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Warda F, Batch J, Graham L, Haas MJ, Mooradian AD. D-allulose enhances lipid oxidation in HepG2 cells via peroxisome proliferator-activated receptor α (PPARα). Biochim Biophys Acta Mol Cell Biol Lipids 2025; 1870:159599. [PMID: 39884381 DOI: 10.1016/j.bbalip.2025.159599] [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: 03/28/2024] [Revised: 12/31/2024] [Accepted: 01/27/2025] [Indexed: 02/01/2025]
Abstract
Lipid accumulation in hepatocytes in non-alcoholic steatohepatitis (NASH) is attributed partly to loss of insulin-responsiveness and/or an increased pro-inflammatory state. Since the rare sugar D-allulose has insulin mimetic and anti-inflammatory properties, its effects on lipid accumulation in liver-derived cells was tested. In HepG2 cells exposed to 200 μM oleic acid for 72 h, D-allulose treatment decreased intracellular lipid accumulation with an IC50 = 0.45 ± 0.07 mM. A similar effect was observed in cells treated with 10 μM gemfibrozil. D-allulose and gemfibrozil treatment increased oleic acid β-oxidation. Both D-allulose and gemfibrozil increased peroxisome proliferator-activated receptor α (PPARα) expression (two-fold) relative to control cells, while retinoid X receptor was unchanged. D-allulose and gemfibrozil increased PPARα-dependent genes including those involved in fatty acid β-oxidation (acyl-coenzyme A oxidase 1, long-chain-fatty-acid-coenzyme A ligase 5, and carnitine palmitoyltransferase 1 A). D-allulose and gemfibrozil also increased PPARα reporter gene expression and phosphorylation (Serine 12) which were both inhibited by the mitogen-activated protein (MAP) kinase inhibitor PD098059. Other MAP kinase inhibitors, including SB203580, SP600125, and BIX10289 had no effect on reporter gene expression. Oleic acid treatment, but not D-allulose or gemfibrozil, decreased sterol response element binding protein 1 and sterol response element binding protein 2 expression relative to cells not exposed to oleic acid, while peroxisome proliferator-activated receptor γ expression did not change. These results indicate that D-alluose mimics gemfibrozil effects on lipid content in HepG2 cells by promoting fatty acid β-oxidation via PPARα.
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Affiliation(s)
- Firas Warda
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, FL 32209, United States of America
| | - Jennifer Batch
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, FL 32209, United States of America
| | - Lauren Graham
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, FL 32209, United States of America
| | - Michael J Haas
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, FL 32209, United States of America.
| | - Arshag D Mooradian
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, FL 32209, United States of America
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2
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Liang J, Liu H, Lv G, Chen X, Yang Z, Hu K, Sun H. Exploring the molecular mechanisms of tirzepatide in alleviating metabolic dysfunction-associated fatty liver in mice through integration of metabolomics, lipidomics, and proteomics. Lipids Health Dis 2025; 24:8. [PMID: 39794823 PMCID: PMC11720920 DOI: 10.1186/s12944-024-02416-2] [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: 10/16/2024] [Accepted: 12/19/2024] [Indexed: 01/13/2025] Open
Abstract
Clinical studies have suggested that tirzepatide may also possess hepatoprotective effects; however, the molecular mechanisms underlying this association remain unclear. In our study, we performed biochemical analyses of serum and histopathological examinations of liver tissue in mice. To preliminarily explore the molecular mechanisms of tirzepatide on metabolic dysfunction-associated fatty liver disease (MAFLD), liquid chromatography-mass spectrometry (LC-MS) was employed for comprehensive metabolomic, lipidomic, and proteomic analyses in MAFLD mice fed a high-fat diet (HFD). The results demonstrated that tirzepatide significantly reduced serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), as well as hepatic triglycerides (TG) and total cholesterol (TC), indicating its efficacy in treating MAFLD. Further findings revealed that tirzepatide reduced fatty acid uptake by downregulating Cd36 and Fabp2/4, as well as enhance the mitochondrial-lysosomal function by upregulating Lamp1/2. In addition, tirzepatide promoted cholesterol efflux and reduced cholesterol reabsorption by upregulating the expression of Hnf4a, Abcg5, and Abcg8. These results suggest that tirzepatide exerts its therapeutic effects on MAFLD by reducing fatty acid uptake, promoting cholesterol excretion, and enhancing mitochondrial-lysosomal function, providing a theoretical basis for a comprehensive understanding of tirzepatide.
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Affiliation(s)
- Jinliang Liang
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Huanyi Liu
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Guo Lv
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Xiaotong Chen
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Zhaoshou Yang
- The First Affiliated Hospital, The First School of Clinical Medicine of Guangdong Pharmaceutical University, Guangdong Pharmaceutical University, Guangzhou, 510080, China
| | - Kunhua Hu
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
| | - Hongyan Sun
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
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3
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Mignini I, Galasso L, Piccirilli G, Calvez V, Termite F, Esposto G, Borriello R, Miele L, Ainora ME, Gasbarrini A, Zocco MA. Interplay of Oxidative Stress, Gut Microbiota, and Nicotine in Metabolic-Associated Steatotic Liver Disease (MASLD). Antioxidants (Basel) 2024; 13:1532. [PMID: 39765860 PMCID: PMC11727446 DOI: 10.3390/antiox13121532] [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: 09/29/2024] [Revised: 12/10/2024] [Accepted: 12/12/2024] [Indexed: 01/15/2025] Open
Abstract
Oxidative stress has been described as one of the main drivers of intracellular damage and metabolic disorders leading to metabolic syndrome, a major health problem worldwide. In particular, free radicals alter lipid metabolism and promote lipid accumulation in the liver, existing in the hepatic facet of metabolic syndrome, the metabolic dysfunction-associated steatotic liver disease (MASLD). Recent literature has highlighted how nicotine, especially if associated with a high-fat diet, exerts a negative effect on the induction and progression of MASLD by upregulating inflammation and increasing oxidative stress, abdominal fat lipolysis, and hepatic lipogenesis. Moreover, considerable evidence shows the central role of intestinal dysbiosis in the pathogenesis of MASLD and the impact of nicotine-induced oxidative stress on the gut microbiome. This results in an intricate network in which oxidative stress stands at the intersection point between gut microbiome, nicotine, and MASLD. The aim of this review is to delve into the molecular mechanisms linking tobacco smoking and MASLD, focusing on nicotine-induced microbiota modifications and their impact on MASLD development.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Maria Assunta Zocco
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (I.M.); (L.G.); (G.P.); (V.C.); (F.T.); (G.E.); (R.B.); (L.M.); (M.E.A.); (A.G.)
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4
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Jose J, Fonteh AN. A charge reversal approach for the sensitive quantification of dicarboxylic acids using Liquid chromatography-tandem mass spectrometry. J Chromatogr A 2024; 1737:465426. [PMID: 39423602 DOI: 10.1016/j.chroma.2024.465426] [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: 08/15/2024] [Revised: 10/03/2024] [Accepted: 10/06/2024] [Indexed: 10/21/2024]
Abstract
Dicarboxylic acids (DCAs) are essential for intermediate metabolism and are implicated in multiple processes associated with various diseases. Several DCAs contribute to energy metabolism, impact mitochondrial function, and play a crucial role in body function. However, the low abundance of some DCAs in various body fluids makes their quantification particularly challenging. Therefore, an extremely sensitive method is required to determine DCA level fluctuations in biological samples in different diseases. We developed and optimized an LC-MS/MS method to quantify DCAs. We achieved charge reversal of the compounds from negative to positive ionization through chemical derivatization with dimethylaminophenacyl bromide (DmPABr) targeting the carboxyl group (R-COOH) under mild basic conditions. Derivatization enhanced sensitivity, mass fragmentation, and chromatographic separation for LC-tandem mass spectrometric quantification. The method was analytically optimized and demonstrated excellent linearity for individual DCAs (R2>0.99), as well as an exceptionally lower limit of detection (LLOD<266 fg) and lower limit of quantification (LLOQ<805 fg) for all DCAs. Furthermore, most derivatized DCAs were stable at room temperature and after ten repeated freeze-thaw cycles. After DCA extraction and quantification detection, we found differences in their distribution in plasma and urine. The rank order for DCAs in plasma is C4>C6>C7>C9>C5>C8>C22, whereas in the urine sample, the order is C4>C7>C6>C9>C5>C8>C10. For longer chains (C > 16), their proportions were >10x higher in plasma than in urine. Our optimized method using LC-MS/MS enables the quantification of DCAs with excellent sensitivity. The method will help in future studies investigating dicarboxylic acids' crucial role in health and biomarker discovery studies using targeted metabolomics.
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Affiliation(s)
- Joby Jose
- Biomarker and Neuro-disease Mechanism Lab, Neuroscience Department, Huntington Medical Research Institutes, Pasadena, CA, USA
| | - Alfred N Fonteh
- Biomarker and Neuro-disease Mechanism Lab, Neuroscience Department, Huntington Medical Research Institutes, Pasadena, CA, USA.
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5
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Atoum MF, Padma KR, Don KR. Curcumin is a potential therapeutic agent that ameliorates diabetes among non-alcoholic fatty liver disease coexist with type 2 diabetes. NUTRITION AND HEALTHY AGING 2024; 9:77-90. [DOI: 10.3233/nha-231504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) harmonize and act synergistically in clinical practices. About 70–80% of diabetic patients develop NAFLD. At the same time, NAFLD existence increases T2DM development. Meanwhile, the presence of T2DM increases the progression to liver disease such as NAFLD, and to non-alcoholic steatohepatitis (NASH). The most prevalent chronic liver disease worldwide is a NAFLD. NAFLD and (T2DM) have a two-way pathophysiologic relationship, with the latter driving the development of the former into NASH. Nonetheless, NASH enhances the threat of cirrhosis as well as hepatocellular carcinoma (HCC), both cases in turn need transplantation of the liver. The only treatment for NAFLD is still lifestyle management because there are no FDA-approved drugs for the condition. In the current study, we review how curcumin (a naturally occurring phytopolyphenol pigment) treats NAFLD. Also we showed broad insights on curcumin-based therapy, by severe reduction of hepatic inflammation. Thus, our review showed that curcumin ingestion considerably decreased glycemic parameters (fasting blood glucose, glycosylated hemoglobin, insulin resistance index (HOMA-IR), and free fatty acids) and adipocyte-fatty acid binding protein (A-FABP), and adipokine released from adipocytes. Clinical trials are needed to evaluate the effects of curcumin and its specific dosage on liver enzymes, glycemic consequences, among NAFLD coexist with T2DM patients.
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Affiliation(s)
- Manar Fayiz Atoum
- Department of Medical Laboratory Sciences, Faculty of Applied Health Sciences, The Hashemite University, Zarqa, Jordan
| | - Kanchi Ravi Padma
- Department of Biotechnology, Sri Padmavati Mahila Visvavidyalayam (Women’s) University, Tirupati, AP, India
| | - Kanchi Ravi Don
- Department of Oral Pathology and Microbiology, Sree Balaji Dental College and Hospital, Bharath Institute of Higher Education and Research (BIHER) Bharath University, Chennai, Tamil Nadu, India
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6
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Liu S, Zhao L, Peng Y, Liu X, Yan W, Zhang L, Zhang J. Obesity induced caveolin-1 impairs osteogenesis via activating mitophagy and inhibiting Sirt1 signaling. Bone 2024; 186:117146. [PMID: 38844017 DOI: 10.1016/j.bone.2024.117146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 06/01/2024] [Accepted: 06/03/2024] [Indexed: 07/08/2024]
Abstract
Obesity has become a major global health problem and the effect on bone formation has received increasing attention. However, the interaction between obesity and bone metabolism is complex and still not fully understood. Here, we show that caveolin-1 (Cav1), a membrane scaffold protein involved in regulating a variety of cellular processes, plays a key regulatory role as a bridge connecting obesity and bone metabolism. High-fat diet (HFD)-induced obese C57BL/6J mouse displayed a significant increase in Cav1 expression and lower osteogenic activity; In vitro treatment of osteoblastic MC3T3-E1 cells with 1 mM free fatty acids (FFA) significantly promoted Cav1 expression and PINK1/Parkin regulated mitophagy, but inhibited the expression of osteogenic marker genes. Conversely, reduced expression of the Cav1 gene prevented these effects. Both endogenous oxidative stress and Sirt1 pathway were also significantly reduced after Cav1 knockdown in FFA-treated cells. Finally, Cav1-Sirt1 docking and co-immunoprecipitation results showed that Cav1 interacted with Sirt1 and FFA enhanced the interaction. Taken together, these results suggest that obesity impairs bone development and formation through up-regulation of the Cav1 gene, which lead to inhibition of Sirt1/FOXO1 and Sirt1/PGC-1α signaling pathways through interacting with Sirt1 molecule, and an increase of mitophagy level.
