactive oxygen species (ROS) and enhanced the antioxidant capacity via an increase in Superoxide dismutase (SOD), Catalase (CAT), and Glutathione peroxidase (GPx) activities. The mitochondria are the site for FAO, and ROS can damage mitochondrial function. DIO relieved mitochondrial fission and fusion disorder by inhibiting DRP1 and increasing MFN1/MFN2 expressions. Mitochondrial apoptosis was then inhibited by DIO. In conclusion, the present study suggests that DIO protects against D-NAFLD by inhibiting DNL and improving FAO and mitochondrial function.
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20
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Lv XT, Wang RH, Liu XT, Ye YJ, Liu XY, Qiao JD, Wang GE. Theacrine ameliorates experimental liver fibrosis in rats by lowering cholesterol storage via activation of the Sirtuin 3-farnesoid X receptor signaling pathway. Chem Biol Interact 2022; 364:110051. [PMID: 35872049 DOI: 10.1016/j.cbi.2022.110051] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 07/09/2022] [Accepted: 07/13/2022] [Indexed: 01/25/2023]
Abstract
Formulations against liver fibrosis (LF) mitigate the progression of hepatitis to cirrhosis. However, notable toxicity of the currently available anti-LF drugs limits their long-term use. In the study, we aimed to investigate the anti-LF effects of theacrine, a purine alkaloid without obvious toxicity, on high-fat diet-, alcohol-, and carbon tetrachloride-induced LF in rats. The results indicated that 10 and 20 mg/kg of theacrine ameliorated hepatic fibrosis, steatosis, and inflammation in LF rats. Mechanistically, theacrine reduced hepatic stellate cell (HSC)-related α-smooth muscle actin expression, and decreased cholesterol accumulation, followed by decreased expression of transforming growth factor-β1, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α. In addition, theacrine upregulated the phosphorylation of AMP-activated protein kinase, accompanied by decreased expression of β-catenin and stearoyl-CoA desaturase 1, and increased the expression of sirtuin 3 (SIRT3). Further investigation revealed that the theacrine-mediated decrease in cholesterol was independent of cholesterol synthesis or low-density lipoprotein (LDL) uptake in hyperlipidemia mice. However, theacrine activated farnesoid X receptor (FXR), a β-catenin conjugated protein, accompanied with decreased expression of cholesterol 7α-hydroxylase and sterol 12α-hydroxylase. In conclusion, theacrine alleviated experimental LF in rats by lowering cholesterol storage and decreasing cholesterol-related HSC activation. A plausible mechanism of theacrine on cholesterol metabolism may involve activation of SIRT3-FXR signaling pathway followed by decreased intestinal cholesterol absorption.
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Affiliation(s)
- Xi-Ting Lv
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Ruo-Hong Wang
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Xiao-Ting Liu
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Yu-Jing Ye
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Xin-Yu Liu
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Jing-Da Qiao
- Institute of Neuroscience and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China
| | - Guo-En Wang
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
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21
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Flessa C, Kyrou I, Nasiri‐Ansari N, Kaltsas G, Kassi E, Randeva HS. Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD). J Cell Biochem 2022; 123:1585-1606. [PMID: 35490371 DOI: 10.1002/jcb.30247] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/09/2022] [Accepted: 03/28/2022] [Indexed: 02/06/2023]
Affiliation(s)
- Christina‐Maria Flessa
- Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens Athens Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) University Hospitals Coventry and Warwickshire NHS Trust Coventry UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) University Hospitals Coventry and Warwickshire NHS Trust Coventry UK
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School University of Warwick Coventry UK
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing Coventry University Coventry UK
- Aston Medical School, College of Health and Life Sciences Aston University Birmingham UK
- Department of Food Science & Human Nutrition Agricultural University of Athens Athens Greece
| | - Narjes Nasiri‐Ansari
- Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens Athens Greece
| | - Gregory Kaltsas
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital National and Kapodistrian University of Athens Athens Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens Athens Greece
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital National and Kapodistrian University of Athens Athens Greece
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) University Hospitals Coventry and Warwickshire NHS Trust Coventry UK
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School University of Warwick Coventry UK
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22
