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Parker LE, Papanicolaou KN, Zalesak-Kravec S, Weinberger EM, Kane MA, Foster DB. Retinoic acid signaling and metabolism in heart failure. Am J Physiol Heart Circ Physiol 2025; 328:H792-H813. [PMID: 39933792 DOI: 10.1152/ajpheart.00871.2024] [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: 12/13/2024] [Revised: 12/24/2024] [Accepted: 02/03/2025] [Indexed: 02/13/2025]
Abstract
Nearly 70 years after studies first showed that the offspring of vitamin A (retinol, ROL)-deficient rats exhibit structural cardiac defects and over 20 years since the role of vitamin A's potent bioactive metabolite hormone, all-trans retinoic acid (ATRA), was elucidated in embryonic cardiac development, the role of the vitamin A metabolites, or retinoids, in adult heart physiology and heart and vascular disease, remains poorly understood. Studies have shown that low serum levels of retinoic acid correlate with higher all-cause and cardiovascular mortality, though the relationship between circulating retinol and ATRA levels, cardiac tissue ATRA levels, and intracellular cardiac ATRA signaling in the context of heart and vascular disease has only begun to be addressed. We have recently shown that patients with idiopathic dilated cardiomyopathy show a nearly 40% decline of in situ cardiac ATRA levels, despite adequate local stores of retinol. Moreover, we and others have shown that the administration of ATRA forestalls the development of heart failure (HF) in rodent models. In this review, we summarize key facets of retinoid metabolism and signaling and discuss mechanisms by which impaired ATRA signaling contributes to several HF hallmarks including hypertrophy, contractile dysfunction, poor calcium handling, redox imbalance, and fibrosis. We highlight unresolved issues in cardiac ATRA metabolism whose pursuit will help refine therapeutic strategies aimed at restoring ATRA homeostasis.
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Affiliation(s)
- Lauren E Parker
- Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States
| | - Kyriakos N Papanicolaou
- Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States
| | | | - Eva M Weinberger
- School of Medicine, Imperial College London, London, United Kingdom
| | - Maureen A Kane
- School of Pharmacy, University of Maryland, Baltimore, Maryland, United States
| | - D Brian Foster
- Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States
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2
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Rodríguez-Rodríguez R, Baena M, Zagmutt S, Paraiso WK, Reguera AC, Fadó R, Casals N. International Union of Basic and Clinical Pharmacology: Fundamental insights and clinical relevance regarding the carnitine palmitoyltransferase family of enzymes. Pharmacol Rev 2025; 77:100051. [PMID: 40106976 DOI: 10.1016/j.pharmr.2025.100051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 02/14/2025] [Indexed: 03/22/2025] Open
Abstract
The carnitine palmitoyltransferases (CPTs) play a key role in controlling the oxidation of long-chain fatty acids and are potential therapeutic targets for diseases with a strong metabolic component, such as obesity, diabetes, and cancer. Four distinct proteins are CPT1A, CPT1B, CPT1C, and CPT2, differing in tissue expression and catalytic activity. CPT1s are finely regulated by malonyl-CoA, a metabolite whose intracellular levels reflect the cell's nutritional state. Although CPT1C does not exhibit significant catalytic activity, it is capable of modulating the functioning of other neuronal proteins. Structurally, all CPTs share a Y-shaped catalytic tunnel that allows the entry of 2 substrates and accommodation of the acyl group in a hydrophobic pocket. Several molecules targeting these enzymes have been described, some showing potential in normalizing blood glucose levels in diabetic patients, and others that, through a central mechanism, are anorexigenic and enhance energy expenditure. However, given the critical roles that CPTs play in certain tissues, such as the heart, liver, and brain, it is essential to fully understand the differences between the various isoforms. We analyze in detail the structure of these proteins, their cellular and physiological functions, and their potential as therapeutic targets in diseases such as obesity, diabetes, and cancer. We also describe drugs identified to date as having inhibitory or activating capabilities for these proteins. This knowledge will support the design of new drugs specific to each isoform, and the development of nanomedicines that can selectively target particular tissues or cells. SIGNIFICANCE STATEMENT: Carnitine palmitoyltransferase (CPT) proteins, as gatekeepers of fatty acid oxidation, have great potential as pharmacological targets to treat metabolic diseases like obesity, diabetes, and cancer. In recent years, significant progress has been made in understanding the 3-dimensional structure of CPTs and their pathophysiological functions. A deeper understanding of the differences between the various CPT family members will enable the design of selective drugs and therapeutic approaches with fewer side effects.
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Affiliation(s)
- Rosalía Rodríguez-Rodríguez
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.
| | - Miguel Baena
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, Spain
| | - Sebastián Zagmutt
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, Spain
| | - West Kristian Paraiso
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, Spain
| | - Ana Cristina Reguera
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, Spain
| | - Rut Fadó
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, Spain
| | - Núria Casals
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.
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Ng YH, Koay YC, Marques FZ, Kaye DM, O’Sullivan JF. Leveraging metabolism for better outcomes in heart failure. Cardiovasc Res 2024; 120:1835-1850. [PMID: 39351766 PMCID: PMC11630082 DOI: 10.1093/cvr/cvae216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 06/26/2024] [Accepted: 08/07/2024] [Indexed: 12/11/2024] Open
Abstract
Whilst metabolic inflexibility and substrate constraint have been observed in heart failure for many years, their exact causal role remains controversial. In parallel, many of our fundamental assumptions about cardiac fuel use are now being challenged like never before. For example, the emergence of sodium-glucose cotransporter 2 inhibitor therapy as one of the four 'pillars' of heart failure therapy is causing a revisit of metabolism as a key mechanism and therapeutic target in heart failure. Improvements in the field of cardiac metabolomics will lead to a far more granular understanding of the mechanisms underpinning normal and abnormal human cardiac fuel use, an appreciation of drug action, and novel therapeutic strategies. Technological advances and expanding biorepositories offer exciting opportunities to elucidate the novel aspects of these metabolic mechanisms. Methodologic advances include comprehensive and accurate substrate quantitation such as metabolomics and stable-isotope fluxomics, improved access to arterio-venous blood samples across the heart to determine fuel consumption and energy conversion, high quality cardiac tissue biopsies, biochemical analytics, and informatics. Pairing these technologies with recent discoveries in epigenetic regulation, mitochondrial dynamics, and organ-microbiome metabolic crosstalk will garner critical mechanistic insights in heart failure. In this state-of-the-art review, we focus on new metabolic insights, with an eye on emerging metabolic strategies for heart failure. Our synthesis of the field will be valuable for a diverse audience with an interest in cardiac metabolism.
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Affiliation(s)
- Yann Huey Ng
- Cardiometabolic Medicine, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Room 3E71 D17, Camperdown, NSW 2006, Australia
- Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Office 3E72, Camperdown, NSW 2006, Australia
| | - Yen Chin Koay
- Cardiometabolic Medicine, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Room 3E71 D17, Camperdown, NSW 2006, Australia
- Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Office 3E72, Camperdown, NSW 2006, Australia
| | - Francine Z Marques
- Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, Melbourne, VIC 3800, Australia
- Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, VIC 3800, Australia
- Victorian Heart Institute, Monash University, Melbourne, VIC 3800, Australia
| | - David M Kaye
- Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, VIC 3800, Australia
- Department of Cardiology, Alfred Hospital, Melbourne, VIC 3004, Australia
- Monash-Alfred-Baker Centre for Cardiovascular Research, Monash University, Melbourne, VIC 3800, Australia
| | - John F O’Sullivan
- Cardiometabolic Medicine, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Room 3E71 D17, Camperdown, NSW 2006, Australia
- Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Office 3E72, Camperdown, NSW 2006, Australia
- Department of Cardiology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
- Department of Medicine, Technische Univeristat Dresden, 01062 Dresden, Germany
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Zhang YY, Wang JX, Qiao F, Zhang ML, Luo Y, Du ZY. Pparα activation stimulates autophagic flux through lipid catabolism-independent route. FISH PHYSIOLOGY AND BIOCHEMISTRY 2024; 50:1141-1155. [PMID: 38401031 DOI: 10.1007/s10695-024-01327-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 02/16/2024] [Indexed: 02/26/2024]
Abstract
Autophagy is a cellular process that involves the fusion of autophagosomes and lysosomes to degrade damaged proteins or organelles. Triglycerides are hydrolyzed by autophagy, releasing fatty acids for energy through mitochondrial fatty acid oxidation (FAO). Inhibited mitochondrial FAO induces autophagy, establishing a crosstalk between lipid catabolism and autophagy. Peroxisome proliferator-activated receptor α (PPARα), a transcription factor, stimulates lipid catabolism genes, including fatty acid transport and mitochondrial FAO, while also inducing autophagy through transcriptional regulation of transcription factor EB (TFEB). Therefore, the study explores whether PPARα regulates autophagy through TFEB transcriptional control or mitochondrial FAO. In aquaculture, addressing liver lipid accumulation in fish is crucial. Investigating the link between lipid catabolism and autophagy is significant for devising lipid-lowering strategies and maintaining fish health. The present study investigated the impact of dietary fenofibrate and L-carnitine on autophagy by activating Pparα and enhancing FAO in Nile tilapia (Oreochromis niloticus), respectively. The dietary fenofibrate and L-carnitine reduced liver lipid content and enhanced ATP production, particularly fenofibrate. FAO enhancement by L-carnitine showed no changes in autophagic protein levels and autophagic flux. Moreover, fenofibrate-activated Pparα promoted the expression and nuclear translocation of Tfeb, upregulating autophagic initiation and lysosomal biogenesis genes. Pparα activation exhibited an increasing trend of LC3II protein at the basal autophagy and cumulative p62 protein trends after autophagy inhibition in zebrafish liver cells. These data show that Pparα activation-induced autophagic flux should be independent of lipid catabolism.
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Affiliation(s)
- Yan-Yu Zhang
- LANEH, School of Life Sciences, East China Normal University, Shanghai, China
| | - Jun-Xian Wang
- LANEH, School of Life Sciences, East China Normal University, Shanghai, China
| | - Fang Qiao
- LANEH, School of Life Sciences, East China Normal University, Shanghai, China
| | - Mei-Ling Zhang
- LANEH, School of Life Sciences, East China Normal University, Shanghai, China
| | - Yuan Luo
- LANEH, School of Life Sciences, East China Normal University, Shanghai, China
| | - Zhen-Yu Du
- LANEH, School of Life Sciences, East China Normal University, Shanghai, China.
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Ding J, Liu J, Chen J, Cheng X, Cao H, Guo X, Hu G, Zhuang Y. Sodium butyrate alleviates free fatty acid-induced steatosis in primary chicken hepatocytes via the AMPK/PPARα pathway. Poult Sci 2024; 103:103482. [PMID: 38387286 PMCID: PMC10899032 DOI: 10.1016/j.psj.2024.103482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 01/15/2024] [Accepted: 01/16/2024] [Indexed: 02/24/2024] Open
Abstract
Fatty liver hemorrhagic syndrome (FLHS) is a prevalent metabolic disorder observed in egg-laying hens, characterized by fatty deposits and cellular steatosis in the liver. Our preliminary investigations have revealed a marked decrease in the concentration of butyric acid in the FLHS strain of laying hens. It has been established that sodium butyrate (NaB) protects against metabolic disorders. However, the underlying mechanism by which butyrate modulates hepato-lipid metabolism to a great extent remains unexplored. In this study, we constructed an isolated in vitro model of chicken primary hepatocytes to induce hepatic steatosis by free fatty acids (FFA). Our results demonstrate that treatment with NaB effectively mitigated FFA-induced hepatic steatosis in chicken hepatocytes by inhibiting lipid accumulation, downregulating the mRNA expression of lipo-synthesis-related genes (sterol regulatory element binding transcription factor 1 (SREBF1), acetyl-CoA carboxylase 1(ACC1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), liver X receptor α (LXRα), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR)) (P < 0.05), and upregulating the mRNA and protein expression of AMP-activated protein kinase α1 (AMPKα1), peroxisome proliferator-activated receptor α (PPARα), and carnitine palmitoyl-transferase 1A (CPT1A) (P < 0.05). Moreover, AMPK and PPARα inhibitors (Compound C (Comp C) and GW6471, respectively) reversed the protective effects of NaB against FFA-induced hepatic steatosis by blocking the AMPK/PPARα pathway, leading to lipid droplet accumulation and triglyceride (TG) contents in chicken primary hepatocytes. With these findings, NaB can alleviate hepatocyte lipoatrophy injury by activating the AMPK/PPARα pathway, promoting fatty acid oxidation, and reducing lipid synthesis in chicken hepatocytes, potentially being able to provide new ideas for the treatment of FLHS.
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Affiliation(s)
- Jiayi Ding
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, Jiangxi, PR China
| | - Jiuyue Liu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, Jiangxi, PR China
| | - Jinyan Chen
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, Jiangxi, PR China
| | - Xinyi Cheng
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, Jiangxi, PR China
| | - Huabin Cao
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, Jiangxi, PR China
| | - Xiaoquan Guo
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, Jiangxi, PR China
| | - Guoliang Hu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, Jiangxi, PR China
| | - Yu Zhuang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, Jiangxi, PR China.