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Affiliation(s)
- Shuai Liu
- Bioengineering College, Zhuhai campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Lixia Zhao
- Bioengineering College, Zhuhai campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Yanqiu Peng
- Bioengineering College, Zhuhai campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Xing Liu
- Bioengineering College, Zhuhai campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Wenmin Yan
- Bioengineering College, Zhuhai campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Lizi Zhang
- Bioengineering College, Zhuhai campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Jian Zhang
- Bioengineering College, Zhuhai campus of Zunyi Medical University, Zhuhai, Guangdong, China.
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Weinisch P, Raffler J, Römisch-Margl W, Arnold M, Mohney RP, Rist MJ, Prehn C, Skurk T, Hauner H, Daniel H, Suhre K, Kastenmüller G. The HuMet Repository: Watching human metabolism at work. Cell Rep 2024; 43:114416. [PMID: 39033506 PMCID: PMC11513335 DOI: 10.1016/j.celrep.2024.114416] [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: 11/09/2023] [Revised: 05/11/2024] [Accepted: 06/13/2024] [Indexed: 07/23/2024] Open
Abstract
Metabolism oscillates between catabolic and anabolic states depending on food intake, exercise, or stresses that change a multitude of metabolic pathways simultaneously. We present the HuMet Repository for exploring dynamic metabolic responses to oral glucose/lipid loads, mixed meals, 36-h fasting, exercise, and cold stress in healthy subjects. Metabolomics data from blood, urine, and breath of 15 young, healthy men at up to 56 time points are integrated and embedded within an interactive web application, enabling researchers with and without computational expertise to search, visualize, analyze, and contextualize the dynamic metabolite profiles of 2,656 metabolites acquired on multiple platforms. With examples, we demonstrate the utility of the resource for research into the dynamics of human metabolism, highlighting differences and similarities in systemic metabolic responses across challenges and the complementarity of metabolomics platforms. The repository, providing a reference for healthy metabolite changes to six standardized physiological challenges, is freely accessible through a web portal.
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Affiliation(s)
- Patrick Weinisch
- Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Johannes Raffler
- Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Digital Medicine, University Hospital of Augsburg, Augsburg, Germany
| | - Werner Römisch-Margl
- Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Matthias Arnold
- Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
| | | | - Manuela J Rist
- Department of Physiology and Biochemistry of Nutrition, Max Rubner-Institut, Karlsruhe, Germany
| | - Cornelia Prehn
- Metabolomics and Proteomics Core, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Thomas Skurk
- ZIEL Institute for Food and Health, Core Facility Human Studies, Technical University of Munich, Freising, Germany; Else Kröner Fresenius Center for Nutritional Medicine, School of Life Sciences, Technical University of Munich, Freising, Germany
| | - Hans Hauner
- Else Kröner Fresenius Center for Nutritional Medicine, School of Life Sciences, Technical University of Munich, Freising, Germany; Institute for Nutritional Medicine, School of Medicine and Health, Technical University of Munich, Munich, Germany
| | - Hannelore Daniel
- School of Life Sciences, Technical University of Munich, Freising, Germany
| | - Karsten Suhre
- Department of Biophysics and Physiology, Weill Cornell Medicine - Qatar, Doha, Qatar
| | - Gabi Kastenmüller
- Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
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8
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Amor M, Diaz M, Bianco V, Svecla M, Schwarz B, Rainer S, Pirchheim A, Schooltink L, Mukherjee S, Grabner GF, Beretta G, Lamina C, Norata GD, Hackl H, Kratky D. Identification of regulatory networks and crosstalk factors in brown adipose tissue and liver of a cold-exposed cardiometabolic mouse model. Cardiovasc Diabetol 2024; 23:298. [PMID: 39143620 PMCID: PMC11325583 DOI: 10.1186/s12933-024-02397-7] [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: 04/30/2024] [Accepted: 08/07/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND Activation of brown adipose tissue (BAT) has gained attention due to its ability to dissipate energy and counteract cardiometabolic diseases (CMDs). METHODS This study investigated the consequences of cold exposure on the BAT and liver proteomes of an established CMD mouse model based on LDL receptor-deficient (LdlrKO) mice fed a high-fat, high-sucrose, high-cholesterol diet for 16 weeks. We analyzed energy metabolism in vivo and performed untargeted proteomics on BAT and liver of LdlrKO mice maintained at 22 °C or 5 °C for 7 days. RESULTS We identified several dysregulated pathways, miRNAs, and transcription factors in BAT and liver of cold-exposed Ldlrko mice that have not been previously described in this context. Networks of regulatory interactions based on shared downstream targets and analysis of ligand-receptor pairs identified fibrinogen alpha chain (FGA) and fibronectin 1 (FN1) as potential crosstalk factors between BAT and liver in response to cold exposure. Importantly, genetic variations in the genes encoding FGA and FN1 have been associated with cardiometabolic-related phenotypes and traits in humans. DISCUSSION This study describes the key factors, pathways, and regulatory networks involved in the crosstalk between BAT and the liver in a cold-exposed CMD mouse model. These findings may provide a basis for future studies aimed at testing whether molecular mediators, as well as regulatory and signaling mechanisms involved in tissue adaption upon cold exposure, could represent a target in cardiometabolic disorders.
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Affiliation(s)
- Melina Amor
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria
| | - Malena Diaz
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria
| | - Valentina Bianco
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Monika Svecla
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria
- Department of Neurosurgery, Charité- Universitätsmedizin Berlin, Berlin, Germany
| | - Birgit Schwarz
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria
| | - Silvia Rainer
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria
| | - Anita Pirchheim
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria
| | - Laszlo Schooltink
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria
| | - Suravi Mukherjee
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria
| | - Gernot F Grabner
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria
| | - Giangiacomo Beretta
- Department of Environmental Science and Policy, Università degli Studi di Milano, Milan, Italy
| | - Claudia Lamina
- Department of Genetics and Pharmacology, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Giuseppe Danilo Norata
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Hubert Hackl
- Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Dagmar Kratky
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria.
- BioTechMed-Graz, Graz, Austria.
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9
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Léger T, Alilat S, Ferron PJ, Dec L, Bouceba T, Lanceleur R, Huet S, Devriendt-Renault Y, Parinet J, Clément B, Fessard V, Le Hégarat L. Chlordecone-induced hepatotoxicity and fibrosis are mediated by the proteasomal degradation of septins. JOURNAL OF HAZARDOUS MATERIALS 2024; 476:135177. [PMID: 39018595 DOI: 10.1016/j.jhazmat.2024.135177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 07/08/2024] [Accepted: 07/09/2024] [Indexed: 07/19/2024]
Abstract
Chlordecone (CLD) is a pesticide persisting in soils and contaminating food webs. CLD is sequestered in the liver and poorly metabolized into chlordecol (CLDOH). In vitro liver cell models were used to investigate the fate and mechanistic effects of CLD and CLDOH using multiomics. A 3D-cell model was used to investigate whether CLD and CLDOH can affect susceptibility to the metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocytes were more sensitive to CLD than CLDOH. CLDOH was intensively metabolized into a glucuronide conjugate, whereas CLD was sequestered. CLD but not CLDOH induced a depletion of Septin-2,- 7,- 9,- 10,- 11 due to proteasomal degradation. Septin binding with CLD and CLDOH was confirmed by surface plasmon resonance. CLD disrupted lipid droplet size and increased saturated long-chain dicarboxylic acid production by inhibiting stearoyl-CoA desaturase (SCD) abundance. Neither CLD nor CLDOH induced steatosis, but CLD induced fibrosis in the 3D model of MASLD. To conclude, CLD hepatoxicity is specifically driven by the degradation of septins. CLDOH, was too rapidly metabolized to induce septin degradation. We show that the conversion of CLD to CLDOH reduced hepatotoxicity and fibrosis in liver organoids. This suggests that protective strategies could be explored to reduce the hepatotoxicity of CLD.
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Affiliation(s)
- Thibaut Léger
- ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Toxicology of Contaminants Unit, Fougères Laboratory, 35306 Fougères CEDEX, France.
| | - Sarah Alilat
- ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Toxicology of Contaminants Unit, Fougères Laboratory, 35306 Fougères CEDEX, France
| | - Pierre-Jean Ferron
- INSERM, University of Rennes, INRAE, Institut NuMeCan (Nutrition, Metabolisms and Cancer) UMR_A 1317, UMR_S 1241, Previtox Network, 35000 Rennes, France
| | - Léonie Dec
- ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Toxicology of Contaminants Unit, Fougères Laboratory, 35306 Fougères CEDEX, France
| | - Tahar Bouceba
- Sorbonne University, CNRS, Institut de Biologie Paris-Seine (IBPS), Protein Engineering Platform, Molecular Interaction Service, Paris, France
| | - Rachelle Lanceleur
- ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Toxicology of Contaminants Unit, Fougères Laboratory, 35306 Fougères CEDEX, France
| | - Sylvie Huet
- ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Toxicology of Contaminants Unit, Fougères Laboratory, 35306 Fougères CEDEX, France
| | - Yoann Devriendt-Renault
- ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Pesticides and Marine Biotoxins (PBM) unit, Maison-Alfort Laboratory, 94701 Maison-Alfort CEDEX, France
| | - Julien Parinet
- ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Pesticides and Marine Biotoxins (PBM) unit, Maison-Alfort Laboratory, 94701 Maison-Alfort CEDEX, France
| | - Bruno Clément
- INSERM, University of Rennes, INRAE, Institut NuMeCan (Nutrition, Metabolisms and Cancer) UMR_A 1317, UMR_S 1241, Previtox Network, 35000 Rennes, France
| | - Valérie Fessard
- ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Toxicology of Contaminants Unit, Fougères Laboratory, 35306 Fougères CEDEX, France
| | - Ludovic Le Hégarat
- ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Toxicology of Contaminants Unit, Fougères Laboratory, 35306 Fougères CEDEX, France
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10
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Gowda D, Shekhar C, B. Gowda SG, Chen Y, Hui SP. Crosstalk between Lipids and Non-Alcoholic Fatty Liver Disease. LIVERS 2023; 3:687-708. [DOI: 10.3390/livers3040045] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), a complex liver disorder that can result in non-alcoholic steatohepatitis, cirrhosis, and liver cancer, is the accumulation of fat in the liver seen in people due to metabolic dysfunction. The pathophysiology of NAFLD is influenced by several variables, such as metabolic dysregulation, oxidative stress, inflammation, and genetic susceptibility. This illness seriously threatens global health because of its link to obesity, insulin resistance, type 2 diabetes, and other metabolic disorders. In recent years, lipid–NAFLD crosstalk has drawn a lot of interest. Through numerous methods, lipids have been connected to the onset and advancement of the illness. The connection between lipids and NAFLD is the main topic of the current review, along with the various therapeutic targets and currently available drugs. The importance of hepatic lipid metabolism in the progression of NAFLD is summarized with the latest results in the field.
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Affiliation(s)
- Divyavani Gowda
- Faculty of Health Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Chandra Shekhar
- Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Siddabasave Gowda B. Gowda
- Faculty of Health Sciences, Hokkaido University, Sapporo 060-0812, Japan
- Graduate School of Global Food Resources, Hokkaido University, Sapporo 060-0812, Japan
| | - Yifan Chen
- Faculty of Health Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Shu-Ping Hui
- Faculty of Health Sciences, Hokkaido University, Sapporo 060-0812, Japan
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11
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Jouenne A, Hamici K, Varlet I, Sourdon J, Daudé P, Lan C, Kober F, Landrier JF, Bernard M, Desrois M. Relationship of cardiac remodeling and perfusion alteration with hepatic lipid metabolism in a prediabetic high fat high sucrose diet female rat model. Biochem Biophys Res Commun 2023; 682:207-215. [PMID: 37826944 DOI: 10.1016/j.bbrc.2023.09.089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/08/2023] [Accepted: 09/28/2023] [Indexed: 10/14/2023]
Abstract
BACKGROUND AND AIMS Cardiovascular disease (CVD) is known to be linked with metabolic associated fatty liver disease and type 2 diabetes, but few studies assessed this relationship in prediabetes, especially among women, who are at greater risk of CVD. We aimed to evaluate cardiac alterations and its relationship with hepatic lipid metabolism in prediabetic female rats submitted to high-fat-high-sucrose diet (HFS). METHODS AND RESULTS Wistar female rats were divided into 2 groups fed for 5 months with standard or HFS diet. We analyzed cardiac morphology, function, perfusion and fibrosis by Magnetic Resonance Imaging. Hepatic lipid contents along with inflammation and lipid metabolism gene expression were assessed. Five months of HFS diet induced glucose intolerance (p < 0.05), cardiac remodeling characterized by increased left-ventricular volume, wall thickness and mass (p < 0.05). No significant differences were found in left-ventricular ejection fraction and cardiac fibrosis but increased myocardial perfusion (p < 0.01) and reduced cardiac index (p < 0.05) were shown. HFS diet induced hepatic lipid accumulation with increased total lipid mass (p < 0.001) and triglyceride contents (p < 0.05), but also increased mitochondrial (CPT1a, MCAD; (p < 0.001; p < 0.05) and peroxisomal (ACO, LCAD; (p < 0.05; p < 0.001) β-oxidation gene expression. Myocardial wall thickness and perfusion were correlated with hepatic β-oxidation genes expression. Furthermore, myocardial perfusion was also correlated with hepatic lipid content and glucose intolerance. CONCLUSION This study brings new insights on the relationship between cardiac sub-clinical alterations and hepatic metabolism in female prediabetic rats. Further studies are warranted to explore its involvement in the higher CVD risk observed among prediabetic women.