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Paul B, Lewinska M, Andersen JB. Lipid alterations in chronic liver disease and liver cancer. JHEP Rep 2022; 4:100479. [PMID: 35469167 PMCID: PMC9034302 DOI: 10.1016/j.jhepr.2022.100479] [Citation(s) in RCA: 136] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 03/01/2022] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Lipids are a complex and diverse group of molecules with crucial roles in many physiological processes, as well as in the onset, progression, and maintenance of cancers. Fatty acids and cholesterol are the building blocks of lipids, orchestrating these crucial metabolic processes. In the liver, lipid alterations are prevalent as a cause and consequence of chronic hepatitis B and C virus infections, alcoholic hepatitis, and non-alcoholic fatty liver disease and steatohepatitis. Recent developments in lipidomics have also revealed that dynamic changes in triacylglycerols, phospholipids, sphingolipids, ceramides, fatty acids, and cholesterol are involved in the development and progression of primary liver cancer. Accordingly, the transcriptional landscape of lipid metabolism suggests a carcinogenic role of increasing fatty acids and sterol synthesis. However, limited mechanistic insights into the complex nature of the hepatic lipidome have so far hindered the development of effective therapies.
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Li HY, Peng ZG. Targeting lipophagy as a potential therapeutic strategy for nonalcoholic fatty liver disease. Biochem Pharmacol 2022; 197:114933. [PMID: 35093393 DOI: 10.1016/j.bcp.2022.114933] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 01/04/2022] [Accepted: 01/21/2022] [Indexed: 02/09/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming an increasingly serious disease worldwide. Unfortunately, no specific drug has been approved to treat NAFLD. Accumulating evidence suggests that lipotoxicity, which is induced by an excess of intracellular triacylglycerols (TAGs), is a potential mechanism underlying the ill-defined progression of NAFLD. Under physiological conditions, a balance is maintained between TAGs and free fatty acids (FFAs) in the liver. TAGs are catabolized to FFAs through neutral lipolysis and/or lipophagy, while FFAs can be anabolized to TAGs through an esterification reaction. However, in the livers of patients with NAFLD, lipophagy appears to fail. Reversing this abnormal state through several lipophagic molecules (mTORC1, AMPK, PLIN, etc.) facilitates NAFLD amelioration; therefore, restoring failed lipophagy may be a highly efficient therapeutic strategy for NAFLD. Here, we outline the lipophagy phases with the relevant important proteins and discuss the roles of lipophagy in the progression of NAFLD. Additionally, the potential candidate drugs with therapeutic value targeting these proteins are discussed to show novel strategies for future treatment of NAFLD.
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Affiliation(s)
- Hong-Ying Li
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Zong-Gen Peng
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Key Laboratory of Biotechnology of Antibiotics, The National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
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24
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Jeyakumar SM, Vajreswari A. Stearoyl-CoA desaturase 1: A potential target for non-alcoholic fatty liver disease?-perspective on emerging experimental evidence. World J Hepatol 2022; 14:168-179. [PMID: 35126846 PMCID: PMC8790397 DOI: 10.4254/wjh.v14.i1.168] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/18/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a progressive disease and one of the leading causes of death. An unnamed disease has become a global epidemic disease of public health concern. This spectrum of diseases manifests itself with initial accumulation of excessive triglycerides (due to de novo lipogenesis) in the hepatocytes, leading to simple steatosis. Although its aetiology is multi-factorial, lifestyle changes (diet and physical activity) are considered to be the key thriving factors. In this context, high fructose consumption is associated with an increased risk for developing NAFLD in humans, while high-fructose feeding to experimental animals results in hepatic steatosis and non-alcoholic steatohepatitis, by increasing hepatic lipogenesis. Among several lipogenic genes, the endoplasmic reticulum-bound stearoyl-CoA desaturase 1 (SCD1) is the key determinant of triglycerides biosynthesis pathway, by providing monounsaturated fatty acids, through the incorporation of a double bond at the delta-9 position of saturated fatty acids, specifically, palmitic (C16:0) and stearic (C18:0) acids, yielding palmitoleic (C16:1) and oleic (C18:1) acids, respectively. Various experimental studies involving SCD1 gene knockout and diet-induced rodent models have demonstrated that SCD1 plays a key role in the development of NAFLD, by modulating hepatic lipogenesis and thus triglyceride accumulation in the liver. Several pharmacological and dietary intervention studies have shown the benefits of inhibiting hepatic SCD1 in the pathogenesis of NAFLD. In this review, we give an overview of SCD1 in NAFLD, based on the current experimental evidence and the translational applicability of SCD1 inhibition in human NAFLD conditions, besides discussing the limitations and way-forward.