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Szrok-Jurga S, Czumaj A, Turyn J, Hebanowska A, Swierczynski J, Sledzinski T, Stelmanska E. The Physiological and Pathological Role of Acyl-CoA Oxidation. Int J Mol Sci 2023; 24:14857. [PMID: 37834305 PMCID: PMC10573383 DOI: 10.3390/ijms241914857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/27/2023] [Accepted: 09/30/2023] [Indexed: 10/15/2023] Open
Abstract
Fatty acid metabolism, including β-oxidation (βOX), plays an important role in human physiology and pathology. βOX is an essential process in the energy metabolism of most human cells. Moreover, βOX is also the source of acetyl-CoA, the substrate for (a) ketone bodies synthesis, (b) cholesterol synthesis, (c) phase II detoxication, (d) protein acetylation, and (d) the synthesis of many other compounds, including N-acetylglutamate-an important regulator of urea synthesis. This review describes the current knowledge on the importance of the mitochondrial and peroxisomal βOX in various organs, including the liver, heart, kidney, lung, gastrointestinal tract, peripheral white blood cells, and other cells. In addition, the diseases associated with a disturbance of fatty acid oxidation (FAO) in the liver, heart, kidney, lung, alimentary tract, and other organs or cells are presented. Special attention was paid to abnormalities of FAO in cancer cells and the diseases caused by mutations in gene-encoding enzymes involved in FAO. Finally, issues related to α- and ω- fatty acid oxidation are discussed.
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Affiliation(s)
- Sylwia Szrok-Jurga
- Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland; (S.S.-J.); (J.T.); (A.H.)
| | - Aleksandra Czumaj
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-211 Gdansk, Poland;
| | - Jacek Turyn
- Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland; (S.S.-J.); (J.T.); (A.H.)
| | - Areta Hebanowska
- Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland; (S.S.-J.); (J.T.); (A.H.)
| | - Julian Swierczynski
- Institue of Nursing and Medical Rescue, State University of Applied Sciences in Koszalin, 75-582 Koszalin, Poland;
| | - Tomasz Sledzinski
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-211 Gdansk, Poland;
| | - Ewa Stelmanska
- Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland; (S.S.-J.); (J.T.); (A.H.)
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Wang J, Zeng J, Yin G, Deng Z, Wang L, Liu J, Yao K, Long Z, Jiang X, Tan J. Long non-coding RNA FABP5P3/miR-22 axis improves TGFβ1-induced fatty acid oxidation deregulation and fibrotic changes in proximal tubular epithelial cells of renal fibrosis. Cell Cycle 2023; 22:433-449. [PMID: 36196456 PMCID: PMC9879175 DOI: 10.1080/15384101.2022.2122286] [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] [Indexed: 01/29/2023] Open
Abstract
Severe hydronephrosis increases the risk of urinary tract infection and irretrievable renal fibrosis. While TGFβ1-mediated fibrotic changes in proximal tubular epithelial cells and fatty acid oxidation (FAO) deregulation contribute to renal fibrosis and hydronephrosis. Firstly, a few elements were analyzed in this paper, including differentially-expressed long non-coding RNAs (lncRNAs), and miRNAs correlated to CPT1A, RXRA, and NCOA1. This paper investigated TGFβ1 effects on lncRNA FABP5P3, CPT1A, RXRA, and NCOA1 expression and fibrotic changes in HK-2 cells and FABP5P3 overexpression effects on TGFβ1-induced changes. Moreover, this paper predicted and proved that miR-22 binding to lncRNA FABP5P3, 3'UTR of CPT1A, RXRA, and NCOA1 was validated. The dynamic effects of the FABP5P3/miR-22 axis on TGFβ1-induced changes were investigated. A Renal fibrosis model was established in unilateral ureteral obstruction (UUO) mice, and FABP5P3 effects were investigated. Eventually, this paper concluded that TGFβ1 inhibited lncRNA FABP5P3, CPT1A, RXRA, and NCOA1 expression, induced fibrotic changes in HK-2 cells, and induced metabolic reprogramming within HK-2 cells, especially lower FAO. FABP5P3 overexpression partially reversed TGFβ1-induced changes. miR-22 targeted lncRNA FABP5P3, CPT1A, RXRA, and NCOA1. LncRNA FABP5P3 counteracted miR-22 inhibition of CPT1A, NCOA1, and RXRA through competitive binding. TGFβ1 stimulation induced the activation of TGFβ/SMAD and JAG/Notch signaling pathways; Nocth2 knockdown reversed TGFβ1 suppression on lncRNA FABP5P3. FABP5P3 overexpression attenuated renal fibrosis in unilateral ureteral obstruction mice. The LncRNA FABP5P3/miR-22 axis might be a potent target for improving the FAO deregulation and fibrotic changes in proximal TECs under TGFβ1 stimulation.
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Affiliation(s)
- Jingrong Wang
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jia Zeng
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Guangmin Yin
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Zhijun Deng
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Long Wang
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jianye Liu
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Kun Yao
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Zhi Long
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Xianzhen Jiang
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jing Tan
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China
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Senn L, Costa AM, Avallone R, Socała K, Wlaź P, Biagini G. Is the peroxisome proliferator-activated receptor gamma a putative target for epilepsy treatment? Current evidence and future perspectives. Pharmacol Ther 2023; 241:108316. [PMID: 36436690 DOI: 10.1016/j.pharmthera.2022.108316] [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: 09/14/2022] [Revised: 11/20/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022]
Abstract
The peroxisome proliferator-activated receptor gamma (PPARγ), which belongs to the family of nuclear receptors, has been mainly studied as an important factor in metabolic disorders. However, in recent years the potential role of PPARγ in different neurological diseases has been increasingly investigated. Especially, in the search of therapeutic targets for patients with epilepsy the question of the involvement of PPARγ in seizure control has been raised. Epilepsy is a chronic neurological disorder causing a major impact on the psychological, social, and economic conditions of patients and their families, besides the problems of the disease itself. Considering that the world prevalence of epilepsy ranges between 0.5% - 1.0%, this condition is the fourth for importance among the other neurological disorders, following migraine, stroke, and dementia. Among others, temporal lobe epilepsy (TLE) is the most common form of epilepsy in adult patients. About 65% of individuals who receive antiseizure medications (ASMs) experience seizure independence. For those in whom seizures still recur, investigating PPARγ could lead to the development of novel ASMs. This review focuses on the most important findings from recent investigations about the potential intracellular PPARγ-dependent processes behind different compounds that exhibited anti-seizure effects. Additionally, recent clinical investigations are discussed along with the promising results found for PPARγ agonists and the ketogenic diet (KD) in various rodent models of epilepsy.
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Affiliation(s)
- Lara Senn
- Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; PhD School of Clinical and Experimental Medicine (CEM), University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Anna-Maria Costa
- Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Rossella Avallone
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Katarzyna Socała
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, PL 20-033 Lublin, Poland
| | - Piotr Wlaź
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, PL 20-033 Lublin, Poland
| | - Giuseppe Biagini
- Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
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Iqbal A, Yu H, Jiang P, Zhao Z. Deciphering the Key Regulatory Roles of KLF6 and Bta-miR-148a on Milk Fat Metabolism in Bovine Mammary Epithelial Cells. Genes (Basel) 2022; 13:genes13101828. [PMID: 36292712 PMCID: PMC9602136 DOI: 10.3390/genes13101828] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/24/2022] [Accepted: 10/04/2022] [Indexed: 11/04/2022] Open
Abstract
MicroRNAs (miRNAs) are non-coding RNAs that regulate the expression of their target genes involved in many cellular functions at the post-transcriptional level. Previously, bta-miR-148a showed significantly high expression in bovine mammary epithelial cells (BMECs) of Chinese Holstein cows producing high milk fat compared to those with low milk fat content. Here, we investigated the role of bta-miR-148a through targeting Krüppel-like factor 6 (KLF6) and further analyzed the role of KLF6 in regulating fat metabolism through targeting PPARA, AMPK/mTOR/PPARG, and other fat marker genes in BMECs of Chinese Holstein. The bioinformatics analysis showed that the 3’ UTR of KLF6 mRNA possesses the binding sites for bta-miR-148a, which was further verified through dual-luciferase reporter assay. The BMECs were transfected with bta-miR-148a-mimic, inhibitor, and shNC, and the expression of KLF6 was found to be negatively regulated by bta-miR-148a. Moreover, the contents of triglyceride (TG), and cholesterol (CHO) in BMECs transfected with bta-miR-148a-mimic were significantly lower than the contents in BMECs transfected with bta-miR-148a-shNC. Meanwhile, the TG and CHO contents were significantly increased in BMECs transfected with bta-miR-148a-inhibitor than in BMECs transfected with bta-miR-148a-shNC. In addition, the TG and CHO contents were significantly decreased in BMECs upon the down-regulation of KLF6 through transfection with pb7sk-KLF6-siRNA1 compared to the control group. Contrarily, when KLF6 was overexpressed in BMECs through transfection with pBI-CMV3-KLF6, the TG and CHO contents were significantly increased compared to the control group. Whereas, the qPCR and Western blot evaluation of PPARA, AMPK/mTOR/PPARG, and other fat marker genes revealed that all of the genes were considerably down-regulated in the KLF6-KO-BMECs compared to the normal BMECs. Taking advantage of deploying new molecular markers and regulators for increasing the production of better-quality milk with tailored fat contents would be the hallmark in dairy sector. Hence, bta-miR-148a and KLF6 are potential candidates for increased milk synthesis and the production of valuable milk components in dairy cattle through marker-assisted selection in molecular breeding. Furthermore, this study hints at the extrapolation of a myriad of functions of other KLF family members in milk fat synthesis.
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Xing G, Meng L, Cao S, Liu S, Wu J, Li Q, Huang W, Zhang L. PPARα alleviates iron overload-induced ferroptosis in mouse liver. EMBO Rep 2022; 23:e52280. [PMID: 35703725 PMCID: PMC9346473 DOI: 10.15252/embr.202052280] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 05/23/2022] [Accepted: 05/23/2022] [Indexed: 01/04/2023] Open
Abstract
Ferroptosis is an iron-dependent form of non-apoptotic cell death implicated in liver, brain, kidney, and heart pathology. How ferroptosis is regulated remains poorly understood. Here, we show that PPARα suppresses ferroptosis by promoting the expression of glutathione peroxidase 4 (Gpx4) and by inhibiting the expression of the plasma iron carrier TRF. PPARα directly induces Gpx4 expression by binding to a PPRE element within intron 3. PPARα knockout mice develop more severe iron accumulation and ferroptosis in the liver when fed a high-iron diet than wild-type mice. Ferrous iron (Fe2+ ) triggers ferroptosis via Fenton reactions and ROS accumulation. We further find that a rhodamine-based "turn-on" fluorescent probe(probe1) is suitable for the in vivo detection of Fe2+ . Probe1 displays high selectivity towards Fe2+ , and exhibits a stable response for Fe2+ with a concentration of 20 μM in tissue. Our data thus show that PPARα activation alleviates iron overload-induced ferroptosis in mouse livers through Gpx4 and TRF, suggesting that PPARα may be a promising therapeutic target for drug discovery in ferroptosis-related tissue injuries. Moreover, we identified a fluorescent probe that specifically labels ferrous ions and can be used to monitor Fe2+ in vivo.
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Affiliation(s)
- Guowei Xing
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
- Hubei Hongshan LaboratoryWuhanChina
| | - Lihua Meng
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Shiyao Cao
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Shenghui Liu
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Jiayan Wu
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Qian Li
- State Key Laboratory of Kidney DiseasesDepartment of NephrologyChinese PLA General Hospital, Chinese PLA Institute of NephrologyNational Clinical Research Center for Kidney DiseasesBeijingChina
| | - Wendong Huang
- Department of Diabetes Complications and MetabolismBeckman Research Institute of City of HopeDuarteCAUSA
| | - Lisheng Zhang
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
- Hubei Hongshan LaboratoryWuhanChina
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Identification of Differential Expression Genes between Volume and Pressure Overloaded Hearts Based on Bioinformatics Analysis. Genes (Basel) 2022; 13:genes13071276. [PMID: 35886059 PMCID: PMC9318830 DOI: 10.3390/genes13071276] [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: 05/08/2022] [Revised: 07/15/2022] [Accepted: 07/16/2022] [Indexed: 01/27/2023] Open
Abstract
Volume overload (VO) and pressure overload (PO) are two common pathophysiological conditions associated with cardiac disease. VO, in particular, often occurs in a number of diseases, and no clinically meaningful molecular marker has yet been established. We intend to find the main differential gene expression using bioinformatics analysis. GSE97363 and GSE52796 are the two gene expression array datasets related with VO and PO, respectively. The LIMMA algorithm was used to identify differentially expressed genes (DEGs) of VO and PO. The DEGs were divided into three groups and subjected to functional enrichment analysis, which comprised GO analysis, KEGG analysis, and the protein–protein interaction (PPI) network. To validate the sequencing data, cardiomyocytes from AR and TAC mouse models were used to extract RNA for qRT-PCR. The three genes with random absolute values of LogFC and indicators of heart failure (natriuretic peptide B, NPPB) were detected: carboxylesterase 1D (CES1D), whirlin (WHRN), and WNK lysine deficient protein kinase 2 (WNK2). The DEGs in VO and PO were determined to be 2761 and 1093, respectively, in this study. Following the intersection, 305 genes were obtained, 255 of which expressed the opposing regulation and 50 of which expressed the same regulation. According to the GO and pathway enrichment studies, DEGs with opposing regulation are mostly common in fatty acid degradation, propanoate metabolism, and other signaling pathways. Finally, we used Cytoscape’s three techniques to identify six hub genes by intersecting 255 with the opposite expression and constructing a PPI network. Peroxisome proliferator-activated receptor (PPARα), acyl-CoA dehydrogenase medium chain (ACADM), patatin-like phospholipase domain containing 2 (PNPLA2), isocitrate dehydrogenase 3 (IDH3), heat shock protein family D member 1 (HSPD1), and dihydrolipoamide S-acetyltransferase (DLAT) were identified as six potential genes. Furthermore, we predict that the hub genes PPARα, ACADM, and PNPLA2 regulate VO myocardial changes via fatty acid metabolism and acyl-Coa dehydrogenase activity, and that these genes could be employed as basic biomarkers for VO diagnosis and treatment.