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Affiliation(s)
- A Jouenne
- Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.
| | - K Hamici
- Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.
| | - I Varlet
- Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.
| | - J Sourdon
- Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.
| | - P Daudé
- Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.
| | - C Lan
- Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.
| | - F Kober
- Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.
| | - J F Landrier
- Aix-Marseille Univ, INSERM, INRAE, C2VN, Marseille, France.
| | - M Bernard
- Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.
| | - M Desrois
- Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.
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12
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Struwe MA, Scheidig AJ, Clement B. The mitochondrial amidoxime reducing component-from prodrug-activation mechanism to drug-metabolizing enzyme and onward to drug target. J Biol Chem 2023; 299:105306. [PMID: 37778733 PMCID: PMC10637980 DOI: 10.1016/j.jbc.2023.105306] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 09/17/2023] [Accepted: 09/24/2023] [Indexed: 10/03/2023] Open
Abstract
The mitochondrial amidoxime-reducing component (mARC) is one of five known molybdenum enzymes in eukaryotes. mARC belongs to the MOSC domain superfamily, a large group of so far poorly studied molybdoenzymes. mARC was initially discovered as the enzyme activating N-hydroxylated prodrugs of basic amidines but has since been shown to also reduce a variety of other N-oxygenated compounds, for example, toxic nucleobase analogs. Under certain circumstances, mARC might also be involved in reductive nitric oxide synthesis through reduction of nitrite. Recently, mARC enzymes have received a lot of attention due to their apparent involvement in lipid metabolism and, in particular, because many genome-wide association studies have shown a common variant of human mARC1 to have a protective effect against liver disease. The mechanism linking mARC enzymes with lipid metabolism remains unknown. Here, we give a comprehensive overview of what is currently known about mARC enzymes, their substrates, structure, and apparent involvement in human disease.
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Affiliation(s)
- Michel A Struwe
- Zoologisches Institut - Strukturbiologie, Christian-Albrechts-Universität Kiel, Kiel, Germany; Pharmazeutisches Institut, Christian-Albrechts-Universität Kiel, Kiel, Germany.
| | - Axel J Scheidig
- Zoologisches Institut - Strukturbiologie, Christian-Albrechts-Universität Kiel, Kiel, Germany
| | - Bernd Clement
- Pharmazeutisches Institut, Christian-Albrechts-Universität Kiel, Kiel, Germany
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13
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Nam Y, Kim M, Erdenebileg S, Cha KH, Ryu DH, Kim HY, Lee SH, Jung JH, Nho CW. Sanguisorba officinalis L. Ameliorates Hepatic Steatosis and Fibrosis by Modulating Oxidative Stress, Fatty Acid Oxidation, and Gut Microbiota in CDAHFD-Induced Mice. Nutrients 2023; 15:3779. [PMID: 37686810 PMCID: PMC10490207 DOI: 10.3390/nu15173779] [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: 07/31/2023] [Revised: 08/19/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver diseases and encompasses non-alcoholic steatosis, steatohepatitis, and fibrosis. Sanguisorba officinalis L. (SO) roots have traditionally been used for their antioxidant properties and have beneficial effects on metabolic disorders, including diabetes and obesity. However, its effects on hepatic steatosis and fibrosis remain unclear. In this study, we explored the effects of a 95% ethanolic SO extract (SOEE) on NAFLD and fibrosis in vivo and in vitro. The SOEE was orally administered to C57BL/6J mice fed a choline-deficient, L-amino-acid-defined, high-fat diet for 10 weeks. The SOEE inhibited hepatic steatosis by modulating hepatic malondialdehyde levels and the expression of oxidative stress-associated genes, regulating fatty-acid-oxidation-related genes, and inhibiting the expression of genes that are responsible for fibrosis. The SOEE suppressed the deposition of extracellular matrix hydroxyproline and mRNA expression of fibrosis-associated genes. The SOEE decreased the expression of fibrosis-related genes in vitro by inhibiting SMAD2/3 phosphorylation. Furthermore, the SOEE restored the gut microbial diversity and modulated specific bacterial genera associated with NAFLD and fibrosis. This study suggests that SOEE might be the potential candidate for inhibiting hepatic steatosis and fibrosis by modulating oxidative stress, fatty acid oxidation, and gut microbiota composition.
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Affiliation(s)
- Yunseong Nam
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Republic of Korea; (Y.N.); (M.K.); (S.E.); (K.H.C.); (H.Y.K.)
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (D.H.R.); (S.H.L.); (J.H.J.)
| | - Myungsuk Kim
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Republic of Korea; (Y.N.); (M.K.); (S.E.); (K.H.C.); (H.Y.K.)
- Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea
- Department of Convergence Medicine, Wonju College of Medicine, Yonsei University, Wonju 26493, Republic of Korea
| | - Saruul Erdenebileg
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Republic of Korea; (Y.N.); (M.K.); (S.E.); (K.H.C.); (H.Y.K.)
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (D.H.R.); (S.H.L.); (J.H.J.)
| | - Kwang Hyun Cha
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Republic of Korea; (Y.N.); (M.K.); (S.E.); (K.H.C.); (H.Y.K.)
- Department of Convergence Medicine, Wonju College of Medicine, Yonsei University, Wonju 26493, Republic of Korea
- Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea
| | - Da Hye Ryu
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (D.H.R.); (S.H.L.); (J.H.J.)
| | - Ho Youn Kim
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Republic of Korea; (Y.N.); (M.K.); (S.E.); (K.H.C.); (H.Y.K.)
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (D.H.R.); (S.H.L.); (J.H.J.)
| | - Su Hyeon Lee
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (D.H.R.); (S.H.L.); (J.H.J.)
| | - Je Hyeong Jung
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (D.H.R.); (S.H.L.); (J.H.J.)
| | - Chu Won Nho
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Republic of Korea; (Y.N.); (M.K.); (S.E.); (K.H.C.); (H.Y.K.)
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (D.H.R.); (S.H.L.); (J.H.J.)
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Weinisch P, Raffler J, Römisch-Margl W, Arnold M, Mohney RP, Rist MJ, Prehn C, Skurk T, Hauner H, Daniel H, Suhre K, Kastenmüller G. The HuMet Repository: Watching human metabolism at work. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.08.550079. [PMID: 37609175 PMCID: PMC10441358 DOI: 10.1101/2023.08.08.550079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
The human metabolism constantly responds to stimuli such as food intake, fasting, exercise, and stress, triggering adaptive biochemical processes across multiple metabolic pathways. To understand the role of these processes and disruptions thereof in health and disease, detailed documentation of healthy metabolic responses is needed but still scarce on a time-resolved metabolome-wide level. Here, we present the HuMet Repository, a web-based resource for exploring dynamic metabolic responses to six physiological challenges (exercise, 36 h fasting, oral glucose and lipid loads, mixed meal, cold stress) in healthy subjects. For building this resource, we integrated existing and newly derived metabolomics data measured in blood, urine, and breath samples of 15 young healthy men at up to 56 time points during the six highly standardized challenge tests conducted over four days. The data comprise 1.1 million data points acquired on multiple platforms with temporal profiles of 2,656 metabolites from a broad range of biochemical pathways. By embedding the dataset into an interactive web application, we enable users to easily access, search, filter, analyze, and visualize the time-resolved metabolomic readouts and derived results. Users can put metabolites into their larger context by identifying metabolites with similar trajectories or by visualizing metabolites within holistic metabolic networks to pinpoint pathways of interest. In three showcases, we outline the value of the repository for gaining biological insights and generating hypotheses by analyzing the wash-out of dietary markers, the complementarity of metabolomics platforms in dynamic versus cross-sectional data, and similarities and differences in systemic metabolic responses across challenges. With its comprehensive collection of time-resolved metabolomics data, the HuMet Repository, freely accessible at https://humet.org/, is a reference for normal, healthy responses to metabolic challenges in young males. It will enable researchers with and without computational expertise, to flexibly query the data for their own research into the dynamics of human metabolism.
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Affiliation(s)
- Patrick Weinisch
- Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Johannes Raffler
- Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
- Digital Medicine, University Hospital of Augsburg, Augsburg, Germany
| | - Werner Römisch-Margl
- Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Matthias Arnold
- Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
- Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
| | | | - Manuela J. Rist
- Department of Physiology and Biochemistry of Nutrition, Max Rubner-Institut, Karlsruhe, Germany
| | - Cornelia Prehn
- Metabolomics and Proteomics Core, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Thomas Skurk
- ZIEL Institute for Food and Health, Core Facility Human Studies, Technical University of Munich, Freising, Germany
- Else Kröner Fresenius Center of Nutritional Medicine, Department of Food and Nutrition, Technical University of Munich, Freising, Germany
| | - Hans Hauner
- Else Kröner Fresenius Center of Nutritional Medicine, Department of Food and Nutrition, Technical University of Munich, Freising, Germany
- Institute for Nutritional Medicine, School of Medicine, Technical University of Munich, Munich, Germany
| | - Hannelore Daniel
- Department of Food and Nutrition, Technical University of Munich, Freising, Germany
| | - Karsten Suhre
- Department of Biophysics and Physiology, Weill Cornell Medicine - Qatar, Doha, Qatar
| | - Gabi Kastenmüller
- Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
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15
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Aleksic M, Golic I, Jankovic A, Cvoro A, Korac A. ACOX-driven peroxisomal heterogeneity and functional compartmentalization in brown adipocytes of hypothyroid rats. ROYAL SOCIETY OPEN SCIENCE 2023; 10:230109. [PMID: 37153362 PMCID: PMC10154930 DOI: 10.1098/rsos.230109] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 04/11/2023] [Indexed: 05/09/2023]
Abstract
We previously demonstrated that hypothyroidism increases peroxisomal biogenesis in rat brown adipose tissue (BAT). We also showed heterogeneity in peroxisomal origin and their unique structural association with mitochondria and/or lipid bodies to carry out β-oxidation, contributing thus to BAT thermogenesis. Distinctive heterogeneity creates structural compartmentalization within peroxisomal population, raising the question of whether it is followed by their functional compartmentalization regarding localization/colocalization of two main acyl-CoA oxidase (ACOX) isoforms, ACOX1 and ACOX3. ACOX is the first and rate-limiting enzyme of peroxisomal β-oxidation, and, to date, their protein expression patterns in BAT have not been fully defined. Therefore, we used methimazole-induced hypothyroidism to study ACOX1 and ACOX3 protein expression and their tissue immunolocalization. Additionally, we analysed their specific peroxisomal localization and colocalization in parallel with peroxisomal structural compartmentalization in brown adipocytes. Hypothyroidism caused a linear increase in ACOX1 expression, while a temporary decrease in ACOX3 levels is only recovered to the control level at day 21. Peroxisomal ACOX1 and ACOX3 localization and colocalization patterns entirely mirrored heterogeneous peroxisomal biogenesis pathways and structural compartmentalization, e.g. associations with mitochondria and/or lipid bodies. Hence, different ACOX isoforms localization/colocalization creates distinct functional heterogeneity of peroxisomes and drives their functional compartmentalization in rat brown adipocytes.
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Affiliation(s)
- Marija Aleksic
- Center for Electron Microscopy, Faculty of Biology, University of Belgrade, Belgrade 11000, Serbia
| | - Igor Golic
- Center for Electron Microscopy, Faculty of Biology, University of Belgrade, Belgrade 11000, Serbia
| | - Aleksandra Jankovic
- Institute for Biological Research 'Sinisa Stankovic'—National Institute of Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
| | - Aleksandra Cvoro
- Center for Electron Microscopy, Faculty of Biology, University of Belgrade, Belgrade 11000, Serbia
| | - Aleksandra Korac
- Center for Electron Microscopy, Faculty of Biology, University of Belgrade, Belgrade 11000, Serbia
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16
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Gu X, Wei M, Hu F, Ouyang H, Huang Z, Lu B, Ji L. Chlorogenic acid ameliorated non-alcoholic steatohepatitis via alleviating hepatic inflammation initiated by LPS/TLR4/MyD88 signaling pathway. Chem Biol Interact 2023; 376:110461. [PMID: 36965689 DOI: 10.1016/j.cbi.2023.110461] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/15/2023] [Accepted: 03/19/2023] [Indexed: 03/27/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is a severe pathological stage in non-alcoholic fatty liver disease (NAFLD) and is generally recognized to be induced by chronic inflammation. Natural compound chlorogenic acid (CGA) is well-known for its anti-inflammatory capacity. This study aimed at evaluating the alleviation of CGA on NASH and further exploring its engaged mechanism via focusing on abrogating hepatic inflammation. Our results showed that CGA had a good amelioration on NASH in vivo. CGA alleviated liver oxidative injury by inducing nuclear factor erythroid 2-related factor 2 (Nrf2) activation and reduced liver steatosis via up-regulating peroxisome proliferator-activated receptor-alpha (PPARα). CGA attenuated hepatic inflammation in vivo, but didn't decrease the elevated lipopolysaccharide (LPS) content. CGA blocked the activation of nuclear factor kappa-B (NFκB) or inflammasome both in MCDD-fed mice and in LPS-stimulated macrophages. CGA was found to directly bind to myeloid differentiation primary response 88 (MyD88), and thus competitively blocked the interaction between toll-like receptor 4 (TLR4) and MyD88, thereby abrogating hepatic inflammation initiated by LPS-TLR4-MyD88. Moreover, the CGA-provided anti-inflammatory effect was obviously disappeared in macrophages overexpressed MyD88. Hence, CGA has an excellent efficacy in improving NASH. CGA alleviated liver inflammation during NASH progression through blocking LPS-TLR4-MyD88 signaling pathway via directly binding to MyD88.