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Affiliation(s)
- Shanmugam Murugaiha Jeyakumar
- Division of Lipid Biochemistry, National Institute of Nutrition, Hyderabad 500007, Telangana, India
- Department of Clinical Pharmacology, National Institute for Research in Tuberculosis, Chennai 600031, Tamil Nadu, India
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25
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Wiśniewska A, Stachowicz A, Kuś K, Ulatowska-Białas M, Totoń-Żurańska J, Kiepura A, Stachyra K, Suski M, Gajda M, Jawień J, Olszanecki R. Inhibition of Atherosclerosis and Liver Steatosis by Agmatine in Western Diet-Fed apoE-Knockout Mice Is Associated with Decrease in Hepatic De Novo Lipogenesis and Reduction in Plasma Triglyceride/High-Density Lipoprotein Cholesterol Ratio. Int J Mol Sci 2021; 22:ijms221910688. [PMID: 34639029 PMCID: PMC8509476 DOI: 10.3390/ijms221910688] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/26/2021] [Accepted: 09/28/2021] [Indexed: 12/15/2022] Open
Abstract
Atherosclerosis and NAFLD are the leading causes of death worldwide. The hallmark of NAFLD is triglyceride accumulation caused by an imbalance between lipogenesis de novo and fatty acid oxidation. Agmatine, an endogenous metabolite of arginine, exerts a protective effect on mitochondria and can modulate fatty acid metabolism. In the present study, we investigate the influence of agmatine on the progression of atherosclerotic lesions and the development of hepatic steatosis in apoE−/− mice fed with a Western high-fat diet, with a particular focus on its effects on the DNL pathway in the liver. We have proved that treatment of agmatine inhibits the progression of atherosclerosis and attenuates hepatic steatosis in apoE−/− mice on a Western diet. Such effects are associated with decreased total macrophage content in atherosclerotic plaque as well as a decrease in the TG levels and the TG/HDL ratio in plasma. Agmatine also reduced TG accumulation in the liver and decreased the expression of hepatic genes and proteins involved in lipogenesis de novo such as SREBP-1c, FASN and SCD1. In conclusion, agmatine may present therapeutic potential for the treatment of atherosclerosis and fatty liver disease. However, an exact understanding of the mechanisms of the advantageous actions of agmatine requires further study.
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Affiliation(s)
- Anna Wiśniewska
- Chair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland; (A.W.); (A.S.); (K.K.); (J.T.-Ż.); (A.K.); (K.S.); (M.S.); (J.J.)
| | - Aneta Stachowicz
- Chair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland; (A.W.); (A.S.); (K.K.); (J.T.-Ż.); (A.K.); (K.S.); (M.S.); (J.J.)
| | - Katarzyna Kuś
- Chair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland; (A.W.); (A.S.); (K.K.); (J.T.-Ż.); (A.K.); (K.S.); (M.S.); (J.J.)
| | | | - Justyna Totoń-Żurańska
- Chair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland; (A.W.); (A.S.); (K.K.); (J.T.-Ż.); (A.K.); (K.S.); (M.S.); (J.J.)
| | - Anna Kiepura
- Chair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland; (A.W.); (A.S.); (K.K.); (J.T.-Ż.); (A.K.); (K.S.); (M.S.); (J.J.)