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12
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Persad KL, Lopaschuk GD. Energy Metabolism on Mitochondrial Maturation and Its Effects on Cardiomyocyte Cell Fate. Front Cell Dev Biol 2022; 10:886393. [PMID: 35865630 PMCID: PMC9294643 DOI: 10.3389/fcell.2022.886393] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/20/2022] [Indexed: 12/12/2022] Open
Abstract
Alterations in energy metabolism play a major role in the lineage of cardiomyocytes, such as the dramatic changes that occur in the transition from neonate to newborn. As cardiomyocytes mature, they shift from a primarily glycolytic state to a mitochondrial oxidative metabolic state. Metabolic intermediates and metabolites may have epigenetic and transcriptional roles in controlling cell fate by increasing mitochondrial biogenesis. In the maturing cardiomyocyte, such as in the postnatal heart, fatty acid oxidation increases in conjunction with increased mitochondrial biogenesis driven by the transcriptional coregulator PGC1-α. PGC1-α is necessary for mitochondrial biogenesis in the heart at birth, with deficiencies leading to postnatal cardiomyopathy. While stem cell therapy as a treatment for heart failure requires further investigation, studies suggest that adult stem cells may secrete cardioprotective factors which may regulate cardiomyocyte differentiation and survival. This review will discuss how metabolism influences mitochondrial biogenesis and how mitochondrial biogenesis influences cell fate, particularly in the context of the developing cardiomyocyte. The implications of energy metabolism on stem cell differentiation into cardiomyocytes and how this may be utilized as a therapy against heart failure and cardiovascular disease will also be discussed.
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Ławniczak A, Wrońska A, Wierzbicki P, Kmieć Z. Aging and short-term calorie restriction differently affect the cardiac and skeletal muscle expression of genes regulating energy substrate utilization in male rats. Biogerontology 2022; 23:325-340. [PMID: 35606458 DOI: 10.1007/s10522-022-09965-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 04/29/2022] [Indexed: 01/11/2023]
Abstract
Aging affects the energy metabolism differently in the cardiac and skeletal muscles. The study aim was to assess the effects of short-term calorie restriction (SCR) and refeeding on the expression of genes involved in the control of cardiac and skeletal muscle energy metabolism in old vs. young male rats. Young (4 mo) and old (24 mo) rats were subjected to 60% SCR for 30 days, and refed ad libitum for 2 or 4 days. In the cardiac (CM) and skeletal muscles (SM) we compared the gene expression (qPCR) of carnitine palmitoyltransferase-I (Cpt-I), peroxisome proliferator-activated receptor beta/delta (Ppar-β/δ), glucose transporter 4 (Glut4), peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc-1α), and sirtuin 3 (Sirt3). In CM, aging increased Cpt-I expression but did not affect the other genes. In SM, Cpt-I, Glut4, Pgc-1α, and Sirt3 mRNA levels were lower in old than young rats. In CM of only young rats SCR increased Cpt-I expression which remained elevated after refeeding. Upon SCR, the expression of Ppar-β/δ, Glut4, Pgc-1α, and Sirt3 in CM increased in young but not old rats, and refeeding re-established control levels. In SM of young rats SCR increased Ppar-β/δ and Pgc-1α, and decreased Sirt3 expression, whereas refeeding generally decreased these mRNA levels. In SM of old rats SCR decreased only Pgc-1α expression. The adaptive response to SCR and subsequent refeeding is muscle tissue-specific and differs in young and old male rats. SCR appears to increase the efficiency of glucose and fatty acid utilization in the cardiac muscle of young, but not old male rats.
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Affiliation(s)
- Aleksandra Ławniczak
- Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, 80-211, Gdańsk, Poland
| | - Agata Wrońska
- Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, 80-211, Gdańsk, Poland.
| | - Piotr Wierzbicki
- Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, 80-211, Gdańsk, Poland
| | - Zbigniew Kmieć
- Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, 80-211, Gdańsk, Poland
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Arulkumar R, Jung HJ, Noh SG, Chung HY. Soyasapogenol C from Fermented Soybean ( Glycine Max) Acting as a Novel AMPK/PPARα Dual Activator Ameliorates Hepatic Steatosis: A Novel SANDA Methodology. Int J Mol Sci 2022; 23:5468. [PMID: 35628280 PMCID: PMC9141180 DOI: 10.3390/ijms23105468] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/07/2022] [Accepted: 05/09/2022] [Indexed: 02/06/2023] Open
Abstract
(1) Background: Soyasapogenol C (SSC), a derivative of soyasapogenol B (SSB), is specifically found high in many fermented soybean (Glycine max) products, including Cheonggukjang (in Korean). However, the biological activities for preventing and treating hepatic steatosis, and the precise underlying mechanisms of SSC, remain to be explored. (2) Methods: A novel SANDA (structural screening, ADMET prediction, network pharmacology, docking validation, and activity evaluation) methodology was used to examine whether SSC exerts hepatoprotective effects in silico and in vitro. (3) Results: SSC had better ADMET characteristics and a higher binding affinity with predicted targets chosen from network pathway analysis than SSB. SSC induced the phosphorylation of AMP-activated protein kinase (AMPK) and stimulated the nuclear translocation of peroxisome proliferator-activated receptor alpha (PPARα), further enhancing PPAR response element (PPRE) binding activity in HepG2 cells. Concurrently, SSC significantly inhibited triglyceride accumulation, which was associated with the suppression of lipogenesis genes and the enhancement of fatty acid oxidation gene expression in HepG2 cells. (4) Conclusions: Soyasapogenol C, discovered using a novel SANDA methodology from fermented soybean, is a novel AMPK/PPARα dual activator that is effective against hepatic steatosis. Dietary supplementation with soyasapogenol C may prevent the development of hepatic steatosis and other diseases associated with fat accumulation in the liver.
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Affiliation(s)
- Radha Arulkumar
- Interdisciplinary Research Program of Bioinformatics and Longevity Science, Pusan National University, Busan 46241, Korea; (R.A.); (S.G.N.)
| | - Hee Jin Jung
- Department of Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, Korea;
| | - Sang Gyun Noh
- Interdisciplinary Research Program of Bioinformatics and Longevity Science, Pusan National University, Busan 46241, Korea; (R.A.); (S.G.N.)
| | - Hae Young Chung
- Interdisciplinary Research Program of Bioinformatics and Longevity Science, Pusan National University, Busan 46241, Korea; (R.A.); (S.G.N.)
- Department of Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, Korea;
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Exploring the Pattern of Metabolic Alterations Causing Energy Imbalance via PPARα Dysregulation in Cardiac Muscle During Doxorubicin Treatment. Cardiovasc Toxicol 2022; 22:436-461. [PMID: 35157213 DOI: 10.1007/s12012-022-09725-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 02/02/2022] [Indexed: 12/14/2022]
Abstract
Cardiotoxicity by anthracycline antineoplastic drug doxorubicin is one of the systemic toxicity of the cardiovascular system. The mechanism responsible for doxorubicin cardiotoxicity and lipid metabolism remains elusive. The current study tested the hypotheses that the role of peroxisome proliferator-activated receptor α (PPARα) in the progress of doxorubicin-induced cardiomyopathy and its mechanism behind lipid metabolism. In the present study, male rats were subjected to intraperitoneal injection (5-week period) of doxorubicin with different dosages such as low dosage (1.5 mg/kg body weight) and high dosage (15 mg/kg body weight) to induce doxorubicin cardiomyopathy. Myocardial PPARα was impaired in both low dosage and high dosage of doxorubicin-treated rats in a dose-dependent manner. The attenuated level of PPARα impairs the expression of the genes involved in mitochondrial transporter, fatty acid transportation, lipolysis, lipid metabolism, and fatty acid oxidation. Moreover, it disturbs the reverse triacylglycerol transporter apolipoprotein B-100 (APOB) in the myocardium. Doxorubicin elevates the circulatory lipid profile and glucose. Further aggravated lipid profile in circulation impedes the metabolism of lipid in cardiac tissue, which causes a lipotoxic condition in the heart and subsequently associated disease for the period of doxorubicin treatment. Elevated lipids in the circulation translocate into the heart dysregulates lipid metabolism in the heart, which causes augmented oxidative stress and necro-apoptosis and mediates lipotoxic conditions. This finding determines the mechanistic role of doxorubicin-disturbed lipid metabolism via PPARα, which leads to cardiac dysfunction.
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Wen S, Unuma K, Funakoshi T, Aki T, Uemura K. Altered cardiac mitochondrial dynamics and biogenesis in rat after short-term cocaine administration. Sci Rep 2021; 11:24129. [PMID: 34916603 PMCID: PMC8677764 DOI: 10.1038/s41598-021-03631-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 11/30/2021] [Indexed: 11/10/2022] Open
Abstract
Abuse of the potent psychostimulant cocaine is widely established to have cardiovascular consequences. The cardiotoxicity of cocaine is mainly associated with oxidative stress and mitochondrial dysfunction. Mitochondrial dynamics and biogenesis, as well as the mitochondrial unfolded protein response (UPRmt), guarantee cardiac mitochondrial homeostasis. Collectively, these mechanisms act to protect against stress, injury, and the detrimental effects of chemicals on mitochondria. In this study, we examined the effects of cocaine on cardiac mitochondrial dynamics, biogenesis, and UPRmt in vivo. Rats administered cocaine via the tail vein at a dose of 20 mg/kg/day for 7 days showed no structural changes in the myocardium, but electron microscopy revealed a significant increase in the number of cardiac mitochondria. Correspondingly, the expressions of the mitochondrial fission gene and mitochondrial biogenesis were increased after cocaine administration. Significant increase in the expression and nuclear translocation of activating transcription factor 5, the major active regulator of UPRmt, were observed after cocaine administration. Accordingly, our findings show that before any structural changes are observable in the myocardium, cocaine alters mitochondrial dynamics, elevates mitochondrial biogenesis, and induces the activation of UPRmt. These alterations might reflect cardiac mitochondrial compensation to protect against the cardiotoxicity of cocaine.
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Affiliation(s)
- Shuheng Wen
- Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Kana Unuma
- Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Takeshi Funakoshi
- Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Toshihiko Aki
- Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
| | - Koichi Uemura
- Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
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Roles of IκB kinases and TANK-binding kinase 1 in hepatic lipid metabolism and nonalcoholic fatty liver disease. Exp Mol Med 2021; 53:1697-1705. [PMID: 34848839 PMCID: PMC8639992 DOI: 10.1038/s12276-021-00712-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/31/2021] [Accepted: 09/07/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is strongly associated with obesity-related ectopic fat accumulation in the liver. Hepatic lipid accumulation encompasses a histological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma. Given that dysregulated hepatic lipid metabolism may be an onset factor in NAFLD, understanding how hepatic lipid metabolism is modulated in healthy subjects and which steps are dysregulated in NAFLD subjects is crucial to identify effective therapeutic targets. Additionally, hepatic inflammation is involved in chronic hepatocyte damage during NAFLD progression. As a key immune signaling hub that mediates NF-κB activation, the IκB kinase (IKK) complex, including IKKα, IKKβ, and IKKγ (NEMO), has been studied as a crucial regulator of the hepatic inflammatory response and hepatocyte survival. Notably, TANK-binding kinase 1 (TBK1), an IKK-related kinase, has recently been revealed as a potential link between hepatic inflammation and energy metabolism. Here, we review (1) the biochemical steps of hepatic lipid metabolism; (2) dysregulated lipid metabolism in obesity and NAFLD; and (3) the roles of IKKs and TBK1 in obesity and NAFLD.
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18
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Fasting and Refeeding Affect the Goose Liver Transcriptome Mainly Through the PPAR Signaling Pathway. J Poult Sci 2021; 58:245-257. [PMID: 34899020 PMCID: PMC8630407 DOI: 10.2141/jpsa.0200095] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 01/20/2021] [Indexed: 11/21/2022] Open
Abstract
Nutrition and energy are essential for poultry growth and production performance. Fasting and refeeding have been widely used to study the effects of nutrition, energy, and related mechanisms in chicken. Previous studies have shown that geese have a strong capacity for fat synthesis and storage; thus, changes in the goose liver transcriptome may be different from those in chicken assessed with a model of fasting and refeeding. However, the responses of the goose liver transcriptome to fasting and refeeding have not yet been addressed. In this study, 36 70-day-old Si Ji geese with similar body weight were randomly assigned to three groups: control (ad libitum feeding), fasting (fasted for 24 h), and refeeding (fast for 24 h followed by 2-h feeding) groups. After treatment, eight geese per group were sacrificed for sample collection. Liver samples from four geese in each group were subjected to transcriptome analysis, followed by validation of differentially expressed genes (DEGs) using quantitative polymerase chain reaction with the remaining samples. As a result, 155 DEGs (73 up-regulated) were identified between the control and fasting groups, and 651 DEGs (321 up-regulated) were identified between the fasting and refeeding groups. The enrichment analyses of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways showed that fasting mainly influenced material metabolism in the liver, especially lipid metabolism; in contrast, refeeding affected not only lipid metabolism but also glucose and amino acid metabolism. In addition, the peroxisome proliferator-activated receptor (PPAR) signaling pathway may play an important role in lipid metabolism. In conclusion, fasting and refeeding have a strong effect on lipid metabolism in the goose liver; specifically, fasting promotes fatty acid oxidation and inhibits fatty acid synthesis, and refeeding has the opposite effect. The model of fasting and refeeding is suitable for goose nutrition studies.