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Affiliation(s)
- Xinnan Gu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Mengjuan Wei
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Feifei Hu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hao Ouyang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zhenlin Huang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Bin Lu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lili Ji
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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17
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Li D, Dai D, Xiong G, Lan S, Zhang C. Metal-Based Nanozymes with Multienzyme-Like Activities as Therapeutic Candidates: Applications, Mechanisms, and Optimization Strategy. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2205870. [PMID: 36513384 DOI: 10.1002/smll.202205870] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/21/2022] [Indexed: 06/17/2023]
Abstract
Most nanozymes in development for medical applications only exhibit single-enzyme-like activity, and are thus limited by insufficient catalytic activity and dysfunctionality in complex pathological microenvironments. To overcome the impediments of limited substrate availabilities and concentrations, some metal-based nanozymes may mimic two or more activities of natural enzymes to catalyze cascade reactions or to catalyze multiple substrates simultaneously, thereby amplifying catalysis. Metal-based nanozymes with multienzyme-like activities (MNMs) may adapt to dissimilar catalytic conditions to exert different enzyme-like effects. These multienzyme-like activities can synergize to realize "self-provision of the substrate," in which upstream catalysts produce substrates for downstream catalytic reactions to overcome the limitation of insufficient substrates in the microenvironment. Consequently, MNMs exert more potent antitumor, antibacterial, and anti-inflammatory effects in preclinical models. This review summarizes the cellular effects and underlying mechanisms of MNMs. Their potential medical utility and optimization strategy from the perspective of clinical requirements are also discussed, with the aim to provide a theoretical reference for the design, development, and therapeutic application of their catalytic effects.
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Affiliation(s)
- Dan Li
- Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Danni Dai
- Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Gege Xiong
- Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Shuquan Lan
- Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Chao Zhang
- Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China
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18
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Apoptosis induction in human prostate cancer cells related to the fatty acid metabolism by wogonin-mediated regulation of the AKT-SREBP1-FASN signaling network. Food Chem Toxicol 2022; 169:113450. [DOI: 10.1016/j.fct.2022.113450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 09/04/2022] [Accepted: 09/28/2022] [Indexed: 11/21/2022]
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19
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Kong A, Xu D, Hao T, Liu Q, Zhan R, Mai K, Ai Q. Role of acyl-coenzyme A oxidase 1 (ACOX1) on palmitate-induced inflammation and ROS production of macrophages in large yellow croaker (Larimichthys crocea). DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2022; 136:104501. [PMID: 35961593 DOI: 10.1016/j.dci.2022.104501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 07/28/2022] [Accepted: 07/28/2022] [Indexed: 06/15/2023]
Abstract
Acyl-coenzyme A oxidase 1 (ACOX1) is the rate-limiting enzyme in peroxisomal β-oxidation, and it plays an essential role in mediating the inflammatory response and reactive oxygen species (ROS) metabolism in mammals. However, the role of ACOX1 in fish has not been completely elucidated. Herein, this study was conducted to investigate the role of large yellow croaker (Larimichthys crocea) ACOX1 (Lc-ACOX1) on palmitate (PA)-induced inflammation and ROS production. In this study, Lc-ACOX1 was cloned and characterized. The full-length CDS of Lc-acox1 was 1986 bp, encoding 661 amino acids. Tissue distribution results showed that the gene expression of Lc-acox1 was the highest in the intestine and the lowest in the spleen. Moreover, results showed that the mRNA expression of Lc-acox1 was upregulated by PA, with elevated pro-inflammatory gene expression, including il-1β, il-6, il-8, tnf-α, cox2 and ifn-γ, as well as ROS content in macrophages of large yellow croaker. Furthermore, the role of Lc-ACOX1 in inflammation induced by PA was investigated by using the ACOX1 inhibitor TDYA. Treatment of macrophages with TDYA reduced the mRNA expression of pro-inflammatory genes induced by PA. Moreover, inhibition of ACOX1 reduced the elevated level of ROS caused by PA and increased the mRNA expression of antioxidant genes. In conclusion, this study first identified that fish ACOX1 was involved in the PA-induced inflammatory response and ROS production.
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Affiliation(s)
- Adong Kong
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Dan Xu
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Tingting Hao
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Qiangde Liu
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Rui Zhan
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Kangsen Mai
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, 1 Wenhai Road, 266237, Qingdao, Shandong, PR China
| | - Qinghui Ai
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, 1 Wenhai Road, 266237, Qingdao, Shandong, PR China.
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20
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Xia QS, Gao Y, Wen-Bin W, Wu F, Dong H, Xu LJ, Fang K, Hu ML, Yuan F, Lu FE, Gong J. Ban-xia-xie-xin-tang ameliorates hepatic steatosis by regulating Cidea and Cidec expression in HFD-fed mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 105:154351. [PMID: 35908522 DOI: 10.1016/j.phymed.2022.154351] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/03/2022] [Accepted: 07/19/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Ban-xia-xie-xin-tang (BXXXT) has been applied in treating metabolic diseases, such as nonalcohol fatty liver disease, diabetes mellitus, and obesity. However, the underlying molecular mechanism of BXXXT in treating diabetes mellitus is unknown. PURPOSE To clarify the underlying molecular mechanism of BXXXT in alleviating hepatic steatosis in high-fat diet (HFD)-fed mice. METHODS After 12 weeks of HFD treatment, mice were administered BXXXT for 4 weeks. The main chemical components of BXXXT were identified by UPLC-TQ-MS/MS. Indicators associated with insulin resistance and lipid metabolism were detected. The effect of improving glucose and lipid metabolism between BXXXT and the different components was compared. Differentially expressed genes (DEGs) were identified by hepatic transcriptomics. Key DEGs and proteins were further detected by real-time quantitative polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence staining. LDs and mitochondria were detected by transmission electron microscopy. RESULTS First of all, our data demonstrated that the capacity to improve glucose and lipid metabolism for BXXXT was significantly superior to different components of BXXXT. BXXXT was found to improve HFD-induced insulin resistance. Moreover, BXXXT decreased weight, serum/hepatic triglycerides, total cholesterol, and FFAs to alleviate HFD-induced hepatic steatosis. According to the results of the hepatic transcription, Cidea and Cidec were identified as critical DEGs for promoting LD fusion and reducing FFAs β-oxidation in mitochondria and peroxisome resulting in hepatic steatosis, which was reversed by BXXXT. CONCLUSION BXXXT ameliorates HFD-induced hepatic steatosis and insulin resistance by increasing Cidea and Cidec-mediated mitochondrial and peroxisomal fatty acid oxidation, which may provide a potential strategy for therapy of NAFLD and T2DM.
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Affiliation(s)
- Qing-Song Xia
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Yang Gao
- Beijing Tcmages Pharmaceutical Co., Ltd, Beijing 100000, China
| | - Wu Wen-Bin
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Fan Wu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Hui Dong
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Li-Jun Xu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Ke Fang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Mei-Lin Hu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Fen Yuan
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Fu-Er Lu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
| | - Jing Gong
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
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21
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Wang Z, Ye M, Zhang XJ, Zhang P, Cai J, Li H, She ZG. Impact of NAFLD and its pharmacotherapy on lipid profile and CVD. Atherosclerosis 2022; 355:30-44. [PMID: 35872444 DOI: 10.1016/j.atherosclerosis.2022.07.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 06/16/2022] [Accepted: 07/13/2022] [Indexed: 11/21/2022]
Abstract
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Increasing evidence suggests that, in addition to traditional metabolic risk factors such as obesity, hypercholesterolemia, hypertension, diabetes mellitus, and insulin resistance (IR), nonalcoholic fatty liver disease (NAFLD) is an emerging driver of ASCVD via multiple mechanisms, mainly by disrupting lipid metabolism. The lack of pharmaceutical treatment has spurred substantial investment in the research and development of NAFLD drugs. However, many reagents with promising therapeutic potential for NAFLD also have considerable impacts on the circulating lipid profile. In this review, we first summarize the mechanisms linking lipid dysregulation in NAFLD to the progression of ASCVD. Importantly, we highlight the potential risks of/benefits to ASCVD conferred by NAFLD pharmaceutical treatments and discuss potential strategies and next-generation drugs for treating NAFLD without the unwanted side effects.
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Affiliation(s)
- Zhenya Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China
| | - Mao Ye
- Department of Cardiology, Huanggang Central Hospital, HuBei Province, China; Huanggang Institute of Translational Medicine, 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, Changsha, China
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China; Huanggang Institute of Translational Medicine, Huanggang, China.
| | - Zhi-Gang She
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China.
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22
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Aggarwal S, Trehanpati N, Nagarajan P, Ramakrishna G. The Clock-NAD + -Sirtuin connection in nonalcoholic fatty liver disease. J Cell Physiol 2022; 237:3164-3180. [PMID: 35616339 DOI: 10.1002/jcp.30772] [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: 02/26/2022] [Revised: 04/27/2022] [Accepted: 05/02/2022] [Indexed: 11/10/2022]
Abstract
Nonalcoholic or metabolic associated fatty liver disease (NAFLD/MAFLD) is a hepatic reflection of metabolic derangements characterized by excess fat deposition in the hepatocytes. Identifying metabolic regulatory nodes in fatty liver pathology is essential for effective drug targeting. Fatty liver is often associated with circadian rhythm disturbances accompanied with alterations in physical and feeding activities. In this regard, both sirtuins and clock machinery genes have emerged as critical metabolic regulators in maintaining liver homeostasis. Knockouts of either sirtuins or clock genes result in obesity associated with the fatty liver phenotype. Sirtuins (SIRT1-SIRT7) are a highly conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, protecting cells from metabolic stress by deacetylating vital proteins associated with lipid metabolism. Circadian rhythm is orchestrated by oscillations in expression of master regulators (BMAL1 and CLOCK), which in turn regulate rhythmic expression of clock-controlled genes involved in lipid metabolism. The circadian metabolite, NAD+ , serves as a crucial link connecting clock genes to sirtuin activity. This is because, NAMPT which is a rate limiting enzyme in NAD+ biosynthesis is transcriptionally regulated by the clock genes and NAD+ in turn is a cofactor regulating the deacetylation activity of sirtuins. Intriguingly, on one hand the core circadian clock regulates the sirtuin activity and on the other hand the activated sirtuins regulate the acetylation status of clock proteins thereby affecting their transcriptional functions. Thus, the Clock-NAD+-Sirtuin connection represents a novel "feedback loop" circuit that regulates the metabolic machinery. The current review underpins the importance of NAD+ on the sirtuin and clock connection in preventing fatty liver disorder.