| | - Kamila Stachyra
- Chair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland; (A.W.); (A.S.); (K.K.); (J.T.-Ż.); (A.K.); (K.S.); (M.S.); (J.J.)
| | - Maciej Suski
- Chair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland; (A.W.); (A.S.); (K.K.); (J.T.-Ż.); (A.K.); (K.S.); (M.S.); (J.J.)
| | - Mariusz Gajda
- Department of Histology, Jagiellonian University Medical College, 31-034 Cracow, Poland;
| | - Jacek Jawień
- Chair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland; (A.W.); (A.S.); (K.K.); (J.T.-Ż.); (A.K.); (K.S.); (M.S.); (J.J.)
| | - Rafał Olszanecki
- Chair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland; (A.W.); (A.S.); (K.K.); (J.T.-Ż.); (A.K.); (K.S.); (M.S.); (J.J.)
- Correspondence: ; Tel.: +48-12-421-1168
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Liang Y, Zhang Z, Tu J, Wang Z, Gao X, Deng K, El-Samahy MA, You P, Fan Y, Wang F. γ-Linolenic Acid Prevents Lipid Metabolism Disorder in Palmitic Acid-Treated Alpha Mouse Liver-12 Cells by Balancing Autophagy and Apoptosis via the LKB1-AMPK-mTOR Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:8257-8267. [PMID: 34281337 DOI: 10.1021/acs.jafc.1c02596] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Excessive fat deposition is the main character in nonalcoholic fatty liver disease (NAFLD), while γ-linolenic acid (GLA) is a polyunsaturated fatty acid that can reduce lipid deposition. This study investigated the effect and regulatory mechanism of GLA (100 μM) on lipid metabolism in alpha mouse liver 12 (AML-12) cells treated by 400 μM palmitic acid (PA). GLA reduced lipid content and increased fatty acid β oxidation, as indicated by decreasing triglyceride and cholesterol contents and increasing mRNA and protein expressions of CPT1α and PPARα. GLA relieved oxidative stress caused by PA, upregulated mRNA levels of superoxide dismutase and glutathione peroxidase, and decreased reactive oxygen species content. GLA reduced apoptosis, as indicated by decreases in the BAX/BCL2 expression level and apoptosis percentage. GLA activated autophagy, autophagosome-lysosome fusion, and LKB1-AMPK-mTOR signaling and upregulated mRNA and protein expressions of Beclin-1, autophagy-related 5, and liver kinase B1 (LKB1). These effects of GLA on lipid metabolism disorders of PA-treated hepatocytes were reversed by autophagy inhibitor 3MA and AMPK inhibitor compound C, confirming our conclusions. Overall, GLA can protect AML-12 cells from lipid metabolism disorder caused by PA via balancing autophagy and apoptosis mediated by the LKB1-AMPK-mTOR pathway. Consequently, GLA, as a dietary supplement, can help to prevent and treat NAFLD by regulating lipid metabolism and autophagy.