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Monroy-Ramirez HC, Galicia-Moreno M, Sandoval-Rodriguez A, Meza-Rios A, Santos A, Armendariz-Borunda J. PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases. Int J Mol Sci 2021; 22:ijms22158298. [PMID: 34361064 PMCID: PMC8347792 DOI: 10.3390/ijms22158298] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 12/12/2022] Open
Abstract
Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.
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Affiliation(s)
- Hugo Christian Monroy-Ramirez
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Marina Galicia-Moreno
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Ana Sandoval-Rodriguez
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Alejandra Meza-Rios
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
| | - Arturo Santos
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
| | - Juan Armendariz-Borunda
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
- Correspondence:
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20
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Hassan RM, Aboutabl ME, Bozzi M, El-Behairy MF, El Kerdawy AM, Sampaolese B, Desiderio C, Vincenzoni F, Sciandra F, Ghannam IAY. Discovery of 4-benzyloxy and 4-(2-phenylethoxy) chalcone fibrate hybrids as novel PPARα agonists with anti-hyperlipidemic and antioxidant activities: Design, synthesis and in vitro/in vivo biological evaluation. Bioorg Chem 2021; 115:105170. [PMID: 34332233 DOI: 10.1016/j.bioorg.2021.105170] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/07/2021] [Accepted: 07/09/2021] [Indexed: 10/20/2022]
Abstract
In the current work, a series of novel 4-benzyloxy and 4-(2-phenylethoxy) chalcone fibrate hybrids (10a-o) and (11a-e) were synthesized and evaluated as new PPARα agonists in order to find new agents with higher activity and fewer side effects. The 2-propanoic acid derivative 10a and the 2-butanoic acid congener 10i showed the best overall PPARα agonistic activity showing Emax% values of 50.80 and 90.55%, respectively, and EC50 values of 8.9 and 25.0 μM, respectively, compared to fenofibric acid with Emax = 100% and EC50 = 23.22 μM, respectively. These two compounds also stimulated carnitine palmitoyltransferase 1A gene transcription in HepG2 cells and PPARα protein expression. Molecular docking simulations were performed for the newly synthesized compounds to study their predicted binding pattern and energies in PPARα active site to rationalize their promising activity. In vivo, compounds 10a and 10i elicited a significant hypolipidemic activity improving the lipid profile in triton WR-1339-induced hyperlipidemic rats, including serum triglycerides, total cholesterol, LDL, HDL and VLDL levels. Compound 10i possessed better anti-hyperlipidemic activity than 10a. At a dose of 200 mg/kg, it demonstrated significantly lower TC, TG, LDL and VLDL levels than that of fenofibrate at the same dose with similar HDL levels. Compounds 10i and 10a possessed atherogenic indices (CRR, AC, AI, CRI-II) like that of fenofibrate. Additionally, a promising antioxidant activity indicated by the increased tissue reduced glutathione and plasma total antioxidant capacity with decreased plasma malondialdehyde levels was demonstrated by compounds 10a and 10i. No histopathological alterations were recorded in the hepatic tissue of compound 10i (200 mg/kg).
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Affiliation(s)
- Rasha M Hassan
- Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), P.O. 12622, Dokki, Giza, Egypt
| | - Mona E Aboutabl
- Medicinal and Pharmaceutical Chemistry Department (Pharmacology Group), Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), 33 El Bohouth St., P.O. 12622, Dokki, Giza, Egypt
| | - Manuela Bozzi
- Dipartimento Universitario di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Sezione di Biochimica e Biochimica Clinica, Università Cattolica del Sacro Cuore di Roma, Largo F. Vito 1, 00168 Roma, Italy; Istituto di Scienze e Tecnologie Chimiche "Giulio Natta"- SCITEC (CNR) Sede di Roma, Largo F. Vito 1, 00168 Roma, Italy.
| | - Mohammed F El-Behairy
- Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City 32897, Egypt
| | - Ahmed M El Kerdawy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; Department of Pharmaceutical Chemistry, School of Pharmacy, New Giza University, Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt
| | - Beatrice Sampaolese
- Istituto di Scienze e Tecnologie Chimiche "Giulio Natta"- SCITEC (CNR) Sede di Roma, Largo F. Vito 1, 00168 Roma, Italy
| | - Claudia Desiderio
- Istituto di Scienze e Tecnologie Chimiche "Giulio Natta"- SCITEC (CNR) Sede di Roma, Largo F. Vito 1, 00168 Roma, Italy
| | - Federica Vincenzoni
- Dipartimento Universitario di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Sezione di Biochimica e Biochimica Clinica, Università Cattolica del Sacro Cuore di Roma, Largo F. Vito 1, 00168 Roma, Italy; Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Largo A. Gemelli 8, 00168 Roma, Italy
| | - Francesca Sciandra
- Istituto di Scienze e Tecnologie Chimiche "Giulio Natta"- SCITEC (CNR) Sede di Roma, Largo F. Vito 1, 00168 Roma, Italy.
| | - Iman A Y Ghannam
- Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Cairo 12622, Egypt.
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The Glitazars Paradox: Cardiotoxicity of the Metabolically Beneficial Dual PPARα and PPARγ Activation. J Cardiovasc Pharmacol 2021; 76:514-526. [PMID: 33165133 DOI: 10.1097/fjc.0000000000000891] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The most common complications in patients with type-2 diabetes are hyperglycemia and hyperlipidemia that can lead to cardiovascular disease. Alleviation of these complications constitutes the major therapeutic approach for the treatment of diabetes mellitus. Agonists of peroxisome proliferator-activated receptor (PPAR) alpha and PPARγ are used for the treatment of hyperlipidemia and hyperglycemia, respectively. PPARs belong to the nuclear receptors superfamily and regulate fatty acid metabolism. PPARα ligands, such as fibrates, reduce circulating triglyceride levels, and PPARγ agonists, such as thiazolidinediones, improve insulin sensitivity. Dual-PPARα/γ agonists (glitazars) were developed to combine the beneficial effects of PPARα and PPARγ agonism. Although they improved metabolic parameters, they paradoxically aggravated congestive heart failure in patients with type-2 diabetes via mechanisms that remain elusive. Many of the glitazars, such as muraglitazar, tesaglitazar, and aleglitazar, were abandoned in phase-III clinical trials. The objective of this review article pertains to the understanding of how combined PPARα and PPARγ activation, which successfully targets the major complications of diabetes, causes cardiac dysfunction. Furthermore, it aims to suggest interventions that will maintain the beneficial effects of dual PPARα/γ agonism and alleviate adverse cardiac outcomes in diabetes.
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22
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Ide T, Origuchi I. An Oil Rich in γ-Linolenic Acid Differently Affects Hepatic Fatty Acid Oxidation in Mice and Rats. Biol Pharm Bull 2021; 43:1382-1392. [PMID: 32879213 DOI: 10.1248/bpb.b20-00322] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The effects of different dietary fats on hepatic fatty acid oxidation were compared in male ICR mice and Sprague-Dawley rats. Animals were fed diets containing 100 g/kg of either palm oil (saturated fat), safflower oil (rich in linoleic acid), an oil of evening primrose origin (γ-linolenic acid, GLA oil), perilla oil (α-linolenic acid) or fish oil (eicosapentaenoic and doxosahexaenoic acids) for 21 d. GLA, perilla and fish oils, compared with palm and safflower oils, increased the activity of fatty acid oxidation enzymes in both mice and rats, with some exceptions. In mice, GLA and fish oils greatly increased the peroxisomal palmitoyl-CoA oxidation rate, and the activity of acyl-CoA oxidase and enoyl-CoA hydratase to the same degree. The effects were much smaller with perilla oil. In rats, enhancing effects were more notable with fish oil than with GLA and perilla oils, excluding the activity of enoyl-CoA hydratase, and were comparable between GLA and perilla oils. In mice, strong enhancing effects of GLA oil, which were greater than with perilla oil and comparable to those of fish oil, were confirmed on mRNA levels of peroxisomal but not mitochondrial fatty acid oxidation enzymes. In rats, the effects of GLA and perilla oils on mRNA levels of peroxisomal and mitochondrial enzymes were indistinguishable, and lower than those observed with fish oil. Therefore, considerable diversity in the response to dietary polyunsaturated fats, especially the oil rich in γ-linolenic acid and fish oil, of hepatic fatty acid oxidation pathway exists between mice and rats.
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Affiliation(s)
- Takashi Ide
- Department of Food and Nutrition, Faculty of Human Life, Jumonji University
| | - Izumi Origuchi
- Department of Food and Nutrition, Faculty of Human Life, Jumonji University
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Zander-Fox D, Villarosa L, McPherson NO. Albumin used in human IVF contain different levels of lipids and modify embryo and fetal growth in a mouse model. J Assist Reprod Genet 2021; 38:2371-2381. [PMID: 34114110 DOI: 10.1007/s10815-021-02255-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 06/03/2021] [Indexed: 11/25/2022] Open
Abstract
PURPOSE Different commercial human embryo culture mediums can alter embryo quality and change birthweight. One component that could be contributing to variations but is not widely investigated is human serum albumin (HSA). HSA plays a multitude of roles during embryo culture and is a carrier for molecules including lipids. It remains unclear if lipid composition of HSA varies among commercial products and its effects on embryo quality, implantation, and fetal outcomes are relatively unknown. METHODS Utilizing a mouse model of embryo culture, we cultured zygotes until the blastocyst stage (72-h culture) in G1/G2 containing either Vitrolife HSA, Sage HSA, or Recombinant HSA at 10%. Blastocyst quality (development, total cell number, superoxide generation), blastocyst lipid content (neutral lipids, non-esterified fatty acids, phospholipids, and triglycerides), implantation, and fetal lengths and weights were assessed. Fatty acid quantification of HSA source was assessed by standard thin-layer chromatography. RESULTS Sage HSA had the greatest fatty acid composition, with an eightfold increase in saturated fatty acids. This coincided with reduced blastocyst development, increased superoxide generation, neutral lipids and triglycerides levels of blastocysts, and decreased implantation rates (p < 0.05). Unexpectedly, while Recombinant HSA had the lowest overall lipids it had 70-fold increase in palmitoleic acid and the lowest fetal weights (p < 0.05). CONCLUSION Indicates the importance of a balance between different types/amount of lipids, and an "optimal ratio" required for embryo and fetal development. Therefore, the lipid content of HSA should be considered when choosing a suitable HSA source for use in clinical IVF.
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Affiliation(s)
- Deirdre Zander-Fox
- Repromed, Dulwich South Australia, Australia.
- Department of Bioengineering, University of South Australia, Adelaide, Australia.
- Monash University, Clayton, Australia.
- Monash IVF Group, Richmond, Victoria, Australia.
- Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
- School of Medicine, University of Adelaide, Adelaide, Australia.
| | - Lauren Villarosa
- Repromed, Dulwich South Australia, Australia
- Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia
| | - Nicole O McPherson
- Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia
- School of Medicine, University of Adelaide, Adelaide, Australia
- Freemasons Center for Male Health and Wellbeing, University of Adelaide, Adelaide, South Australia, Australia
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24
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Gherardi G, De Mario A, Mammucari C. The mitochondrial calcium homeostasis orchestra plays its symphony: Skeletal muscle is the guest of honor. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 362:209-259. [PMID: 34253296 DOI: 10.1016/bs.ircmb.2021.03.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
Abstract
Skeletal muscle mitochondria are placed in close proximity of the sarcoplasmic reticulum (SR), the main intracellular Ca2+ store. During muscle activity, excitation of sarcolemma and of T-tubule triggers the release of Ca2+ from the SR initiating myofiber contraction. The rise in cytosolic Ca2+ determines the opening of the mitochondrial calcium uniporter (MCU), the highly selective channel of the inner mitochondrial membrane (IMM), causing a robust increase in mitochondrial Ca2+ uptake. The Ca2+-dependent activation of TCA cycle enzymes increases the synthesis of ATP required for SERCA activity. Thus, Ca2+ is transported back into the SR and cytosolic [Ca2+] returns to resting levels eventually leading to muscle relaxation. In recent years, thanks to the molecular identification of MCU complex components, the role of mitochondrial Ca2+ uptake in the pathophysiology of skeletal muscle has been uncovered. In this chapter, we will introduce the reader to a general overview of mitochondrial Ca2+ accumulation. We will tackle the key molecular players and the cellular and pathophysiological consequences of mitochondrial Ca2+ dyshomeostasis. In the second part of the chapter, we will discuss novel findings on the physiological role of mitochondrial Ca2+ uptake in skeletal muscle. Finally, we will examine the involvement of mitochondrial Ca2+ signaling in muscle diseases.