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Affiliation(s)
- Savera Aggarwal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Nirupma Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Perumal Nagarajan
- Department of Experimental Animal Facility, National Institute of Immunology, New Delhi, India
| | - Gayatri Ramakrishna
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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23
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Errafii K, Khalifa O, Al-Akl NS, Arredouani A. Comparative Transcriptome Analysis Reveals That Exendin-4 Improves Steatosis in HepG2 Cells by Modulating Signaling Pathways Related to Lipid Metabolism. Biomedicines 2022; 10:1020. [PMID: 35625757 PMCID: PMC9138370 DOI: 10.3390/biomedicines10051020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 04/09/2022] [Accepted: 04/11/2022] [Indexed: 01/27/2023] Open
Abstract
No therapy exists for non-alcoholic fatty liver disease (NAFLD). However, glucagon-like peptide receptor agonists (GLP-1RAs) showed a beneficial effect on NAFLD, although the underpinning mechanisms remain unclear due to their pleiotropic effects. We examined the implicated signaling pathways using comparative transcriptomics in a cell model of steatosis to overcome pleiotropy. We treated steatotic HepG2 cells with the GLP-1RA Exendin-4 (Ex-4). We compared the transcriptome profiles of untreated steatotic, and Ex-4-treated steatotic cells, and used Ingenuity Pathway Analysis (IPA) to identify the signaling pathways and associated genes involved in the protective effect of Ex-4. Ex-4 treatment significantly reduces steatosis. RNA-seq analysis revealed 209 differentially expressed genes (DEGs) between steatotic and untreated cells, with farnesoid X receptor/retinoid X receptor (FXR/RXR) (p = 8.9 × 10-7) activation being the top regulated canonical pathway identified by IPA. Furthermore, 1644 DEGs were identified between steatotic cells and Ex-4-treated cells, with liver X receptor/retinoid X receptor (LXR/RXR) (p = 2.02 × 10-7) and FXR/RXR (p = 3.28 × 10-7) activation being the two top canonical pathways. The top molecular and cellular functions between untreated and steatotic cells were lipid metabolism, molecular transport, and small molecular biochemistry, while organismal injury and abnormalities, endocrine system disorders, and gastrointestinal disease were the top three molecular and cellular functions between Ex-4-treated and steatotic cells. Genes overlapping steatotic cells and Ex-4-treated cells were associated with several lipid metabolism processes. Unique transcriptomic differences exist between steatotic cells and Ex-4-treated steatotic cells, providing an important resource for understanding the mechanisms that underpin the protective effect of GLP-1RAs on NAFLD and for the identification of novel therapeutic targets for NAFLD.
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Affiliation(s)
- Khaoula Errafii
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar;
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar; (O.K.); (N.S.A.-A.)
- African Genome Center, Mohammed VI Polytechnic University (UM6P), Ben Guerir 43151, Morocco
| | - Olfa Khalifa
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar; (O.K.); (N.S.A.-A.)
| | - Neyla S. Al-Akl
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar; (O.K.); (N.S.A.-A.)
| | - Abdelilah Arredouani
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar;
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar; (O.K.); (N.S.A.-A.)
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24
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Miyahara H, Hasegawa K, Yashiro M, Ohara T, Fujisawa M, Yoshimura T, Matsukawa A, Tsukahara H. Thioredoxin interacting protein protects mice from fasting induced liver steatosis by activating ER stress and its downstream signaling pathways. Sci Rep 2022; 12:4819. [PMID: 35314758 PMCID: PMC8938456 DOI: 10.1038/s41598-022-08791-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
Under normal conditions, fasting results in decreased protein disulfide isomerase (PDI) activity and accumulation of unfolded proteins, leading to the subsequent activation of the unfolded protein response (UPR)/autophagy signaling pathway to eliminate damaged mitochondria. Fasting also induces upregulation of thioredoxin-interacting protein (TXNIP) expression and mice deficient of this protein (TXNIP-KO mice) was shown to develop severe hypoglycemia, hyperlipidemia and liver steatosis (LS). In the present study, we aimed to determine the role of TXNIP in fasting-induced LS by using male TXNIP-KO mice that developed LS without severe hypoglycemia. In TXNIP-KO mice, fasting induced severe microvesicular LS. Examinations by transmission electron microscopy revealed mitochondria with smaller size and deformities and the presence of few autophagosomes. The expression of β-oxidation-associated genes remained at the same level and the level of LC3-II was low. PDI activity level stayed at the original level and the levels of p-IRE1 and X-box binding protein 1 spliced form (sXBP1) were lower. Interestingly, treatment of TXNIP-KO mice with bacitracin, a PDI inhibitor, restored the level of LC3-II after fasting. These results suggest that TXNIP regulates PDI activity and subsequent activation of the UPR/autophagy pathway and plays a protective role in fasting-induced LS.
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Affiliation(s)
- Hiroyuki Miyahara
- Department of Pediatrics, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan. .,Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
| | - Kosei Hasegawa
- Department of Pediatrics, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Masato Yashiro
- Department of Pediatrics, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Toshiaki Ohara
- Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Masayoshi Fujisawa
- Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Teizo Yoshimura
- Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Akihiro Matsukawa
- Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hirokazu Tsukahara
- Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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25
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Szanto I. NADPH Oxidase 4 (NOX4) in Cancer: Linking Redox Signals to Oncogenic Metabolic Adaptation. Int J Mol Sci 2022; 23:ijms23052702. [PMID: 35269843 PMCID: PMC8910662 DOI: 10.3390/ijms23052702] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 02/21/2022] [Accepted: 02/22/2022] [Indexed: 02/04/2023] Open
Abstract
Cancer cells can survive and maintain their high proliferation rate in spite of their hypoxic environment by deploying a variety of adaptative mechanisms, one of them being the reorientation of cellular metabolism. A key aspect of this metabolic rewiring is the promotion of the synthesis of antioxidant molecules in order to counter-balance the hypoxia-related elevation of reactive oxygen species (ROS) production and thus combat the onset of cellular oxidative stress. However, opposite to their negative role in the inception of oxidative stress, ROS are also key modulatory components of physiological cellular metabolism. One of the major physiological cellular ROS sources is the NADPH oxidase enzymes (NOX-es). Indeed, NOX-es produce ROS in a tightly regulated manner and control a variety of cellular processes. By contrast, pathologically elevated and unbridled NOX-derived ROS production is linked to diverse cancerogenic processes. In this respect, NOX4, one of the members of the NOX family enzymes, is of particular interest. In fact, NOX4 is closely linked to hypoxia-related signaling and is a regulator of diverse metabolic processes. Furthermore, NOX4 expression and function are altered in a variety of malignancies. The aim of this review is to provide a synopsis of our current knowledge concerning NOX4-related processes in the oncogenic metabolic adaptation of cancer cells.
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Affiliation(s)
- Ildiko Szanto
- Service of Endocrinology, Diabetology, Nutrition and Patient Education, Department of Internal Medicine, Geneva University Hospitals, Diabetes Center of the Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
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26
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Di Pasqua LG, Cagna M, Berardo C, Vairetti M, Ferrigno A. Detailed Molecular Mechanisms Involved in Drug-Induced Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: An Update. Biomedicines 2022; 10:194. [PMID: 35052872 PMCID: PMC8774221 DOI: 10.3390/biomedicines10010194] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are some of the biggest public health challenges due to their spread and increasing incidence around the world. NAFLD is characterized by intrahepatic lipid deposition, accompanied by dyslipidemia, hypertension, and insulin resistance, leading to more serious complications. Among the various causes, drug administration for the treatment of numerous kinds of diseases, such as antiarrhythmic and antihypertensive drugs, promotes the onset and progression of steatosis, causing drug-induced hepatic steatosis (DIHS). Here, we reviewed in detail the major classes of drugs that cause DIHS and the specific molecular mechanisms involved in these processes. Eight classes of drugs, among the most used for the treatment of common pathologies, were considered. The most diffused mechanism whereby drugs can induce NAFLD/NASH is interfering with mitochondrial activity, inhibiting fatty acid oxidation, but other pathways involved in lipid homeostasis are also affected. PubMed research was performed to obtain significant papers published up to November 2021. The key words included the class of drugs, or the specific compound, combined with steatosis, nonalcoholic steatohepatitis, fibrosis, fatty liver and hepatic lipid deposition. Additional information was found in the citations listed in other papers, when they were not displayed in the original search.
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Affiliation(s)
- Laura Giuseppina Di Pasqua
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Marta Cagna
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Clarissa Berardo
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Mariapia Vairetti
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Andrea Ferrigno
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
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27
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Dutta RK, Lee JN, Maharjan Y, Park C, Choe SK, Ho YS, Park R. Catalase deficiency facilitates the shuttling of free fatty acid to brown adipose tissue through lipolysis mediated by ROS during sustained fasting. Cell Biosci 2021; 11:201. [PMID: 34876210 PMCID: PMC8650429 DOI: 10.1186/s13578-021-00710-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 11/11/2021] [Indexed: 12/30/2022] Open
Abstract
Background Fatty acids (FA) derived from adipose tissue and liver serve as the main fuel in thermogenesis of brown adipose tissue (BAT). Catalase, a peroxisomal enzyme, plays an important role in maintaining intracellular redox homeostasis by decomposing hydrogen peroxide to either water or oxygen that oxidize and provide fuel for cellular metabolism. Although the antioxidant enzymatic activity of catalase is well known, its role in the metabolism and maintenance of energy homeostasis has not yet been revealed. The present study investigated the role of catalase in lipid metabolism and thermogenesis during nutrient deprivation in catalase-knockout (KO) mice. Results We found that hepatic triglyceride accumulation in KO mice decreased during sustained fasting due to lipolysis through reactive oxygen species (ROS) generation in adipocytes. Furthermore, the free FA released from lipolysis were shuttled to BAT through the activation of CD36 and catabolized by lipoprotein lipase in KO mice during sustained fasting. Although the exact mechanism for the activation of the FA receptor enzyme, CD36 in BAT is still unclear, we found that ROS generation in adipocytes mediated the shuttling of FA to BAT. Conclusions Taken together, our findings uncover the novel role of catalase in lipid metabolism and thermogenesis in BAT, which may be useful in understanding metabolic dysfunction. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13578-021-00710-5.
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Affiliation(s)
- Raghbendra Kumar Dutta
- Department of Biomedical Science & Engineering, GRI, Gwangju Institute of Science & Technology, Gwangju, 61005, Republic of Korea
| | - Joon No Lee
- Department of Biomedical Science & Engineering, GRI, Gwangju Institute of Science & Technology, Gwangju, 61005, Republic of Korea
| | - Yunash Maharjan
- Department of Biomedical Science & Engineering, GRI, Gwangju Institute of Science & Technology, Gwangju, 61005, Republic of Korea
| | - Channy Park
- Department of Biomedical Science & Engineering, GRI, Gwangju Institute of Science & Technology, Gwangju, 61005, Republic of Korea
| | - Seong-Kyu Choe
- Department of Microbiology and Center for Metabolic Function Regulation, Wonkwang University School of Medicine, Iksan, Jeonbuk, 54538, Republic of Korea
| | - Ye-Shih Ho
- Institute of Environmental Health Sciences and Department of Biochemistry and Molecular Biology, Wayne State University, Detroit, MI, 48201, USA
| | - Raekil Park
- Department of Biomedical Science & Engineering, GRI, Gwangju Institute of Science & Technology, Gwangju, 61005, Republic of Korea.
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28
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Biagioli M, Fiorucci S. Bile acid activated receptors: Integrating immune and metabolic regulation in non-alcoholic fatty liver disease. LIVER RESEARCH 2021; 5:119-141. [PMID: 39957845 PMCID: PMC11791866 DOI: 10.1016/j.livres.2021.08.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 07/29/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023]
Abstract
Bile acids are a family of atypical steroids generated at the interface of liver-intestinal microbiota acting on a ubiquitously expressed family of membrane and nuclear receptors known as bile acid activated receptors. The two best characterized receptors of this family are the nuclear receptor, farnesoid X receptor (FXR) and the G protein-coupled receptor, G protein-coupled bile acid receptor 1 (GPBAR1). FXR and GPBAR1 regulate major aspects of lipid and glucose metabolism, energy balance, autophagy and immunity and have emerged as potential pharmaceutical targets for the treatment of metabolic and inflammatory disorders. Clinical trials in non-alcoholic fatty liver disease (NAFLD), however, have shown that selective FXR agonists cause side effects while their efficacy is partial. Because FXR and GPBAR1 exert additive effects, dual FXR/GPBAR1 ligands have been developed for the treatment of metabolic disorders and are currently advanced to clinical trials. Here, we will review the role of FXR and GPBAR1 agonism in NAFLD and how the two receptors could be exploited to target multiple components of the disease.
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Affiliation(s)
- Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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29
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Impact of Parenteral Lipid Emulsion Components on Cholestatic Liver Disease in Neonates. Nutrients 2021; 13:nu13020508. [PMID: 33557154 PMCID: PMC7913904 DOI: 10.3390/nu13020508] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/27/2021] [Accepted: 02/02/2021] [Indexed: 12/30/2022] Open
Abstract
Total parenteral nutrition (TPN) is a life-saving intervention for infants that are unable to feed by mouth. Infants that remain on TPN for extended periods of time are at risk for the development of liver injury in the form of parenteral nutrition associated cholestasis (PNAC). Current research suggests the lipid component of TPN is a factor in the development of PNAC. Most notably, the fatty acid composition, vitamin E concentration, and presence of phytosterols are believed key mediators of lipid emulsion driven PNAC development. New emulsions comprised of fish oil and medium chain triglycerides show promise for reducing the incidence of PNAC in infants. In this review we will cover the current clinical studies on the benefit of fish oil and medium chain triglyceride containing lipid emulsions on the development of PNAC, the current constituents of lipid emulsions that may modulate the prevalence of PNAC, and potential new supplements to TPN to further reduce the incidence of PNAC.