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Affiliation(s)
- Yaxu Liang
- Institute of Goats and Sheep Science, Nanjing Agricultural University, No. 1 Weigang, Nanjing, Jiangsu 210095, PR China
| | - Zhen Zhang
- Institute of Goats and Sheep Science, Nanjing Agricultural University, No. 1 Weigang, Nanjing, Jiangsu 210095, PR China
| | - Jiayu Tu
- Institute of Goats and Sheep Science, Nanjing Agricultural University, No. 1 Weigang, Nanjing, Jiangsu 210095, PR China
| | - Zhibo Wang
- Institute of Goats and Sheep Science, Nanjing Agricultural University, No. 1 Weigang, Nanjing, Jiangsu 210095, PR China
| | - Xiaoxiao Gao
- Institute of Goats and Sheep Science, Nanjing Agricultural University, No. 1 Weigang, Nanjing, Jiangsu 210095, PR China
| | - Kaiping Deng
- Institute of Goats and Sheep Science, Nanjing Agricultural University, No. 1 Weigang, Nanjing, Jiangsu 210095, PR China
| | - M A El-Samahy
- Institute of Goats and Sheep Science, Nanjing Agricultural University, No. 1 Weigang, Nanjing, Jiangsu 210095, PR China
| | - Peihua You
- Portal Agri-Industries Co., Ltd., Xingdian Street, Pikou District, Nanjing 210095, PR China
| | - Yixuan Fan
- Institute of Goats and Sheep Science, Nanjing Agricultural University, No. 1 Weigang, Nanjing, Jiangsu 210095, PR China
| | - Feng Wang
- Institute of Goats and Sheep Science, Nanjing Agricultural University, No. 1 Weigang, Nanjing, Jiangsu 210095, PR China
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Flessa CM, Kyrou I, Nasiri-Ansari N, Kaltsas G, Papavassiliou AG, Kassi E, Randeva HS. Endoplasmic Reticulum Stress and Autophagy in the Pathogenesis of Non-alcoholic Fatty Liver Disease (NAFLD): Current Evidence and Perspectives. Curr Obes Rep 2021; 10:134-161. [PMID: 33751456 DOI: 10.1007/s13679-021-00431-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/23/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease with rising prevalence worldwide. Herein, we provide a comprehensive overview of the current knowledge supporting the role of ER stress and autophagy processes in NAFLD pathogenesis and progression. We also highlight the interrelation between these two pathways and the impact of ER stress and autophagy modulators on NAFLD treatment. RECENT FINDINGS The pathophysiological mechanisms involved in NAFLD progression are currently under investigation. The endoplasmic reticulum (ER) stress and the concomitant unfolded protein response (UPR) seem to contribute to its pathogenesis mainly due to high ER content in the liver which exerts significant metabolic functions and can be dysregulated. Furthermore, disruption of autophagy processes has also been identified in NAFLD. The crucial role of these two pathways in NAFLD is underlined by the fact that they have recently emerged as promising targets of therapeutic interventions. There is a greater need for finding the natural/chemical compounds and drugs which can modulate the ER stress pathway and autophagy for the treatment of NAFLD. Clarifying the inter-relation between these two pathways and their interaction with inflammatory and apoptotic mechanisms will allow the development of additional therapeutic options which can better target and reprogram the underlying pathophysiological pathways, aiming to attenuate NAFLD progression.
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Affiliation(s)
- Christina-Maria Flessa
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, B4 7ET, Birmingham, UK
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK
| | - Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Gregory Kaltsas
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece.
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece.
| | - Harpal S Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
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Li N, Jiang W, Wang W, Xiong R, Wu X, Geng Q. Ferroptosis and its emerging roles in cardiovascular diseases. Pharmacol Res 2021; 166:105466. [PMID: 33548489 DOI: 10.1016/j.phrs.2021.105466] [Citation(s) in RCA: 163] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/29/2020] [Accepted: 01/22/2021] [Indexed: 12/14/2022]
Abstract
Ferroptosis is a new form of regulated cell death (RCD) driven by iron-dependent lipid peroxidation, which is morphologically and mechanistically distinct from other forms of RCD including apoptosis, autophagic cell death, pyroptosis and necroptosis. Recently, ferroptosis has been found to participate in the development of various cardiovascular diseases (CVDs) including doxorubicin-induced cardiotoxicity, ischemia/reperfusion-induced cardiomyopathy, heart failure, aortic dissection and stroke. Cardiovascular homeostasis is indulged in delicate equilibrium of assorted cell types composing the heart or vessels, and how ferroptosis contributes to the pathophysiological responses in CVD progression is unclear. Herein, we reviewed recent discoveries on the basis of ferroptosis and its involvement in CVD pathogenesis, together with related therapeutic potentials, aiming to provide insights on fundamental mechanisms of ferroptosis and implications in CVDs and associated disorders.