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Affiliation(s)
- Gaia Gherardi
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Agnese De Mario
- Department of Biomedical Sciences, University of Padua, Padua, Italy
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25
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Pinterić M, Podgorski II, Popović Hadžija M, Tartaro Bujak I, Tadijan A, Balog T, Sobočanec S. Chronic High Fat Diet Intake Impairs Hepatic Metabolic Parameters in Ovariectomized Sirt3 KO Mice. Int J Mol Sci 2021; 22:ijms22084277. [PMID: 33924115 PMCID: PMC8074326 DOI: 10.3390/ijms22084277] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/14/2021] [Accepted: 04/16/2021] [Indexed: 12/12/2022] Open
Abstract
High fat diet (HFD) is an important factor in the development of metabolic diseases, with liver as metabolic center being highly exposed to its influence. However, the effect of HFD-induced metabolic stress with respect to ovary hormone depletion and sirtuin 3 (Sirt3) is not clear. Here we investigated the effect of Sirt3 in liver of ovariectomized and sham female mice upon 10 weeks of feeding with standard-fat diet (SFD) or HFD. Liver was examined by Folch, gas chromatography and lipid hydroperoxide analysis, histology and oil red staining, RT-PCR, Western blot, antioxidative enzyme and oxygen consumption analyses. In SFD-fed WT mice, ovariectomy increased Sirt3 and fatty acids synthesis, maintained mitochondrial function, and decreased levels of lipid hydroperoxides. Combination of ovariectomy and Sirt3 depletion reduced pparα, Scd-1 ratio, MUFA proportions, CII-driven respiration, and increased lipid damage. HFD compromised CII-driven respiration and activated peroxisomal ROS scavenging enzyme catalase in sham mice, whereas in combination with ovariectomy and Sirt3 depletion, increased body weight gain, expression of NAFLD- and oxidative stress-inducing genes, and impaired response of antioxidative system. Overall, this study provides evidence that protection against harmful effects of HFD in female mice is attributed to the combined effect of female sex hormones and Sirt3, thus contributing to preclinical research on possible sex-related therapeutic agents for metabolic syndrome and associated diseases.
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Affiliation(s)
- Marija Pinterić
- Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (M.P.); (I.I.P.); (M.P.H.); (A.T.); (T.B.)
| | - Iva I. Podgorski
- Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (M.P.); (I.I.P.); (M.P.H.); (A.T.); (T.B.)
| | - Marijana Popović Hadžija
- Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (M.P.); (I.I.P.); (M.P.H.); (A.T.); (T.B.)
| | - Ivana Tartaro Bujak
- Division of Materials Chemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia;
| | - Ana Tadijan
- Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (M.P.); (I.I.P.); (M.P.H.); (A.T.); (T.B.)
| | - Tihomir Balog
- Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (M.P.); (I.I.P.); (M.P.H.); (A.T.); (T.B.)
| | - Sandra Sobočanec
- Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (M.P.); (I.I.P.); (M.P.H.); (A.T.); (T.B.)
- Correspondence: ; Tel.: +385-1-4561-172
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26
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Pasqua T, Rocca C, Giglio A, Angelone T. Cardiometabolism as an Interlocking Puzzle between the Healthy and Diseased Heart: New Frontiers in Therapeutic Applications. J Clin Med 2021; 10:721. [PMID: 33673114 PMCID: PMC7918460 DOI: 10.3390/jcm10040721] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/05/2021] [Accepted: 02/07/2021] [Indexed: 12/14/2022] Open
Abstract
Cardiac metabolism represents a crucial and essential connecting bridge between the healthy and diseased heart. The cardiac muscle, which may be considered an omnivore organ with regard to the energy substrate utilization, under physiological conditions mainly draws energy by fatty acids oxidation. Within cardiomyocytes and their mitochondria, through well-concerted enzymatic reactions, substrates converge on the production of ATP, the basic chemical energy that cardiac muscle converts into mechanical energy, i.e., contraction. When a perturbation of homeostasis occurs, such as an ischemic event, the heart is forced to switch its fatty acid-based metabolism to the carbohydrate utilization as a protective mechanism that allows the maintenance of its key role within the whole organism. Consequently, the flexibility of the cardiac metabolic networks deeply influences the ability of the heart to respond, by adapting to pathophysiological changes. The aim of the present review is to summarize the main metabolic changes detectable in the heart under acute and chronic cardiac pathologies, analyzing possible therapeutic targets to be used. On this basis, cardiometabolism can be described as a crucial mechanism in keeping the physiological structure and function of the heart; furthermore, it can be considered a promising goal for future pharmacological agents able to appropriately modulate the rate-limiting steps of heart metabolic pathways.
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Affiliation(s)
- Teresa Pasqua
- Department of Health Science, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy;
| | - Carmine Rocca
- Laboratory of Cellular and Molecular Cardiovascular Pathophysiology, Department of Biology, E. and E.S. (Di.B.E.S.T.), University of Calabria, 87036 Rende (CS), Italy
| | - Anita Giglio
- Department of Biology, E. and E.S. (Di.B.E.S.T.), University of Calabria, 87036 Rende (CS), Italy;
| | - Tommaso Angelone
- Laboratory of Cellular and Molecular Cardiovascular Pathophysiology, Department of Biology, E. and E.S. (Di.B.E.S.T.), University of Calabria, 87036 Rende (CS), Italy
- National Institute of Cardiovascular Research (I.N.R.C.), 40126 Bologna, Italy
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Mehmood A, Zhao L, Wang Y, Pan F, Hao S, Zhang H, Iftikhar A, Usman M. Dietary anthocyanins as potential natural modulators for the prevention and treatment of non-alcoholic fatty liver disease: A comprehensive review. Food Res Int 2021; 142:110180. [PMID: 33773656 DOI: 10.1016/j.foodres.2021.110180] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 01/18/2021] [Accepted: 01/24/2021] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) refers to a metabolic syndrome linked with type 2 diabetes mellitus, obesity, and cardiovascular diseases. It is characterized by the accumulation of triglycerides in the hepatocytes in the absence of alcohol consumption. The prevalence of NAFLD has abruptly increased worldwide, with no effective treatment yet available. Anthocyanins (ACNs) belong to the flavonoid subclass of polyphenols, are commonly present in various edible plants, and possess a broad array of health-promoting properties. ACNs have been shown to have strong potential to combat NAFLD. We critically assessed the literature regarding the pharmacological mechanisms and biopharmaceutical features of the action of ACNs on NAFLD in humans and animal models. We found that ACNs ameliorate NAFLD by improving lipid and glucose metabolism, increasing antioxidant and anti-inflammatory activities, and regulating gut microbiota dysbiosis. In conclusion, ACNs have potential to attenuate NAFLD. However, further mechanistic studies are required to confirm these beneficial impacts of ACNs on NAFLD.
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Affiliation(s)
- Arshad Mehmood
- Beijing Advance Innovation Center for Food Nutrition and Human Health, Beijing Engineering and Technology Research Center of Food Additives, School of Food and Health, Beijing Technology and Business University, Beijing 100048, China
| | - Lei Zhao
- Beijing Advance Innovation Center for Food Nutrition and Human Health, Beijing Engineering and Technology Research Center of Food Additives, School of Food and Health, Beijing Technology and Business University, Beijing 100048, China.
| | - Yong Wang
- Academy of National Food and Strategic Reserves Administration, Beijing 100037, China
| | - Fei Pan
- Beijing Advance Innovation Center for Food Nutrition and Human Health, Beijing Engineering and Technology Research Center of Food Additives, School of Food and Health, Beijing Technology and Business University, Beijing 100048, China
| | - Shuai Hao
- Beijing Advance Innovation Center for Food Nutrition and Human Health, Beijing Engineering and Technology Research Center of Food Additives, School of Food and Health, Beijing Technology and Business University, Beijing 100048, China
| | - Huimin Zhang
- Beijing Advance Innovation Center for Food Nutrition and Human Health, Beijing Engineering and Technology Research Center of Food Additives, School of Food and Health, Beijing Technology and Business University, Beijing 100048, China
| | - Asra Iftikhar
- Department of Pharmacy, Faculty of Pharmaceutical Sciences, The University of Faisalabad, Faisalabad 38000, Pakistan
| | - Muhammad Usman
- Beijing Advance Innovation Center for Food Nutrition and Human Health, Beijing Engineering and Technology Research Center of Food Additives, School of Food and Health, Beijing Technology and Business University, Beijing 100048, China
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28
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Patel BV, Yao F, Howenstine A, Takenaka R, Hyatt JA, Sears KE, Shewchuk BM. Emergent Coordination of the CHKB and CPT1B Genes in Eutherian Mammals: Implications for the Origin of Brown Adipose Tissue. J Mol Biol 2020; 432:6127-6145. [PMID: 33058877 DOI: 10.1016/j.jmb.2020.09.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 09/24/2020] [Accepted: 09/28/2020] [Indexed: 11/17/2022]
Abstract
Mitochondrial fatty acid oxidation (FAO) contributes to the proton motive force that drives ATP synthesis in many mammalian tissues. In eutherian (placental) mammals, brown adipose tissue (BAT) can also dissipate this proton gradient through uncoupling protein 1 (UCP1) to generate heat, but the evolutionary events underlying the emergence of BAT are unknown. An essential step in FAO is the transport of cytoplasmic long chain acyl-coenzyme A (acyl-CoA) into the mitochondrial matrix, which requires the action of carnitine palmitoyltransferase 1B (CPT1B) in striated muscle and BAT. In eutherians, the CPT1B gene is closely linked to the choline kinase beta (CHKB) gene, which is transcribed from the same DNA strand and terminates just upstream of CPT1B. CHKB is a rate-limiting enzyme in the synthesis of phosphatidylcholine (PC), a predominant mitochondrial membrane phospholipid, suggesting that the coordinated expression of CHKB and CPT1B may cooperatively enhance mitochondrial FAO. The present findings show that transcription of the eutherian CHKB and CPT1B genes is linked within a unitary epigenetic domain targeted to the CHKB gene, and that that this regulatory linkage appears to have resulted from an intergenic deletion in eutherians that significantly altered the distribution of CHKB and CPT1B expression. Informed by the timing of this event relative to the emergence of BAT, the phylogeny of CHKB-CPT1B synteny, and the insufficiency of UCP1 to account for eutherian BAT, these data support a mechanism for the emergence of BAT based on the acquisition of a novel capacity for adipocyte FAO in a background of extant UCP1.
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Affiliation(s)
- Bhavin V Patel
- Department of Biochemistry & Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - Fanrong Yao
- Department of Biochemistry & Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - Aidan Howenstine
- Department of Ecology & Evolutionary Biology, College of Life Sciences, University of California Los Angeles, Los Angeles, CA 90095, United States
| | - Risa Takenaka
- Department of Ecology & Evolutionary Biology, College of Life Sciences, University of California Los Angeles, Los Angeles, CA 90095, United States
| | - Jacob A Hyatt
- Department of Biochemistry & Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - Karen E Sears
- Department of Ecology & Evolutionary Biology, College of Life Sciences, University of California Los Angeles, Los Angeles, CA 90095, United States
| | - Brian M Shewchuk
- Department of Biochemistry & Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States.
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Zhang Z, Su H, Ahmed RZ, Zheng Y, Jin X. Critical biomarkers for myocardial damage by fine particulate matter: Focused on PPARα-regulated energy metabolism. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2020; 264:114659. [PMID: 32380395 DOI: 10.1016/j.envpol.2020.114659] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/22/2020] [Accepted: 04/23/2020] [Indexed: 06/11/2023]
Abstract
Fine particulate matter is one of the leading threats to cardiovascular health worldwide. The exploration of novel and sensitive biomarkers to detect damaging effect of fine particulate matter on cardiac tissues is of great importance in the better understanding of haze-caused myocardial injury. A link between heart failure and PPARα-regulated energy metabolism has been confirmed previously. Herein, the study intends to reveal the critical biomarkers of fine particulate matter induced myocardial damage from the PPARα-regulated energy metabolism. Ambient fine particulate matter induced severe pathological alterations in cultured cells, accompanied by the decrease in ATP content. Additionally, the expressions of CPT1/CPT2 and levels of CS and MDH, crucial members in β-oxidation and the TCA cycle, were significantly decreased. In direct contrast, fine particulate matter increased the biomarkers of glycolysis, as measured by the accumulation of pyruvate and lactate contents, and the enhanced activities of HK and PKM1/2. Importantly, fine particulate matter-exposed cardiomyocytes exhibited the reduced PPARα level, that increased when cardiomyocytes were co-incubation with WY-14643 and fine particulate matter. Simultaneously, the adverse impact of fine particulate matter on critical biomarkers were observed in β-oxidation, TCA cycle and glycolysis, associated with WY-14643 additional complement. Fine particulate matter caused the myocardial energy metabolism transformation through the regulation of PPARα expression and translation, which provided novel and critical biomarkers for haze particles-caused myocardial damage.
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Affiliation(s)
- Ze Zhang
- School of Public Health, Qingdao University, Qingdao, China
| | - Huilan Su
- Institutes of Biomedical Sciences, Shanxi University, Taiyuan, China
| | - Rifat Zubair Ahmed
- Dept. of Genetics, University of Karachi, Karachi, Pakistan; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
| | - Yuxin Zheng
- School of Public Health, Qingdao University, Qingdao, China
| | - Xiaoting Jin
- School of Public Health, Qingdao University, Qingdao, China.