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30
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Berardo C, Di Pasqua LG, Cagna M, Richelmi P, Vairetti M, Ferrigno A. Nonalcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: Current Issues and Future Perspectives in Preclinical and Clinical Research. Int J Mol Sci 2020; 21:ijms21249646. [PMID: 33348908 PMCID: PMC7766139 DOI: 10.3390/ijms21249646] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a continuum of liver abnormalities often starting as simple steatosis and to potentially progress into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Because of its increasing prevalence, NAFLD is becoming a major public health concern, in parallel with a worldwide increase in the recurrence rate of diabetes and metabolic syndrome. It has been estimated that NASH cirrhosis may surpass viral hepatitis C and become the leading indication for liver transplantation in the next decades. The broadening of the knowledge about NASH pathogenesis and progression is of pivotal importance for the discovery of new targeted and more effective therapies; aim of this review is to offer a comprehensive and updated overview on NAFLD and NASH pathogenesis, the most recommended treatments, drugs under development and new drug targets. The most relevant in vitro and in vivo models of NAFLD and NASH will be also reviewed, as well as the main molecular pathways involved in NAFLD and NASH development.
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Affiliation(s)
| | | | | | | | | | - Andrea Ferrigno
- Correspondence: (L.G.D.P.); (A.F.); Tel.: +39-0382-986-451 (L.G.D.P.)
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Effect of Adrenergic Agonists on High-Fat Diet-Induced Hepatic Steatosis in Mice. Int J Mol Sci 2020; 21:ijms21249392. [PMID: 33321735 PMCID: PMC7764675 DOI: 10.3390/ijms21249392] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 12/07/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
The autonomic nervous system, consisting of sympathetic and parasympathetic branches, plays an important role in regulating metabolic homeostasis. The sympathetic nervous system (SNS) regulates hepatic lipid metabolism by regulating adrenergic receptor activation, resulting in the stimulation of hepatic very-low-density lipoprotein-triglyceride (TG) production in vivo. However, only a few studies on the relationship between SNS and hepatic steatosis have been reported. Here, we investigate the effect of adrenergic receptor agonists on hepatic steatosis in mice fed a high-fat diet (HFD). The α-adrenergic receptor agonist phenylephrine (10 mg/kg/d) or the β-adrenergic receptor agonist isoproterenol (30 mg/kg/d) was coadministered with HFD to male mice. After five weeks, hepatic steatosis, TG levels, and hepatic fat metabolism-related biomarkers were examined. HFD treatment induced hepatic steatosis, and cotreatment with phenylephrine, but not isoproterenol, attenuated this effect. Phenylephrine administration upregulated the mRNA levels of hepatic peroxisome proliferator-activated receptor alpha and its target genes (such as carnitine palmitoyltransferase 1) and increased hepatic β-hydroxybutyrate levels. Additionally, phenylephrine treatment increased the expression of the autophagosomal marker LC3-II but decreased that of p62, which is selectively degraded during autophagy. These results indicate that phenylephrine inhibits hepatic steatosis through stimulation of β-oxidation and autophagy in the liver.
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Kořínková L, Pražienková V, Černá L, Karnošová A, Železná B, Kuneš J, Maletínská L. Pathophysiology of NAFLD and NASH in Experimental Models: The Role of Food Intake Regulating Peptides. Front Endocrinol (Lausanne) 2020; 11:597583. [PMID: 33324348 PMCID: PMC7726422 DOI: 10.3389/fendo.2020.597583] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 10/28/2020] [Indexed: 12/12/2022] Open
Abstract
Obesity, diabetes, insulin resistance, sedentary lifestyle, and Western diet are the key factors underlying non-alcoholic fatty liver disease (NAFLD), one of the most common liver diseases in developed countries. In many cases, NAFLD further progresses to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and to hepatocellular carcinoma. The hepatic lipotoxicity and non-liver factors, such as adipose tissue inflammation and gastrointestinal imbalances were linked to evolution of NAFLD. Nowadays, the degree of adipose tissue inflammation was shown to directly correlate with the severity of NAFLD. Consumption of higher caloric intake is increasingly emerging as a fuel of metabolic inflammation not only in obesity-related disorders but also NAFLD. However, multiple causes of NAFLD are the reason why the mechanisms of NAFLD progression to NASH are still not well understood. In this review, we explore the role of food intake regulating peptides in NAFLD and NASH mouse models. Leptin, an anorexigenic peptide, is involved in hepatic metabolism, and has an effect on NAFLD experimental models. Glucagon-like peptide-1 (GLP-1), another anorexigenic peptide, and GLP-1 receptor agonists (GLP-1R), represent potential therapeutic agents to prevent NAFLD progression to NASH. On the other hand, the deletion of ghrelin, an orexigenic peptide, prevents age-associated hepatic steatosis in mice. Because of the increasing incidence of NAFLD and NASH worldwide, the selection of appropriate animal models is important to clarify aspects of pathogenesis and progression in this field.
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Affiliation(s)
- L. Kořínková
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czechia
| | - V. Pražienková
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czechia
| | - L. Černá
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czechia
| | - A. Karnošová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czechia
| | - B. Železná
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czechia
| | - J. Kuneš
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czechia
- Institute of Physiology, Czech Academy of Sciences, Prague, Czechia
| | - Lenka Maletínská
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czechia
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The Molecular Mechanisms by Which Vitamin D Prevents Insulin Resistance and Associated Disorders. Int J Mol Sci 2020; 21:ijms21186644. [PMID: 32932777 PMCID: PMC7554927 DOI: 10.3390/ijms21186644] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 09/07/2020] [Accepted: 09/09/2020] [Indexed: 02/06/2023] Open
Abstract
Numerous studies have shown that vitamin D deficiency is very common in modern societies and is perceived as an important risk factor in the development of insulin resistance and related diseases such as obesity and type 2 diabetes (T2DM). While it is generally accepted that vitamin D is a regulator of bone homeostasis, its ability to counteract insulin resistance is subject to debate. The goal of this communication is to review the molecular mechanism by which vitamin D reduces insulin resistance and related complications. The university library, PUBMED, and Google Scholar were searched to find relevant studies to be summarized in this review article. Insulin resistance is accompanied by chronic hyperglycaemia and inflammation. Recent studies have shown that vitamin D exhibits indirect antioxidative properties and participates in the maintenance of normal resting ROS level. Appealingly, vitamin D reduces inflammation and regulates Ca2+ level in many cell types. Therefore, the beneficial actions of vitamin D include diminished insulin resistance which is observed as an improvement of glucose and lipid metabolism in insulin-sensitive tissues.
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Neuschwander-Tetri BA. Therapeutic Landscape for NAFLD in 2020. Gastroenterology 2020; 158:1984-1998.e3. [PMID: 32061596 DOI: 10.1053/j.gastro.2020.01.051] [Citation(s) in RCA: 143] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 01/19/2020] [Accepted: 01/21/2020] [Indexed: 12/13/2022]
Abstract
Lifestyle modifications focused on healthy eating and regular exercise are the primary recommendations for patients with nonalcoholic steatohepatitis (NASH). However, for multiple societal, psychological, physical, genetic, and epigenetic reasons, the ability of people to adopt and sustain such changes is challenging and typically not successful. To end the epidemic of NASH and prevent its complications, including cirrhosis and hepatocellular carcinoma, pharmacological interventions are now being evaluated in clinical trials. Treatments include drugs targeting energy intake, energy disposal, lipotoxic liver injury, and the resulting inflammation and fibrogenesis that lead to cirrhosis. It is likely that patients develop the phenotype of NASH by multiple mechanisms, and thus the optimal treatments of NASH will likely evolve to personalized therapy once we understand the mechanistic underpinnings of NASH in each patient. Reviewed here is the treatment landscape in this rapidly evolving field with an emphasis on drugs in Phase 2 and Phase 3 trials.
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Burgoon LD, Angrish M, Garcia-Reyero N, Pollesch N, Zupanic A, Perkins E. Predicting the Probability that a Chemical Causes Steatosis Using Adverse Outcome Pathway Bayesian Networks (AOPBNs). RISK ANALYSIS : AN OFFICIAL PUBLICATION OF THE SOCIETY FOR RISK ANALYSIS 2020; 40:512-523. [PMID: 31721239 PMCID: PMC7397752 DOI: 10.1111/risa.13423] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 10/17/2019] [Accepted: 10/19/2019] [Indexed: 05/08/2023]
Abstract
Adverse outcome pathway Bayesian networks (AOPBNs) are a promising avenue for developing predictive toxicology and risk assessment tools based on adverse outcome pathways (AOPs). Here, we describe a process for developing AOPBNs. AOPBNs use causal networks and Bayesian statistics to integrate evidence across key events. In this article, we use our AOPBN to predict the occurrence of steatosis under different chemical exposures. Since it is an expert-driven model, we use external data (i.e., data not used for modeling) from the literature to validate predictions of the AOPBN model. The AOPBN accurately predicts steatosis for the chemicals from our external data. In addition, we demonstrate how end users can utilize the model to simulate the confidence (based on posterior probability) associated with predicting steatosis. We demonstrate how the network topology impacts predictions across the AOPBN, and how the AOPBN helps us identify the most informative key events that should be monitored for predicting steatosis. We close with a discussion of how the model can be used to predict potential effects of mixtures and how to model susceptible populations (e.g., where a mutation or stressor may change the conditional probability tables in the AOPBN). Using this approach for developing expert AOPBNs will facilitate the prediction of chemical toxicity, facilitate the identification of assay batteries, and greatly improve chemical hazard screening strategies.
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Affiliation(s)
- Lyle D. Burgoon
- US Army Engineer Research and Development Center, Vicksburg, MS, USA
- Address correspondence to Lyle D. Burgoon, Ph.D., Environmental Laboratory, US Army Corps Engineers, 3909 Halls Ferry Rd, Vicksburg, MS 39180;
| | - Michelle Angrish
- US Environmental Protection Agency, National Center for Environmental Assessment, Research Triangle Park, NC, USA
| | | | - Nathan Pollesch
- US Environmental Protection Agency, Mid-Continent Ecology Division, Duluth, MN, USA
| | - Anze Zupanic
- Eawag, Swiss Federal Institute for Aquatic Science and Technology, Dubendorf, Switzerland
| | - Edward Perkins
- US Army Engineer Research and Development Center, Vicksburg, MS, USA
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Role of farnesoid X receptor in hepatic steatosis in nonalcoholic fatty liver disease. Biomed Pharmacother 2019; 121:109609. [PMID: 31731192 DOI: 10.1016/j.biopha.2019.109609] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 10/23/2019] [Accepted: 10/25/2019] [Indexed: 12/12/2022] Open
Abstract
With the increased incidence of obesity, nonalcoholic fatty liver disease (NAFLD) has become a major global health concern. The pathogenesis of NAFLD has not yet been fully elucidated, and as few efficient pharmaceutical treatments are available for the condition, economic and medical burdens are heavy. Hepatic steatosis, as a precursor of NAFLD, plays a vital role in the pathological process of NAFLD. Hepatic steatosis is a consequence of lipid acquisition (i.e. free fatty acid uptake and de novo lipogenesis) exceeding lipid disposal (i.e. fatty acid oxidation and export as very-low-density lipoproteins). Therefore, restoring lipid homeostasis in the liver is an important therapeutic strategy of NAFLD. Farnesoid X receptor (FXR) is a major member of the ligand-activated nuclear receptor superfamily. Previous reviews have shown that FXR is a multipurpose receptor that plays an important role in regulating bile acid homeostasis, glucose and lipid metabolism, intestinal bacterial growth, and hepatic regeneration. This review focuses on the role of FXR in individual pathways that contribute to hepatic steatosis; it further demonstrates the molecular function of FXR in the pathogenesis of NAFLD.
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Chen YH, Chiu CC, Hung SW, Huang WC, Lee YP, Liu JY, Huang YT, Chen TH, Chuang HL. Gnotobiotic mice inoculated with Firmicutes, but not Bacteroidetes, deteriorate nonalcoholic fatty liver disease severity by modulating hepatic lipid metabolism. Nutr Res 2019; 69:20-29. [PMID: 31470288 DOI: 10.1016/j.nutres.2019.07.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 06/11/2019] [Accepted: 07/25/2019] [Indexed: 12/19/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a serious liver disorder and characterized by the hepatic accumulation of excess fatty acids. Clinical studies and animal models have shown a shift of gut microbiota from bacteroidetes to firmicutes in NAFLD patients and a diet-induced NAFLD mouse model. Therefore, we hypothesized that these 2 groups of bacteria may have differential effects on lipid metabolism in the liver, which further contributed to pathogenesis of NAFLD. To elucidate these effects, we inoculated two species of Bacteroidetes (B-group) or five species of Firmicutes (F-group) which were isolated from healthy individuals into germ-free mice. We found that the F-group induced elevated body weight, liver weight, and hepatic steatosis compared to the B-group under high-fat diet (HFD) conditions. The mRNA expression level of cluster of differentiation 36 (CD36) was elevated in the F-group compared to that in the B-group. Increased mRNA expression levels of fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD1), and diacylglycerol O-acyltransferase 2 (DGAT2) were also seen under HFD conditions in the F-group compared to that in the B-group. In addition, the expression level of miR802-5p was only elevated in the F-group under HFD conditions. Taken together, our results suggested that these specific species of Firmicutes may induce more hepatic steatosis by modulating fatty acid influx and lipogenesis compared to those of Bacteroidetes. These results may provide more understanding of the effects of gut microbiota on NAFLD.