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Affiliation(s)
- Ning Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China; Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wenyang Jiang
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China; Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wei Wang
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China; Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Rui Xiong
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China; Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaojing Wu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China; Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
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Empagliflozin Attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in High Fat Diet Fed ApoE (-/-) Mice by Activating Autophagy and Reducing ER Stress and Apoptosis. Int J Mol Sci 2021; 22:818. [PMID: 33467546 PMCID: PMC7829901 DOI: 10.3390/ijms22020818 ] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
AIMS/HYPOTHESIS SGLT-2 inhibitors (SGLT-2i) have been studied as potential treatments against NAFLD, showing varying beneficial effects. The molecular mechanisms mediating these effects have not been fully clarified. Herein, we investigated the impact of empagliflozin on NAFLD, focusing particularly on ER stress, autophagy and apoptosis. METHODS Five-week old ApoE(-/-) mice were switched from normal to a high-fat diet (HFD). After five weeks, mice were randomly allocated into a control group (HFD + vehicle) and Empa group (HFD + empagliflozin 10 mg/kg/day) for five weeks. At the end of treatment, histomorphometric analysis was performed in liver, mRNA levels of Fasn, Screbp-1, Scd-1, Ppar-γ, Pck-1, Mcp-1, Tnf-α, Il-6, F4/80, Atf4, Elf2α, Chop, Grp78, Grp94, Χbp1, Ire1α, Atf6, mTor, Lc3b, Beclin-1, P62, Bcl-2 and Bax were measured by qRT-PCR, and protein levels of p-EIF2α, EIF2a, CHOP, LC3II, P62, BECLIN-1 and cleaved CASPASE-8 were assessed by immunoblotting. RESULTS Empagliflozin-treated mice exhibited reduced fasting glucose, total cholesterol and triglyceride serum levels, as well as decreased NAFLD activity score, decreased expression of lipogenic enzymes (Fasn, Screbp-1c and Pck-1) and inflammatory molecules (Mcp-1 and F4/80), compared to the Control group. Empagliflozin significantly decreased the expression of ER stress molecules Grp78, Ire1α, Xbp1, Elf2α, Atf4, Atf6, Chop, P62(Sqstm1) and Grp94; whilst activating autophagy via increased AMPK phosphorylation, decreased mTOR and increased LC3B expression. Finally, empagliflozin increased the Bcl2/Bax ratio and inhibited CASPASE-8 cleavage, reducing liver cell apoptosis. Immunoblotting analysis confirmed the qPCR results. CONCLUSION These novel findings indicate that empagliflozin treatment for five weeks attenuates NAFLD progression in ApoE(-/-) mice by promoting autophagy, reducing ER stress and inhibiting hepatic apoptosis.
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Nasiri-Ansari N, Nikolopoulou C, Papoutsi K, Kyrou I, Mantzoros CS, Kyriakopoulos G, Chatzigeorgiou A, Kalotychou V, Randeva MS, Chatha K, Kontzoglou K, Kaltsas G, Papavassiliou AG, Randeva HS, Kassi E. Empagliflozin Attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in High Fat Diet Fed ApoE (-/-) Mice by Activating Autophagy and Reducing ER Stress and Apoptosis. Int J Mol Sci 2021; 22:818. [PMID: 33467546 PMCID: PMC7829901 DOI: 10.3390/ijms22020818] [Citation(s) in RCA: 188] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/06/2021] [Accepted: 01/12/2021] [Indexed: 12/11/2022] Open
Abstract
AIMS/HYPOTHESIS SGLT-2 inhibitors (SGLT-2i) have been studied as potential treatments against NAFLD, showing varying beneficial effects. The molecular mechanisms mediating these effects have not been fully clarified. Herein, we investigated the impact of empagliflozin on NAFLD, focusing particularly on ER stress, autophagy and apoptosis. METHODS Five-week old ApoE(-/-) mice were switched from normal to a high-fat diet (HFD). After five weeks, mice were randomly allocated into a control group (HFD + vehicle) and Empa group (HFD + empagliflozin 10 mg/kg/day) for five weeks. At the end of treatment, histomorphometric analysis was performed in liver, mRNA levels of Fasn, Screbp-1, Scd-1, Ppar-γ, Pck-1, Mcp-1, Tnf-α, Il-6, F4/80, Atf4, Elf2α, Chop, Grp78, Grp94, Χbp1, Ire1α, Atf6, mTor, Lc3b, Beclin-1, P62, Bcl-2 and Bax were measured by qRT-PCR, and protein levels of p-EIF2α, EIF2a, CHOP, LC3II, P62, BECLIN-1 and cleaved CASPASE-8 were assessed by immunoblotting. RESULTS Empagliflozin-treated mice exhibited reduced fasting