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Villanueva-Ortega E, Méndez-García LA, Garibay-Nieto GN, Laresgoiti-Servitje E, Medina-Bravo P, Olivos-García A, Muñoz-Ortega MH, Ventura-Juárez J, Escobedo G. Growth hormone ameliorates high glucose-induced steatosis on in vitro cultured human HepG2 hepatocytes by inhibiting de novo lipogenesis via ChREBP and FAS suppression. Growth Horm IGF Res 2020; 53-54:101332. [PMID: 32698101 DOI: 10.1016/j.ghir.2020.101332] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 05/13/2020] [Accepted: 06/01/2020] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Growth hormone (GH) deficiency has been associated with increased steatosis but the molecular mechanism has not been fully elucidated. We investigated the effect of GH on lipid accumulation of HepG2 cells cultured on an in vitro steatosis model and examined the potential involvement of insulin-like growth factor 1 (IGF-1) as well as lipogenic and lipolytic molecules. METHODS Control and steatosis conditions were induced by culturing HepG2 cells with 5.5 or 25 mmol/l glucose for 24 h, respectively. Afterward, cells were exposed to 0, 5, 10 or 20 ng/ml GH for another 24 h. Lipid content was quantified as well as mRNA and protein levels of IGF-1, carbohydrate responsive element-binding protein (ChREBP), sterol regulatory element-binding protein 1c (SREBP1c), fatty acid synthase (FAS), carnitine palmitoyltransferase 1A (CPT1A), and peroxisome proliferator-activated receptor alpha (PPAR-alpha) by qPCR and western blot, respectively. Data were analyzed by one-way ANOVA and the Games-Howell post-hoc test. RESULTS In the steatosis model, HepG2 hepatocytes showed a significant 2-fold increase in lipid amount as compared to control cells. IGF-1 mRNA and protein levels were significantly increased in control cells exposed to 10 ng/ml GH, whereas high glucose abolished this effect. High glucose also significantly increased both mRNA and protein of ChREBP and FAS without having effect on SREBP1c, CPT1A and PPAR-alpha. However, GH inhibited ChREBP and FAS production, even in HepG2 hepatocytes cultured under steatosis conditions. CONCLUSIONS Growth hormone ameliorates high glucose-induced steatosis in HepG2 cells by suppressing de novo lipogenesis via ChREBP and FAS down-regulation.
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Affiliation(s)
- Eréndira Villanueva-Ortega
- Laboratory for Proteomics and Metabolomics, Research Division, General Hospital of Mexico "Dr. Eduardo Liceaga", 06720, Mexico City, Mexico.; Department of Genetics, General Hospital of Mexico "Dr. Eduardo Liceaga", 06720, Mexico City, Mexico
| | - Lucia A Méndez-García
- Laboratory for Proteomics and Metabolomics, Research Division, General Hospital of Mexico "Dr. Eduardo Liceaga", 06720, Mexico City, Mexico
| | - Guadalupe N Garibay-Nieto
- Department of Genetics, General Hospital of Mexico "Dr. Eduardo Liceaga", 06720, Mexico City, Mexico
| | - Estibalitz Laresgoiti-Servitje
- Clinical Medical Sciences, School of Medicine, Tecnológico de Monterrey, Campus Ciudad de México, 14380, Mexico City, Mexico
| | - Patricia Medina-Bravo
- Endocrinology Department, Hospital Infantil de México Federico Gómez, 06720, Mexico City, Mexico
| | - Alfonso Olivos-García
- Experimental Research Unit, School of Medicine, Universidad Nacional Autónoma de México, General Hospital of Mexico "Dr. Eduardo Liceaga", 06720, Mexico City, Mexico
| | - Martín H Muñoz-Ortega
- Universidad Autónoma de Aguascalientes, Departamento de Morfología, Centro de Ciencias Básicas, Edificio 202, Av. Universidad 940 Ciudad Universitaria C.P. 20130, Aguascalientes, Ags., Mexico
| | - Javier Ventura-Juárez
- Universidad Autónoma de Aguascalientes, Departamento de Morfología, Centro de Ciencias Básicas, Edificio 202, Av. Universidad 940 Ciudad Universitaria C.P. 20130, Aguascalientes, Ags., Mexico
| | - Galileo Escobedo
- Laboratory for Proteomics and Metabolomics, Research Division, General Hospital of Mexico "Dr. Eduardo Liceaga", 06720, Mexico City, Mexico..
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Xiang K, Qin Z, Zhang H, Liu X. Energy Metabolism in Exercise-Induced Physiologic Cardiac Hypertrophy. Front Pharmacol 2020; 11:1133. [PMID: 32848751 PMCID: PMC7403221 DOI: 10.3389/fphar.2020.01133] [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: 05/25/2020] [Accepted: 07/13/2020] [Indexed: 12/17/2022] Open
Abstract
Physiologic hypertrophy of the heart preserves or enhances systolic function without interstitial fibrosis or cell death. As a unique form of physiological stress, regular exercise training can trigger the adaptation of cardiac muscle to cause physiological hypertrophy, partly due to its ability to improve cardiac metabolism. In heart failure (HF), cardiac dysfunction is closely associated with early initiation of maladaptive metabolic remodeling. A large amount of clinical and experimental evidence shows that metabolic homeostasis plays an important role in exercise training, which is conducive to the treatment and recovery of cardiovascular diseases. Potential mechanistic targets for modulation of cardiac metabolism have become a hot topic at present. Thus, exploring the energy metabolism mechanism in exercise-induced physiologic cardiac hypertrophy may produce new therapeutic targets, which will be helpful to design novel effective strategies. In this review, we summarize the changes of myocardial metabolism (fatty acid metabolism, carbohydrate metabolism, and mitochondrial adaptation), metabolically-related signaling molecules, and probable regulatory mechanism of energy metabolism during exercise-induced physiological cardiac hypertrophy.
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Affiliation(s)
- Kefa Xiang
- Department of Clinical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Zhen Qin
- Department of Clinical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Huimin Zhang
- Department of Clinical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Xia Liu
- Department of Clinical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, China
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Maroli G, Braun T. The long and winding road of cardiomyocyte maturation. Cardiovasc Res 2020; 117:712-726. [PMID: 32514522 DOI: 10.1093/cvr/cvaa159] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 05/15/2020] [Accepted: 06/02/2020] [Indexed: 12/13/2022] Open
Abstract
Knowledge about the molecular mechanisms regulating cardiomyocyte (CM) proliferation and differentiation has increased exponentially in recent years. Such insights together with the availability of more efficient protocols for generation of CMs from induced pluripotent stem cells (iPSCs) have raised expectations for new therapeutic strategies to treat congenital and non-congenital heart diseases. However, the poor regenerative potential of the postnatal heart and the incomplete maturation of iPSC-derived CMs represent important bottlenecks for such therapies in future years. CMs undergo dramatic changes at the doorstep between prenatal and postnatal life, including terminal cell cycle withdrawal, change in metabolism, and further specialization of the cellular machinery required for high-performance contraction. Here, we review recent insights into pre- and early postnatal developmental processes that regulate CM maturation, laying specific focus on genetic and metabolic pathways that control transition of CMs from the embryonic and perinatal to the fully mature adult CM state. We recapitulate the intrinsic features of CM maturation and highlight the importance of external factors, such as energy substrate availability and endocrine regulation in shaping postnatal CM development. We also address recent approaches to enhance maturation of iPSC-derived CMs in vitro, and summarize new discoveries that might provide useful tools for translational research on repair of the injured human heart.
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Affiliation(s)
- Giovanni Maroli
- Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany
| | - Thomas Braun
- Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.,German Centre for Cardiovascular Research (DZHK), partner site Rhein-Main, Ludwigstrasse 43, 61231 Bad Nauheim, Germany
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Gao X, Zhang Z, Li X, Wei Q, Li H, Li C, Chen H, Liu C, He K. Ursolic Acid Improves Monocrotaline-Induced Right Ventricular Remodeling by Regulating Metabolism. J Cardiovasc Pharmacol 2020; 75:545-555. [PMID: 32141989 DOI: 10.1097/fjc.0000000000000815] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a progressive and malignant disease characterized by pulmonary small arteries and right ventricle (RV) remodeling that can lead to severe RV dysfunction and death. The current therapeutic targets for RV dysfunction, which is strongly linked to mortality, are far from adequate. Therefore, we investigated the effect of ursolic acid (UA), a pentacyclic triterpenoid carboxylic acid, on PAH-induced RV remodeling and its underlying mechanism. We established a PAH model by injecting Sprague Dawley rats with monocrotaline (MCT, 60 mg/kg, ip), as verified by echocardiography and hemodynamic examination. Proteomic analysis was performed on RV samples using a Q Exactive high-field mass spectrometer, followed by KEGG enrichment analysis. The effect of 4 weeks of UA (50 mg/kg) treatment on RV remodeling was explored based on ultrasound, hemodynamic parameters, and histological changes, with the mechanism verified in vivo and in vitro by qRT-PCR and western blotting. RV hypertrophy, fibrosis, increased apoptosis, and abnormal metabolism were induced by MCT and suppressed by UA via a mechanism that changed the expression of key markers. UA also attenuated the Phenylephrine-induced hypertrophy of neonatal rat ventricular myocytes and upregulated peroxisome proliferator-activated receptor-alpha (PPARα), a key fatty acid metabolism regulator, and its downstream factor carnitine palmitoyl transferase 1b. In conclusion, UA exerts beneficial effects on PAH-induced RV dysfunction and remodeling by regulating PPARα-dependent fatty acid metabolism.
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MESH Headings
- Animals
- Apoptosis/drug effects
- Carnitine O-Palmitoyltransferase/metabolism
- Cells, Cultured
- Disease Models, Animal
- Energy Metabolism/drug effects
- Fatty Acids/metabolism
- Fibrosis
- Heart Ventricles/drug effects
- Heart Ventricles/enzymology
- Heart Ventricles/pathology
- Heart Ventricles/physiopathology
- Hypertrophy, Right Ventricular/chemically induced
- Hypertrophy, Right Ventricular/metabolism
- Hypertrophy, Right Ventricular/physiopathology
- Hypertrophy, Right Ventricular/prevention & control
- Male
- Monocrotaline
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- PPAR alpha/metabolism
- Pulmonary Arterial Hypertension/chemically induced
- Pulmonary Arterial Hypertension/drug therapy
- Pulmonary Arterial Hypertension/metabolism
- Pulmonary Arterial Hypertension/physiopathology
- Rats, Sprague-Dawley
- Triterpenes/pharmacology
- Ventricular Function, Right/drug effects
- Ventricular Remodeling/drug effects
- Ursolic Acid
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Affiliation(s)
- Xiaojian Gao
- Department of Cardiovascular, Chinese PLA General Hospital, Beijing, China
| | - Zeyu Zhang
- Department of Cardiovascular, Chinese PLA General Hospital, Beijing, China
| | - Xin Li
- Laboratory of Translational Medicine, Chinese PLA General Hospital, Beijing, China
- Beijing Key Laboratory of Chronic Heart Failure Precision Medicine, Chinese PLA General Hospital, Beijing, China; and
| | - Qingxia Wei
- Laboratory of Translational Medicine, Chinese PLA General Hospital, Beijing, China
- Beijing Key Laboratory of Chronic Heart Failure Precision Medicine, Chinese PLA General Hospital, Beijing, China; and
| | - Hanlu Li
- Laboratory of Translational Medicine, Chinese PLA General Hospital, Beijing, China
- Beijing Key Laboratory of Chronic Heart Failure Precision Medicine, Chinese PLA General Hospital, Beijing, China; and
| | - Chen Li
- Laboratory of Translational Medicine, Chinese PLA General Hospital, Beijing, China
- Beijing Key Laboratory of Chronic Heart Failure Precision Medicine, Chinese PLA General Hospital, Beijing, China; and
| | - Haixu Chen
- Gastrointestinal Department of Southern Building, General Hospital of Chinese PLA, Beijing, China
| | - Chunlei Liu
- Laboratory of Translational Medicine, Chinese PLA General Hospital, Beijing, China
- Beijing Key Laboratory of Chronic Heart Failure Precision Medicine, Chinese PLA General Hospital, Beijing, China; and
| | - Kunlun He
- Laboratory of Translational Medicine, Chinese PLA General Hospital, Beijing, China
- Beijing Key Laboratory of Chronic Heart Failure Precision Medicine, Chinese PLA General Hospital, Beijing, China; and
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Griffin MD, Pereira SR, DeBari MK, Abbott RD. Mechanisms of action, chemical characteristics, and model systems of obesogens. BMC Biomed Eng 2020; 2:6. [PMID: 32903358 PMCID: PMC7422567 DOI: 10.1186/s42490-020-00040-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 04/07/2020] [Indexed: 02/06/2023] Open
Abstract
There is increasing evidence for the role of environmental endocrine disrupting contaminants, coined obesogens, in exacerbating the rising obesity epidemic. Obesogens can be found in everyday items ranging from pesticides to food packaging. Although research shows that obesogens can have effects on adipocyte size, phenotype, metabolic activity, and hormone levels, much remains unknown about these chemicals. This review will discuss what is currently known about the mechanisms of obesogens, including expression of the PPARs, hormone interference, and inflammation. Strategies for identifying obesogenic chemicals and their mechanisms through chemical characteristics and model systems will also be discussed. Ultimately, research should focus on improving models to discern precise mechanisms of obesogenic action and to test therapeutics targeting these mechanisms.