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Affiliation(s)
- Yi-Hsun Chen
- Graduate Institute of Veterinary Pathobiology, National Chung Hsing University, Taichung, 402, Taiwan.
| | - Chien-Chao Chiu
- Division of Animal Industry, Animal Technology Laboratories, Agricultural Technology Research Institute, Miaoli, 350, Taiwan.
| | - Shao-Wen Hung
- Division of Animal Industry, Animal Technology Laboratories, Agricultural Technology Research Institute, Miaoli, 350, Taiwan.
| | - Wen-Ching Huang
- Department of Exercise and Health Science, National Taipei University of Nursing and Health Sciences, Taipei, 112, Taiwan.
| | - Yen-Peng Lee
- Graduate Institute of Veterinary Pathobiology, National Chung Hsing University, Taichung, 402, Taiwan.
| | - Ju-Yun Liu
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, 100, Taiwan; National Laboratory Animal Center, National Applied Research Laboratories Research Institute, Taipei, 115, Taiwan.
| | - Yen-Te Huang
- National Laboratory Animal Center, National Applied Research Laboratories Research Institute, Taipei, 115, Taiwan.
| | - Ter-Hsin Chen
- Graduate Institute of Veterinary Pathobiology, National Chung Hsing University, Taichung, 402, Taiwan.
| | - Hsiao-Li Chuang
- National Laboratory Animal Center, National Applied Research Laboratories Research Institute, Taipei, 115, Taiwan.
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Liu Y, Liao L, Chen Y, Han F. Effects of daphnetin on lipid metabolism, insulin resistance and oxidative stress in OA‑treated HepG2 cells. Mol Med Rep 2019; 19:4673-4684. [PMID: 30957185 PMCID: PMC6522799 DOI: 10.3892/mmr.2019.10139] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 03/27/2019] [Indexed: 01/07/2023] Open
Abstract
Non‑alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, and has high rates of morbidity and mortality worldwide. Daphnetin (DAP) possesses notable antioxidative, anti‑inflammatory and anticoagulant activities; DAP is an active ingredient extracted from Daphne Koreana Nakai. To investigate the effects and the underlying mechanism of DAP on NAFLD, we treated HepG2 cells with oleic acid (OA) and DAP simultaneously and non‑simultaneously. In the simultaneous treatment condition, HepG2 cells were co‑treated with 0.5 mM OA and DAP (5, 20, and 50 µM) for 24 h. In the non‑simultaneous treatment conditions, HepG2 cells were pretreated with 0.5 mM OA for 24 h, and then treated with DAP (5, 20 and 50 µM) for 24 h. Following the aforementioned treatments, the biochemical indexes associated with NAFLD were measured as follows: i) The intracellular contents of triglyceride (TG), reactive oxygen species (ROS) and fluorescent glucose 2‑[N‑(7‑nitrobenz‑2‑oxa‑1,3‑diazol‑4‑yl) amino]‑2‑deoxyglucose were analyzed with corresponding detection kits; and ii) the cellular expression levels of glycolipid metabolism‑ and oxidative stress‑related genes, including 5'AMP‑activated protein kinase (AMPK), sterol regulatory element‑binding protein‑1C (SREBP‑1C), patatin‑like phospholipase domain‑containing protein 3 (PNPLA3), peroxisome proliferator‑activated receptor α (PPARα), phosphoinositide 3‑kinase (PI3K), protein kinase B (AKT), nuclear factor‑like 2 (Nrf2), cytochrome P450 (CYP) 2E1 and CYP4A were determined by reverse transcription‑quantitative polymerase chain reaction and western blotting. The results revealed the potential mechanism underlying the effects of DAP on NAFLD in vitro: i) By increasing the phosphorylation of AMPK, DAP inhibited the expression of SREBP‑1C and PNPLA3, and induced that of PPARα. Lipid accumulation within hepatocytes was reduced; ii) by upregulating PI3K expression and pAKT/AKT levels, DAP may alleviate insulin resistance and promote hepatocellular glucose uptake; and iii) by upregulating the expression of Nrf2, DAP downregulated the expression of CYP2E1 and CYP4A, and the levels of reactive oxygen species in hepatocytes.
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Affiliation(s)
- Yayun Liu
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan, Hubei 430062, P.R. China
| | - Lu Liao
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan, Hubei 430062, P.R. China
| | - Yong Chen
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan, Hubei 430062, P.R. China
| | - Fengmei Han
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan, Hubei 430062, P.R. China
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Wu KM, Hsu YM, Ying MC, Tsai FJ, Tsai CH, Chung JG, Yang JS, Tang CH, Cheng LY, Su PH, Viswanadha VP, Kuo WW, Huang CY. High-density lipoprotein ameliorates palmitic acid-induced lipotoxicity and oxidative dysfunction in H9c2 cardiomyoblast cells via ROS suppression. Nutr Metab (Lond) 2019; 16:36. [PMID: 31149020 PMCID: PMC6537189 DOI: 10.1186/s12986-019-0356-5] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 04/18/2019] [Indexed: 01/22/2023] Open
Abstract
Background High levels circulating saturated fatty acids are associated with diabetes, obesity and hyperlipidemia. In heart, the accumulation of saturated fatty acids has been determined to play a role in the development of heart failure and diabetic cardiomyopathy. High-density lipoprotein (HDL) has been reported to possess key atheroprotective biological properties, including cellular cholesterol efflux capacity, anti-oxidative and anti-inflammatory activities. However, the underlying mechanisms are still largely unknown. Therefore, the aim of the present study is to test whether HDL could protect palmitic acid (PA)-induced cardiomyocyte injury and explore the possible mechanisms. Results H9c2 cells were pretreated with HDL (50–100 μg/ml) for 2 h followed by PA (0.5 mM) for indicated time period. Our results showed that HDL inhibited PA-induced cell death in a dose-dependent manner. Moreover, HDL rescued PA-induced ROS generation and the phosphorylation of JNK which in turn activated NF-κB-mediated inflammatory proteins expressions. We also found that PA impaired the balance of BCL2 family proteins, destabilized mitochondrial membrane potential, and triggered subsequent cytochrome c release into the cytosol and activation of caspase 3. These detrimental effects were ameliorated by HDL treatment. Conclusion PA-induced ROS accumulation and results in cardiomyocyte apoptosis and inflammation. However, HDL attenuated PA-induced lipotoxicity and oxidative dysfunction via ROS suppression. These results may provide insight into a possible molecular mechanism underlying HDL suppression of the free fatty acid-induced cardiomyocyte apoptosis.
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Affiliation(s)
- Kuen-Ming Wu
- 1Department of chest medicine, Jen-Ai Hospital, Taichung, Taiwan
| | - Yuan-Man Hsu
- 2Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Mei-Chin Ying
- 3Department of Food Nutrition and Health Biotechnology, Asia University, Taichung City, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung City, Taiwan
| | - Fuu-Jen Tsai
- 5School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 40402 Taiwan.,6China Medical University Children's Hospital, China Medical University, Taichung, Taiwan
| | - Chang-Hai Tsai
- 6China Medical University Children's Hospital, China Medical University, Taichung, Taiwan.,7Department of Healthcare Administration, Asia University, Taichung, Taiwan
| | - Jing-Gung Chung
- 2Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Jai-Sing Yang
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Chih-Hsin Tang
- 9Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.,10Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
| | - Li-Yi Cheng
- 11Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
| | - Po-Hua Su
- 12Department of Radiology, Jen-Ai Hospital, Taichung, Taiwan
| | | | - Wei-Wen Kuo
- 2Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Chih-Yang Huang
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.,14Department of Biotechnology, Asia University, Taichung, Taiwan.,15College of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
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Molecular drivers of non-alcoholic steatohepatitis are sustained in mild-to-late fibrosis progression in a guinea pig model. Mol Genet Genomics 2019; 294:649-661. [DOI: 10.1007/s00438-019-01537-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 02/06/2019] [Indexed: 01/03/2023]
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Conophylline inhibits high fat diet-induced non-alcoholic fatty liver disease in mice. PLoS One 2019; 14:e0210068. [PMID: 30689650 PMCID: PMC6349312 DOI: 10.1371/journal.pone.0210068] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 12/14/2018] [Indexed: 01/18/2023] Open
Abstract
Conophylline (CnP), a vinca alkaloid extracted from the leaves of the tropical plant Tabernaemontana divaricate, attenuates hepatic fibrosis in mice. We have previously shown that CnP inhibits non-alcoholic steatohepatitis (NASH) using a methionine-choline-deficient (MCD) diet-fed mouse model. However, little is known about the CnP mediated inhibition of hepatic steatosis in high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) mouse models. CnP (0.5 and 1 μg/g/body weight) was co-administered along with a high-fat diet to male BALB/c mice. After nine weeks of administering the high-fat diet, hepatic steatosis, triglyceride, and hepatic fat metabolism-related markers were examined. Administration of a high-fat diet for 9 weeks was found to induce hepatic steatosis. CnP dose-dependently attenuated the high-fat diet-induced hepatic steatosis. The diet also attenuated hepatic peroxisome proliferator-activated receptor alpha (PPARA) mRNA levels. PPARA is known to be involved in β-oxidation. CnP upregulated the mRNA levels of hepatic PPARA and its target genes, such as carnitine palmitoyl transferase 1 (CPT1) and CPT2, in a dose-dependent manner in the liver. Furthermore, levels of hepatic β-hydroxybutyrate, which is a type of ketone body, were increased by CnP in a dose-dependent manner. Finally, CnP increased the expression of the autophagosomal marker LC3-II and decreased the expression of p62, which are known to be selectively degraded during autophagy. These results indicate that CnP inhibits hepatic steatosis through the stimulation of β-oxidation and autophagy in the liver. Therefore, CnP might prove to be a suitable therapeutic target for NAFLD.
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HIF-1-dependent lipin1 induction prevents excessive lipid accumulation in choline-deficient diet-induced fatty liver. Sci Rep 2018; 8:14230. [PMID: 30242180 PMCID: PMC6155071 DOI: 10.1038/s41598-018-32586-w] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 09/11/2018] [Indexed: 02/06/2023] Open
Abstract
Adaptive responses to hypoxia regulate hepatic lipid metabolism, but their consequences in nonalcoholic fatty liver disease (NAFLD) are largely unknown. Here, we show that hypoxia inducible factor-1 (HIF-1), a key determinant of hypoxic adaptations, prevents excessive hepatic lipid accumulation in the progression of NAFLD. When exposed to a choline-deficient diet (CDD) for 4 weeks, the loss of hepatic Hif-1α gene accelerated liver steatosis with enhanced triglyceride accumulation in the liver compared to wild-type (WT) livers. Expression of genes involved in peroxisomal fatty acid oxidation was suppressed significantly in CDD-treated WT livers, whereas this reduction was further enhanced in Hif-1α-deficient livers. A lack of induction and nuclear accumulation of lipin1, a key regulator of the PPARα/PGC-1α pathway, could be attributed to impaired peroxisomal β-oxidation in Hif-1α-deficient livers. The lipin1-mediated binding of PPARα to the acyl CoA oxidase promoter was markedly reduced in Hif-1α-deficient mice exposed to a CDD. Moreover, forced Lipin1 expression restored the aberrant lipid accumulation caused by Hif-1α deletion in cells incubated in a choline-deficient medium. These results strongly suggest that HIF-1 plays a crucial role in the regulation of peroxisomal lipid metabolism by activating the expression and nuclear accumulation of lipin1 in NAFLD.
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Ipsen DH, Lykkesfeldt J, Tveden-Nyborg P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci 2018; 75:3313-3327. [PMID: 29936596 PMCID: PMC6105174 DOI: 10.1007/s00018-018-2860-6] [Citation(s) in RCA: 949] [Impact Index Per Article: 135.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 06/18/2018] [Accepted: 06/20/2018] [Indexed: 12/17/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently the world's most common liver disease, estimated to affect up to one-fourth of the population. Hallmarked by hepatic steatosis, NAFLD is associated with a multitude of detrimental effects and increased mortality. This narrative review investigates the molecular mechanisms of hepatic steatosis in NAFLD, focusing on the four major pathways contributing to lipid homeostasis in the liver. Hepatic steatosis is a consequence of lipid acquisition exceeding lipid disposal, i.e., the uptake of fatty acids and de novo lipogenesis surpassing fatty acid oxidation and export. In NAFLD, hepatic uptake and de novo lipogenesis are increased, while a compensatory enhancement of fatty acid oxidation is insufficient in normalizing lipid levels and may even promote cellular damage and disease progression by inducing oxidative stress, especially with compromised mitochondrial function and increased oxidation in peroxisomes and cytochromes. While lipid export initially increases, it plateaus and may even decrease with disease progression, sustaining the accumulation of lipids. Fueled by lipo-apoptosis, hepatic steatosis leads to systemic metabolic disarray that adversely affects multiple organs, placing abnormal lipid metabolism associated with NAFLD in close relation to many of the current life-style-related diseases.