glucose, total cholesterol and triglyceride serum levels, as well as decreased NAFLD activity score, decreased expression of lipogenic enzymes (Fasn, Screbp-1c and Pck-1) and inflammatory molecules (Mcp-1 and F4/80), compared to the Control group. Empagliflozin significantly decreased the expression of ER stress molecules Grp78, Ire1α, Xbp1, Elf2α, Atf4, Atf6, Chop, P62(Sqstm1) and Grp94; whilst activating autophagy via increased AMPK phosphorylation, decreased mTOR and increased LC3B expression. Finally, empagliflozin increased the Bcl2/Bax ratio and inhibited CASPASE-8 cleavage, reducing liver cell apoptosis. Immunoblotting analysis confirmed the qPCR results. CONCLUSION These novel findings indicate that empagliflozin treatment for five weeks attenuates NAFLD progression in ApoE(-/-) mice by promoting autophagy, reducing ER stress and inhibiting hepatic apoptosis.
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Affiliation(s)
- Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
| | - Chrysa Nikolopoulou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
| | - Katerina Papoutsi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK;
- Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham B4 7ET, UK
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Christos S. Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;
- Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA 02215, USA
| | - Georgios Kyriakopoulos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
- Department of Pathology, Evangelismos Hospital, 10676 Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Vassiliki Kalotychou
- 1st Department of Internal Medicine, Laiko Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Manpal S. Randeva
- Human Metabolism Research Unit, WISDEM Centre, NHS Trust, Coventry CV2 2DX, UK;
| | - Kamaljit Chatha
- Department of Biochemistry & Immunology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK;
| | - Konstantinos Kontzoglou
- Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens University Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Gregory Kaltsas
- Endocrine Oncology Unit, 1st Department of Propaupedic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK;
- Human Metabolism Research Unit, WISDEM Centre, NHS Trust, Coventry CV2 2DX, UK;
- Division of Translational and Experimental Medicine-Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
- Endocrine Oncology Unit, 1st Department of Propaupedic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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Mika M, Wikiera A, Antończyk A, Grabacka M. The impact of catechins included in high fat diet on AMP-dependent protein kinase in apoE knock-out mice. Int J Food Sci Nutr 2020; 72:348-356. [PMID: 32900230 DOI: 10.1080/09637486.2020.1817345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Due to their health-promoting effects green tea catechins have gained a keen interest in recent years in the context of bodyweight reduction treatments and alleviation of inflammatory diseases. This study was designed to evaluate the impact of native and thermally modified catechins (TMC) on the body weight gain, fatty acid profile in subcutaneous adipose tissue and the activity of the enzymes involved in lipid metabolism regulation: AMP-dependent protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in apoE-deficient mice maintained on a high-fat diet. We observed that TMC decreased bodyweight gain as compared to the control group. Furthermore, TMC increased AMPK activity and reduced ACC activity in the metabolically important tissues: intestine, liver and subcutaneous adipose tissue and affected adipose tissue fatty acid composition. Native catechins produced less pronounced effects. These results suggest that TMC down-regulate endogenous fatty acid synthesis, which should be taken into account in dietary applications of catechins.
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Affiliation(s)
- Magdalena Mika
- Faculty of Food Technology, Department of Biotechnology and General Technology of Foods, University of Agriculture, Krakow, Poland
| | - Agnieszka Wikiera
- Faculty of Food Technology, Department of Biotechnology and General Technology of Foods, University of Agriculture, Krakow, Poland
| | - Anna Antończyk
- Faculty of Food Technology, Department of Biotechnology and General Technology of Foods, University of Agriculture, Krakow, Poland
| | - Maja Grabacka
- Faculty of Food Technology, Department of Biotechnology and General Technology of Foods, University of Agriculture, Krakow, Poland
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