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Affiliation(s)
- Mallory D. Griffin
- Carnegie Mellon University, 5000 Forbes Avenue, Scott Hall, Pittsburgh, PA 15213 USA
| | - Sean R. Pereira
- Carnegie Mellon University, 5000 Forbes Avenue, Scott Hall, Pittsburgh, PA 15213 USA
| | - Megan K. DeBari
- Carnegie Mellon University, 5000 Forbes Avenue, Scott Hall, Pittsburgh, PA 15213 USA
| | - Rosalyn D. Abbott
- Carnegie Mellon University, 5000 Forbes Avenue, Scott Hall, Pittsburgh, PA 15213 USA
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Schlaepfer IR, Joshi M. CPT1A-mediated Fat Oxidation, Mechanisms, and Therapeutic Potential. Endocrinology 2020; 161:5695911. [PMID: 31900483 DOI: 10.1210/endocr/bqz046] [Citation(s) in RCA: 405] [Impact Index Per Article: 81.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 12/31/2019] [Indexed: 12/15/2022]
Abstract
Energy homeostasis during fasting or prolonged exercise depends on mitochondrial fatty acid oxidation (FAO). This pathway is crucial in many tissues with high energy demand and its disruption results in inborn FAO deficiencies. More than 15 FAO genetic defects have been currently described, and pathological variants described in circumpolar populations provide insights into its critical role in metabolism. The use of fatty acids as energy requires more than 2 dozen enzymes and transport proteins, which are involved in the activation and transport of fatty acids into the mitochondria. As the key rate-limiting enzyme of FAO, carnitine palmitoyltransferase I (CPT1) regulates FAO and facilitates adaptation to the environment, both in health and in disease, including cancer. The CPT1 family of proteins contains 3 isoforms: CPT1A, CPT1B, and CPT1C. This review focuses on CPT1A, the liver isoform that catalyzes the rate-limiting step of converting acyl-coenzyme As into acyl-carnitines, which can then cross membranes to get into the mitochondria. The regulation of CPT1A is complex and has several layers that involve genetic, epigenetic, physiological, and nutritional modulators. It is ubiquitously expressed in the body and associated with dire consequences linked with genetic mutations, metabolic disorders, and cancers. This makes CPT1A an attractive target for therapeutic interventions. This review discusses our current understanding of CPT1A expression, its role in heath and disease, and the potential for therapeutic opportunities targeting this enzyme.
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Affiliation(s)
- Isabel R Schlaepfer
- University of Colorado School of Medicine, Division of Medical Oncology, Aurora
| | - Molishree Joshi
- University of Colorado School of Medicine, Department of Pharmacology, Aurora, Colorado
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Luo Y, Zhang YN, Zhang H, Lv HB, Zhang ML, Chen LQ, Du ZY. PPARα activation enhances the ability of nile tilapia (Oreochromis niloticus) to resist Aeromonas hydrophila infection. FISH & SHELLFISH IMMUNOLOGY 2019; 94:675-684. [PMID: 31563556 DOI: 10.1016/j.fsi.2019.09.062] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 09/20/2019] [Accepted: 09/26/2019] [Indexed: 06/10/2023]
Abstract
Peroxisome proliferator-activated receptor α (PPARα) plays critical physiological roles in energy metabolism, antioxidation and immunity of mammals, however, these functions have not been fully understood in fish. In the present study, Nile tilapia (Oreochromis niloticus) were fed with fenofibrate, an agonist of PPARα, for six weeks, and subsequently challenged with Aeromonas hydrophila. The results showed that PPARα was efficiently activated by fenofibrate through increasing mRNA and protein expressions and protein dephosphorylation. PPARα activation increased significantly mitochondrial fatty acid β-oxidation efficiency, the copy number of mitochondrial DNA and expression of monoamine oxidase (MAO), a marker gene of mitochondria. Meanwhile, PPARα activation also increased significantly the expression of NADH dehydrogenase [ubiquinone] 1α subcomplex subunit 9 (NDUFA9, complex I) and mitochondrial cytochrome c oxidase 1 (MTCO1, complex IV). The fenofibrate-fed fish had higher survival rate when exposed to A. hydrophila. Moreover, the fenofibrate-fed fish also had higher activities of immune and antioxidative enzymes, and gene expressions of anti-inflammatory cytokines, while had lower expressions of pro-inflammatory cytokine genes. Taken together, PPARα activation improved the ability of Nile tilapia to resist A. hydrophila, mainly through enhancing mitochondrial fatty acids β-oxidation, immune and antioxidant capacities, as well as inhibiting inflammation. This is the first study showing the regulatory effects of PPARα activation on immune functions through increasing mitochondria-mediated energy supply in fish.
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Affiliation(s)
- Yuan Luo
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, China
| | - Yun-Ni Zhang
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, China
| | - Han Zhang
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, China
| | - Hong-Bo Lv
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, China
| | - Mei-Ling Zhang
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, China
| | - Li-Qiao Chen
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, China.
| | - Zhen-Yu Du
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, China.
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Impact of PPAR-Alpha Polymorphisms-The Case of Metabolic Disorders and Atherosclerosis. Int J Mol Sci 2019; 20:ijms20184378. [PMID: 31489930 PMCID: PMC6770475 DOI: 10.3390/ijms20184378] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 09/01/2019] [Accepted: 09/04/2019] [Indexed: 02/07/2023] Open
Abstract
Peroxisome proliferator activated receptor α (PPARα) has the most relevant biological functions among PPARs. Activation by drugs and dietary components lead to major metabolic changes, from reduced triglyceridemia to improvement in the metabolic syndrome. Polymorphisms of PPARα are of interest in order to improve our understanding of metabolic disorders associated with a raised or reduced risk of diseases. PPARα polymorphisms are mainly characterized by two sequence changes, L162V and V227A, with the latter occurring only in Eastern nations, and by numerous SNPs (Single nucleotide polymorphisms) with a less clear biological role. The minor allele of L162V associates with raised total cholesterol, LDL-C (low-density lipoprotein cholesterol), and triglycerides, reduced HDL-C (high-density lipoprotein metabolism), and elevated lipoprotein (a). An increased cardiovascular risk is not clear, whereas a raised risk of diabetes or of liver steatosis are not well supported. The minor allele of the V227A polymorphism is instead linked to a reduction of steatosis and raised γ-glutamyltranspeptidase levels in non-drinking Orientals, the latter being reduced in drinkers. Lastly, the minor allele of rs4353747 is associated with a raised high-altitude appetite loss. These and other associations indicate the predictive potential of PPARα polymorphisms for an improved understanding of human disease, which also explain variability in the clinical response to specific drug treatments or dietary approaches.
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Li XW, Huang M, Lo K, Chen WL, He YY, Xu Y, Zheng H, Hu H, Wang J. Anti-Diabetic Effect of a Shihunine-Rich Extract of Dendrobium loddigesii on 3T3-L1 Cells and db/db Mice by Up-Regulating AMPK-GLUT4-PPARα. Molecules 2019; 24:molecules24142673. [PMID: 31340585 PMCID: PMC6680686 DOI: 10.3390/molecules24142673] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 07/19/2019] [Accepted: 07/22/2019] [Indexed: 12/12/2022] Open
Abstract
The stems of Dendrobium loddigesii, a Chinese herb, are often used to treat diabetes and its polar extract is rich in shihunine, a water-soluble Orchidaceae alkaloid, but little is known about the anti-diabetes effects and mechanism of shihunine. This study investigated the anti-diabetic effect of a shihunine-rich extract of D. loddigesii (DLS) based on 3T3-L1 cells and db/db mice. The underlying mechanisms were primarily explored using Western blot analysis and immunohistochemical staining. The 3T3-L1 cell experiments showed that DLS can reduce the intracellular accumulation of oil droplets as well as triglycerides (p < 0.001) and promote the 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2deoxyglucose (2-NBDG) uptake of 3T3-L1 cells (p < 0.001). The animal experiments confirmed that after 8 weeks of DLS treatment, the body weight, fasting blood sugar, and serum lipid levels of mice were significantly lowered, and the oral glucose tolerance test and serum insulin level were significantly improved compared to the no-treatment diabetes mellitus group. Further histomorphology observation led to the conclusion that the quantities of islet cells were significantly increased and the increase in adipose cell size was significantly suppressed. The immunohistochemical test of pancreatic tissue revealed that DLS inhibited the expression of cleaved cysteine aspartic acid-specific protease 3 (cleaved caspase-3). Western blot experiments showed that DLS had agonistic effects on adenosine monophosphate (AMP)-activated protein kinase phosphorylation (p-AMPK) and increased the expression levels of peroxisome proliferator-activated receptor α (PPARα) and glucose transporter 4 (GLUT4) in liver or adipose tissues. These data suggest that the shihunine-rich extract of D. loddigesii is an anti-diabetic fraction of D. loddigesii. Under our experimental condition, DLS at a dose of 50 mg/kg has good anti-diabetic efficacy.
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Affiliation(s)
- Xue-Wen Li
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Meixiang Huang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Kakei Lo
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Wei-Li Chen
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Ying-Yan He
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Yongli Xu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Huizhen Zheng
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Haiyan Hu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
| | - Jun Wang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
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Oh HYP, Visvalingam V, Wahli W. The PPAR-microbiota-metabolic organ trilogy to fine-tune physiology. FASEB J 2019; 33:9706-9730. [PMID: 31237779 DOI: 10.1096/fj.201802681rr] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The human gut is colonized by commensal microorganisms, predominately bacteria that have coevolved in symbiosis with their host. The gut microbiota has been extensively studied in recent years, and many important findings on how it can regulate host metabolism have been unraveled. In healthy individuals, feeding timing and type of food can influence not only the composition but also the circadian oscillation of the gut microbiota. Host feeding habits thus influence the type of microbe-derived metabolites produced and their concentrations throughout the day. These microbe-derived metabolites influence many aspects of host physiology, including energy metabolism and circadian rhythm. Peroxisome proliferator-activated receptors (PPARs) are a group of ligand-activated transcription factors that regulate various metabolic processes such as fatty acid metabolism. Similar to the gut microbiota, PPAR expression in various organs oscillates diurnally, and studies have shown that the gut microbiota can influence PPAR activities in various metabolic organs. For example, short-chain fatty acids, the most abundant type of metabolites produced by anaerobic fermentation of dietary fibers by the gut microbiota, are PPAR agonists. In this review, we highlight how the gut microbiota can regulate PPARs in key metabolic organs, namely, in the intestines, liver, and muscle. Knowing that the gut microbiota impacts metabolism and is altered in individuals with metabolic diseases might allow treatment of these patients using noninvasive procedures such as gut microbiota manipulation.-Oh, H. Y. P., Visvalingam, V., Wahli, W. The PPAR-microbiota-metabolic organ trilogy to fine-tune physiology.
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Affiliation(s)
- Hui Yun Penny Oh
- Interdisciplinary Graduate School, Institute for Health Technologies, Nanyang Technological University, Singapore.,Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Vivegan Visvalingam
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Walter Wahli
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.,Unité Mixte de Recherche (UMR) 1331, Institut National de la Recherche Agronomique (INRA)-ToxAlim, Toulouse, France.,Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
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40
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Wang J, Gao T, Wang F, Xue J, Ye H, Xie M. Luteolin improves myocardial cell glucolipid metabolism by inhibiting hypoxia inducible factor-1α expression in angiotensin II/hypoxia-induced hypertrophic H9c2 cells. Nutr Res 2019; 65:63-70. [PMID: 30954346 DOI: 10.1016/j.nutres.2019.02.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 01/16/2019] [Accepted: 02/15/2019] [Indexed: 11/17/2022]
Abstract
Luteolin, a natural flavonoid, can attenuate hepatic lipid accumulation and insulin resistance in obese mice. Therefore, we hypothesized that luteolin may also improve the abnormal glucolipid metabolism of hypertrophic myocardial cells. This study aimed to investigate the effect and possible molecular mechanisms of luteolin. Hypertrophic H9c2 cells were induced by angiotensin II/hypoxia and simultaneously treated with 2 to 8 μg/mL luteolin for 24 h. Luteolin might dose-dependently decrease intracellular total protein, atrial natriuretic peptide, and free fatty acid levels, and increase supernatant glucose levels. Western blot assay showed that luteolin could inhibit the expressions of intracellular hypoxia inducible factor-1α (HIF-1α) and glucose transporter-4 (GLUT-4) proteins, and increase the expressions of intracellular peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase-1A (CPT-1A), and pyruvate dehydrogenase kinase-4 (PDK-4) proteins. These findings demonstrate that luteolin can improve abnormal glucolipid metabolism in angiotensin II/hypoxia-induced hypertrophic H9c2 cells, and its mechanisms are related to the inhibition of HIF-1α expression and subsequent modulation of PPARα-mediated target genes, including CPT-1A, PDK-4, and GLUT-4.
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Affiliation(s)
- Jia Wang
- Department of Pharmacology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu Province, China
| | - Tian Gao
- Department of Pharmacology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu Province, China
| | - Feng Wang
- Department of Pharmacology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu Province, China
| | - Jie Xue
- Department of Pharmacology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu Province, China
| | - Hua Ye
- Leiyunshang Pharmaceutical Co., Ltd., Suzhou 215009, Jiangsu Province, China.
| | - Meilin Xie
- Department of Pharmacology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu Province, China.