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Affiliation(s)
- David Højland Ipsen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg C, Denmark
| | - Jens Lykkesfeldt
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg C, Denmark
| | - Pernille Tveden-Nyborg
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg C, Denmark.
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Bernhard A, Rasinger JD, Wisløff H, Kolbjørnsen Ø, Secher Myrmel L, Berntssen MH, Lundebye AK, Ørnsrud R, Madsen L. Subchronic dietary exposure to ethoxyquin dimer induces microvesicular steatosis in male BALB/c mice. Food Chem Toxicol 2018; 118:608-625. [DOI: 10.1016/j.fct.2018.06.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 05/11/2018] [Accepted: 06/04/2018] [Indexed: 12/13/2022]
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Hwang YC, Oh DH, Choi MC, Lee SY, Ahn KJ, Chung HY, Lim SJ, Chung SH, Jeong IK. Compound K attenuates glucose intolerance and hepatic steatosis through AMPK-dependent pathways in type 2 diabetic OLETF rats. Korean J Intern Med 2018; 33:347-355. [PMID: 28142230 PMCID: PMC5840580 DOI: 10.3904/kjim.2015.208] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 07/09/2015] [Accepted: 08/23/2015] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND/AIMS Non-alcoholic fatty liver disease is associated with insulin resistance. Compound K (CK) is the final metabolite of panaxadiol ginsenosides that have been shown to exert antidiabetic effects. However, the molecular mechanism of the antidiabetic effects in the liver have not been elucidated; further, whether CK has beneficial effects in hepatosteatosis remains unclear. Therefore, we evaluated the effect of CK on hepatosteatosis as well as its mechanism in high-fat diet (HFD)-fed type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. METHODS Twenty-four-week-old male OLETF rats were assigned to four groups: control (saline), CK 10 mg/kg, CK 25 mg/kg, or metformin 300 mg/kg (positive control); all treatments were administered orally for 12 weeks. RESULTS Fasting glucose levels of the CK25 group were significantly lower than those of the control group during the 12 weeks. The results of the oral glucose tolerance test showed that both the glucose concentration after glucose loading and the fasting insulin levels of the CK25 group were significantly lower than those of the control. Hepatosteatosis was significantly improved by CK25. CK25 and metformin significantly increased the phosphorylation of hepatic adenosine monophosphate-activated protein kinase (AMPK). CK25 significantly inhibited the expression of sterol regulatory element-binding protein-1c and fatty acid synthase, while upregulating that of peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase-1. CONCLUSIONS CK improved glucose intolerance and hepatosteatosis in HFD-fed OLETF rats through AMPK activation, which has dual mode of action that involves decreasing the synthesis of fatty acids and increasing fatty acid oxidation.
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Affiliation(s)
- Yoo-Cheol Hwang
- Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea
| | - Da-Hee Oh
- Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea
| | - Moon Chan Choi
- Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea
| | - Sang Yeoul Lee
- Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea
| | - Kyu-Jeong Ahn
- Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea
| | - Ho-Yeon Chung
- Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea
| | - Sung-Jig Lim
- Department of Pathology, Kyung Hee University School of Medicine, Seoul, Korea
| | - Sung Hyun Chung
- Department of Pharmacology and Clinical Pharmacy Laboratory, Kyung Hee University College of Pharmacy, Seoul, Korea
| | - In-Kyung Jeong
- Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea
- Correspondence to In-Kyung Jeong, M.D. Department of Endocrinology and Metabolism, Kyung Hee University Hospital at Gangdong, 892 Dongnam-ro, Gangdong-gu, Seoul 05278, Korea Tel: +82-2-440-6126 Fax: +82-2-440-6799 E-mail:
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A novel PPARα/γ agonist, propane-2-sulfonic acid octadec-9-enyl-amide, ameliorates insulin resistance and gluconeogenesis in vivo and vitro. Eur J Pharmacol 2018; 826:1-8. [PMID: 29476879 DOI: 10.1016/j.ejphar.2018.02.029] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 02/18/2018] [Accepted: 02/19/2018] [Indexed: 12/21/2022]
Abstract
Peroxisome proliferator-activated receptor alpha/gamma (PPARα/γ) agonists have emerged as important pharmacological agents for improving insulin action. Propane-2-sulfonic acid octadec-9-enyl-amide (N15) is a novel PPARα/γ dual agonist synthesized in our laboratory. The present study investigates the efficacy and safety of N15 on insulin resistance regulation in high fat diet (HFD)-and streptozotocin (STZ)-induced diabetic mice and in palmitic acid (PA)-induced HepG2 cells. Our results showed that N15 remarkably ameliorated insulin resistance and dyslipidemia in vivo, as well as rectified the glucose consumption and gluconeogenesis in vitro. Moreover, the glucose-lowering effect of N15 was associated with PPARγ mediated up-regulation of hepatic glucose consumption and down-regulation of gluconeogenesis. Meanwhile, N15 exerted advantageous effects on glucose and lipid metabolism without triggering weight gain and hepatotoxicity in mice. In conclusion, our data demonstrated that by alleviating glucose and lipid abnormalities, N15 could be used as a potential prophylactic and therapeutic agent against type 2 diabetes and related metabolic disorders.
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Lee YH, Kim SH, Kim SN, Kwon HJ, Kim JD, Oh JY, Jung YS. Sex-specific metabolic interactions between liver and adipose tissue in MCD diet-induced non-alcoholic fatty liver disease. Oncotarget 2018; 7:46959-46971. [PMID: 27409675 PMCID: PMC5216916 DOI: 10.18632/oncotarget.10506] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 06/30/2016] [Indexed: 02/06/2023] Open
Abstract
Higher susceptibility to metabolic disease in male exemplifies the importance of sexual dimorphism in pathogenesis. We hypothesized that the higher incidence of non-alcoholic fatty liver disease in males involves sex-specific metabolic interactions between liver and adipose tissue. In the present study, we used a methionine-choline deficient (MCD) diet-induced fatty liver mouse model to investigate sex differences in the metabolic response of the liver and adipose tissue. After 2 weeks on an MCD-diet, fatty liver was induced in a sex-specific manner, affecting male mice more severely than females. The MCD-diet increased lipolytic enzymes in the gonadal white adipose tissue (gWAT) of male mice, whereas it increased expression of uncoupling protein 1 and other brown adipocyte markers in the gWAT of female mice. Moreover, gWAT from female mice demonstrated higher levels of oxygen consumption and mitochondrial content compared to gWAT from male mice. FGF21 expression was increased in liver tissue by the MCD diet, and the degree of upregulation was significantly higher in the livers of female mice. The endocrine effect of FGF21 was responsible, in part, for the sex-specific browning of gonadal white adipose tissue. Collectively, these data demonstrated that distinctively female-specific browning of white adipose tissue aids in protecting female mice against MCD diet-induced fatty liver disease.
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Affiliation(s)
- Yun-Hee Lee
- College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Sou Hyun Kim
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Sang-Nam Kim
- College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Hyun-Jung Kwon
- College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Jeong-Dong Kim
- College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Ji Youn Oh
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Young-Suk Jung
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
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Abstract
Triglyceride molecules represent the major form of storage and transport of fatty acids within cells and in the plasma. The liver is the central organ for fatty acid metabolism. Fatty acids accrue in liver by hepatocellular uptake from the plasma and by de novo biosynthesis. Fatty acids are eliminated by oxidation within the cell or by secretion into the plasma within triglyceride-rich very low-density lipoproteins. Notwithstanding high fluxes through these pathways, under normal circumstances the liver stores only small amounts of fatty acids as triglycerides. In the setting of overnutrition and obesity, hepatic fatty acid metabolism is altered, commonly leading to the accumulation of triglycerides within hepatocytes, and to a clinical condition known as nonalcoholic fatty liver disease (NAFLD). In this review, we describe the current understanding of fatty acid and triglyceride metabolism in the liver and its regulation in health and disease, identifying potential directions for future research. Advances in understanding the molecular mechanisms underlying the hepatic fat accumulation are critical to the development of targeted therapies for NAFLD. © 2018 American Physiological Society. Compr Physiol 8:1-22, 2018.
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Affiliation(s)
- Michele Alves-Bezerra
- Joan & Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, USA
| | - David E Cohen
- Joan & Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, USA
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Bellanti F, Villani R, Facciorusso A, Vendemiale G, Serviddio G. Lipid oxidation products in the pathogenesis of non-alcoholic steatohepatitis. Free Radic Biol Med 2017; 111:173-185. [PMID: 28109892 DOI: 10.1016/j.freeradbiomed.2017.01.023] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 01/11/2017] [Accepted: 01/15/2017] [Indexed: 02/08/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the major public health challenge for hepatologists in the twenty-first century. NAFLD comprises a histological spectrum ranging from simple steatosis or fatty liver, to steatohepatitis, fibrosis, and cirrhosis. It can be categorized into two principal phenotypes: (1) non-alcoholic fatty liver (NAFL), and (2) non-alcoholic steatohepatitis (NASH). The mechanisms of NAFLD progression consist of lipid homeostasis alterations, redox unbalance, insulin resistance, and inflammation in the liver. Even though several studies show an association between the levels of lipid oxidation products and disease state, experimental evidence suggests that compounds such as reactive aldehydes and cholesterol oxidation products, in addition to representing hallmarks of hepatic oxidative damage, may behave as active players in liver dysfunction and the development of NAFLD. This review summarizes the processes that contribute to the metabolic alterations occurring in fatty liver that produce fatty acid and cholesterol oxidation products in NAFLD, with a focus on inflammation, the control of insulin signalling, and the transcription factors involved in lipid metabolism.
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Affiliation(s)
- Francesco Bellanti
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Rosanna Villani
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Antonio Facciorusso
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Gianluigi Vendemiale
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Gaetano Serviddio
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy.
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Nakade Y, Sakamoto K, Yamauchi T, Inoue T, Kobayashi Y, Yamamoto T, Ishii N, Ohashi T, Sumida Y, Ito K, Nakao H, Fukuzawa Y, Umezawa K, Yoneda M. Conophylline inhibits non-alcoholic steatohepatitis in mice. PLoS One 2017; 12:e0178436. [PMID: 28594915 PMCID: PMC5464552 DOI: 10.1371/journal.pone.0178436] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 05/12/2017] [Indexed: 01/18/2023] Open
Abstract
Conophylline (CnP), a vinca alkaloid extracted from the leaves of the tropical plant Ervatamia microphylla, attenuates hepatic fibrosis in mice. However, little is known about whether CnP inhibits steatosis, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH) in mice. A methionine-choline-deficient (MCD) diet was administered to male db/db mice as a NASH model, and CnP (1 μg/kg/d) was co-administered. Eight weeks after the commencement of the MCD diet, hepatic steatosis, inflammation, and fibrosis, and hepatic fat metabolism-, inflammation-, and fibrosis-related markers were examined. Feeding on an MCD for 8 weeks induced hepatic steatosis, inflammation, and fibrosis. CnP significantly attenuated the MCD-induced increases in hepatic steatosis, as well as hepatic inflammation and fibrosis. The MCD diet increased hepatic transforming growth factor-β (TGF-β) mRNA levels, which are correlated with hepatic steatosis, inflammation, and fibrosis. The diet also attenuated acyl-coenzyme A oxidase 1 (ACOX1) and carnitine palmitoyltransferase 1 (CPT1) mRNA levels, which are involved in β-oxidation. The putative mechanism of the CnP effect involves reduced hepatic TGF-β mRNA levels, and increased mRNA levels of hepatic peroxisome proliferator-activated receptor (PPAR) α and its target genes ACOX1 and CPT1. The results of this study indicate that CnP inhibits steatohepatitis, possibly through the inhibition of hepatic TGF-β mRNA levels, and induces an increase in PPARα mRNA levels, resulting in the attenuation of hepatic steatosis, inflammation, and fibrosis in mice. CnP might accordingly be a suitable therapeutic option for NASH.
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Affiliation(s)
- Yukiomi Nakade
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan
- * E-mail:
| | - Kazumasa Sakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan
| | - Taeko Yamauchi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan
| | - Tadahisa Inoue
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan
| | - Yuji Kobayashi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan
| | - Takaya Yamamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan
| | - Norimitsu Ishii
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan
| | - Tomohiko Ohashi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan
| | - Yoshio Sumida
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan
| | - Kiyoaki Ito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan
| | - Haruhisa Nakao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan
| | - Yoshitaka Fukuzawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan
| | - Kazuo Umezawa
- Department of Molecular Target Medicine Screening, Aichi Medical University, Nagakute, Aichi, Japan
| | - Masashi Yoneda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan
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