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Nasci VL, Chuppa S, Griswold L, Goodreau KA, Dash RK, Kriegel AJ. miR-21-5p regulates mitochondrial respiration and lipid content in H9C2 cells. Am J Physiol Heart Circ Physiol 2019; 316:H710-H721. [PMID: 30657727 DOI: 10.1152/ajpheart.00538.2017] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Cardiovascular-related pathologies are the single leading cause of death in patients with chronic kidney disease (CKD). Previously, we found that a 5/6th nephrectomy model of CKD leads to an upregulation of miR-21-5p in the left ventricle, targeting peroxisome proliferator-activated receptor-α and altering the expression of numerous transcripts involved with fatty acid oxidation and glycolysis. In the present study, we evaluated the potential for knockdown or overexpression of miR-21-5p to regulate lipid content, lipid peroxidation, and mitochondrial respiration in H9C2 cells. Cells were transfected with anti-miR-21-5p (40 nM), pre-miR-21-5p (20 nM), or the appropriate scrambled oligonucleotide controls before lipid treatment in culture or as part of the Agilent Seahorse XF fatty acid oxidation assay. Overexpression of miR-21-5p attenuated the lipid-induced increase in cellular lipid content, whereas suppression of miR-21-5p augmented it. The abundance of malondialdehyde, a product of lipid peroxidation, was significantly increased with lipid treatment in control cells but attenuated in pre-miR-21-5p-transfected cells. This suggests that miR-21-5p reduces oxidative stress. The cellular oxygen consumption rate (OCR) was increased in both pre-miR-21-5p- and anti-miR-21-5p-transfected cells. Levels of intracellular ATP were significantly higher in anti-mR-21-5p-transfected cells. Pre-miR-21-5p blocked additional increases in OCR in response to etomoxir and palmitic acid. Conversely, anti-miR-21-5p-transfected cells exhibited reduced OCR with both etomoxir and palmitic acid, and the glycolytic capacity was concomitantly reduced. Together, these results indicate that overexpression of miR-21-5p attenuates both lipid content and lipid peroxidation in H9C2 cells. This likely occurs by reducing cellular lipid uptake and utilization, shifting cellular metabolism toward reliance on the glycolytic pathway. NEW & NOTEWORTHY Both overexpression and suppression of miR-21-5p augment basal and maximal mitochondrial respiration. Our data suggest that reliance on glycolytic and fatty acid oxidation pathways can be modulated by the abundance of miR-21-5p within the cell. miR-21-5p regulation of mitochondrial respiration can be modulated by extracellular lipids.
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Affiliation(s)
- Victoria L Nasci
- Physiology Department, Medical College of Wisconsin , Milwaukee, Wisconsin
| | - Sandra Chuppa
- Physiology Department, Medical College of Wisconsin , Milwaukee, Wisconsin
| | - Lindsey Griswold
- Physiology Department, Medical College of Wisconsin , Milwaukee, Wisconsin
| | - Kathryn A Goodreau
- Physiology Department, Medical College of Wisconsin , Milwaukee, Wisconsin
| | - Ranjan K Dash
- Physiology Department, Medical College of Wisconsin , Milwaukee, Wisconsin.,Biomedical Engineering, Medical College of Wisconsin , Milwaukee, Wisconsin
| | - Alison J Kriegel
- Physiology Department, Medical College of Wisconsin , Milwaukee, Wisconsin.,Center of Systems Molecular Medicine, Medical College of Wisconsin , Milwaukee, Wisconsin.,Cardiovascular Center, Medical College of Wisconsin , Milwaukee, Wisconsin
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Choudhary NS, Kumar N, Duseja A. Peroxisome Proliferator-Activated Receptors and Their Agonists in Nonalcoholic Fatty Liver Disease. J Clin Exp Hepatol 2019; 9:731-739. [PMID: 31889755 PMCID: PMC6926194 DOI: 10.1016/j.jceh.2019.06.004] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 06/23/2019] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. In addition to the liver-related morbidity and mortality, NAFLD is now also associated with various extrahepatic diseases. Pathogenesis of NAFLD is multifactorial with limited pharmacotherapy options for the treatment of patients with NAFLD. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in the transcriptional regulation of lipid metabolism, glucose homeostasis, energy balance, inflammation, and atherosclerosis. PPAR agonists are attractive options for treatment of NAFLD as they can act at multiple targets involved in the pathogenesis of NAFLD. We reviewed the available literature on the pathophysiological role of PPARs and use of PPAR agonists in the treatment of NAFLD. Original studies and review articles available on PubMed regarding the role of PPARs in the pathogenesis and utility of PPAR agonists in the treatment of NAFLD were included in this review article. ClinicalTrials.gov and Clinical Trials Registry-India sites were searched for ongoing studies on saroglitazar. The available literature suggests that PPARs play an important role in the pathogenesis of NAFLD. Use of PPAR gamma agonists is associated with histological improvement in NAFLD. Dual PPAR agonists with no or minimal PPAR gamma activity are being explored in the treatment of NAFLD. Because of the pathophysiological role of PPARs in NAFLD, PPAR agonists are attractive options for the treatment of patients with NAFLD. Dual PPAR agonists without significant gamma activity appear promising for the treatment of NAFLD.
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Affiliation(s)
- Narendra S. Choudhary
- Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, Gurugram, India
| | | | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India,Address for correspondence: Dr. Ajay Duseja MD, DM, FAMS, FAASLD, FACG, FSGEI Professor, Department of Hepatology, Sector 12, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
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Current Models of Fatty Liver Disease; New Insights, Therapeutic Targets and Interventions. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1134:33-58. [PMID: 30919331 DOI: 10.1007/978-3-030-12668-1_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disorders ranging from simple steatosis to steatosis with inflammation and fibrosis. NAFLD is currently the most prevalent chronic liver disease worldwide, with a global prevalence of 25%, and is soon projected to be the leading cause for liver transplantation in the US. Alarmingly, few effective pharmacotherapeutic approaches are currently available to block or attenuate development and progression of NAFLD. Preclinical models are critical for unraveling the complex and multi-factorial etiology of NAFLD and for testing potential therapeutics. Here we review preclinical models that have been instrumental in highlighting molecular and cellular mechanisms underlying the pathogenesis of NAFLD and in facilitating early proof-of-concept investigations into novel intervention strategies.
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Hamilton A, Ly J, Robinson JR, Corder KR, DeMoranville KJ, Schaeffer PJ, Huss JM. Conserved transcriptional activity and ligand responsiveness of avian PPARs: Potential role in regulating lipid metabolism in mirgratory birds. Gen Comp Endocrinol 2018; 268:110-120. [PMID: 30114400 DOI: 10.1016/j.ygcen.2018.08.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Revised: 06/18/2018] [Accepted: 08/07/2018] [Indexed: 01/04/2023]
Abstract
Migratory birds undergo metabolic remodeling in tissues, including increased lipid storage in white adipose and fatty acid uptake and oxidation in skeletal muscle, to optimize energy substrate availability and utilization in preparation for long-distance flight. Different tissues undergo gene expression changes in keeping with their specialized functions and driven by tissue specific transcriptional pathways. Peroxisome proliferator-activated receptors (PPARs) are lipid-activated nuclear receptors that regulate metabolic pathways involved in lipid and glucose utilization or storage in mammals. To examine whether PPARs might mediate fatty acid activation of metabolic gene programs that would be relevant during pre-migratory fattening, we used gray catbird as the focal species. PPAR isoforms cloned from catbird share high amino acid identity with mammalian homologs (% vs human): gcPPARα (88.1%), gcPPARδ (87.3%), gcPPARγ (91.2%). We tested whether gcPPARs activated fatty acid (FA) utilization genes using Lpl and Cpt1b gene promoter-luciferase reporters in mammalian cell lines. In C2C12 mouse myocytes gcPPARα was broadly activated by the saturated and unsaturated FAs tested; while gcPPARδ showed highest activation by the mono-unsaturated FA, 18:1 oleic acid (+80%). In CV-1 monkey kidney cells gcPPARγ responded to the poly-unsaturated fatty acid, 20:5 eicosapentaenoic acid (+60%). Moreover, in agreement with their structural conservation, gcPPARs were activated by isoform selective synthetic agonists similar to the respective mammalian isoform. Adenoviral mediated over-expression of PPARα in C2C12 myocytes induced expression of genes involved in fatty acid transport, including Cd36/Fat, as well as Cpt1b, which mediates a key rate limiting step of mitochondrial β-oxidation. These gene expression changes correlated with increased lipid droplet accumulation in C2C12 myoblasts and differentiated myotubes and enhanced β-oxidation in myotubes. Collectively, the data predict that the PPARs play a conserved role in gray catbirds to regulate lipid metabolism in target tissues that undergo metabolic remodeling throughout the annual migratory cycle.
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Affiliation(s)
- Angelica Hamilton
- Department of Molecular and Cellular Endocrinology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Jennifer Ly
- Department of Molecular and Cellular Endocrinology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Jasmine R Robinson
- Department of Molecular and Cellular Endocrinology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Keely R Corder
- Department of Biology, Miami University, Oxford, OH 45056, USA
| | | | | | - Janice M Huss
- Department of Molecular and Cellular Endocrinology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
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Bougarne N, Weyers B, Desmet SJ, Deckers J, Ray DW, Staels B, De Bosscher K. Molecular Actions of PPARα in Lipid Metabolism and Inflammation. Endocr Rev 2018; 39:760-802. [PMID: 30020428 DOI: 10.1210/er.2018-00064] [Citation(s) in RCA: 521] [Impact Index Per Article: 74.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 07/10/2018] [Indexed: 12/13/2022]
Abstract
Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor of clinical interest as a drug target in various metabolic disorders. PPARα also exhibits marked anti-inflammatory capacities. The first-generation PPARα agonists, the fibrates, have however been hampered by drug-drug interaction issues, statin drop-in, and ill-designed cardiovascular intervention trials. Notwithstanding, understanding the molecular mechanisms by which PPARα works will enable control of its activities as a drug target for metabolic diseases with an underlying inflammatory component. Given its role in reshaping the immune system, the full potential of this nuclear receptor subtype as a versatile drug target with high plasticity becomes increasingly clear, and a novel generation of agonists may pave the way for novel fields of applications.
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Affiliation(s)
- Nadia Bougarne
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Receptor Research Laboratories, Nuclear Receptor Laboratory, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Basiel Weyers
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Receptor Research Laboratories, Nuclear Receptor Laboratory, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Sofie J Desmet
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Receptor Research Laboratories, Nuclear Receptor Laboratory, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Julie Deckers
- Department of Internal Medicine, Ghent University, Ghent, Belgium
- Laboratory of Immunoregulation, VIB Center for Inflammation Research, Ghent (Zwijnaarde), Belgium
| | - David W Ray
- Division of Metabolism and Endocrinology, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, United Kingdom
| | - Bart Staels
- Université de Lille, U1011-European Genomic Institute for Diabetes, Lille, France
- INSERM, U1011, Lille, France
- Centre Hospitalier Universitaire de Lille, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Karolien De Bosscher
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Receptor Research Laboratories, Nuclear Receptor Laboratory, VIB Center for Medical Biotechnology, Ghent, Belgium
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Zhu KC, Song L, Zhao CP, Guo HY, Zhang N, Guo L, Liu BS, Jiang SG, Zhang DC. The Transcriptional Factor PPARαb Positively Regulates Elovl5 Elongase in Golden Pompano Trachinotus ovatus (Linnaeus 1758). Front Physiol 2018; 9:1340. [PMID: 30319448 PMCID: PMC6167968 DOI: 10.3389/fphys.2018.01340] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Accepted: 09/05/2018] [Indexed: 11/13/2022] Open
Abstract
The nuclear peroxisome proliferator-activated receptors (PPARs) regulate the transcription of elongases of very long-chain fatty acids (Elovl), which are involved in polyunsaturated fatty acid (PUFA) biosynthesis in mammals. In the present study, we first characterized the function of Elovl5 elongase in Trachinotus ovatus. The functional study showed that ToElovl5 displayed high elongation activity toward C18 and C20 PUFA. To investigate whether PPARαb was a regulator of Elovl5, we also reported the sequence of T. ovatus PPARαb (ToPPARαb). The open reading frame (ORF) sequence encoded 469 amino acids possessing four typical characteristic domains, including an N-terminal hypervariable region, a DNA-binding domain (DBD), a flexible hinge domain and a ligand-binding domain (LBD). Thirdly, promoter activity experiments showed that the region from PGL3-basic-Elovl5-5 (-146 bp to +459 bp) was defined as the core promoter by progressive deletion mutation of Elovl5. Moreover, PPARαb overexpression led to a clear time-dependent enhancement of ToElovl5 promoter expression in HEK 293T cells. Fourth, the agonist of PPARαb prominently increased PPARαb and Elovl5 expression, while PPARαb depletion by RNAi or an inhibitor was correlated with a significant reduction of Elovl5 transcription in T. ovatus caudal fin cells (TOCF). In conclusion, the present study provides the first evidence of the positive regulation of Elovl5 transcription by PPARαb and contributes to a better understanding of the transcriptional mechanism of PPARαb in fish.
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Affiliation(s)
- Ke-Cheng Zhu
- Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture and Rural Affairs - South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China.,Guangdong Provincial Engineer Technology Research Center of Marine Biological Seed Industry, Guangzhou, China.,Guangdong Provincial Key Laboratory of Fishery Ecology and Environment, Guangzhou, China
| | - Ling Song
- Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture and Rural Affairs - South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China.,College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
| | - Chao-Ping Zhao
- Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture and Rural Affairs - South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China.,College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
| | - Hua-Yang Guo
- Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture and Rural Affairs - South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China.,Guangdong Provincial Engineer Technology Research Center of Marine Biological Seed Industry, Guangzhou, China.,Guangdong Provincial Key Laboratory of Fishery Ecology and Environment, Guangzhou, China
| | - Nan Zhang
- Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture and Rural Affairs - South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China.,Guangdong Provincial Engineer Technology Research Center of Marine Biological Seed Industry, Guangzhou, China.,Guangdong Provincial Key Laboratory of Fishery Ecology and Environment, Guangzhou, China
| | - Liang Guo
- Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture and Rural Affairs - South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China.,Guangdong Provincial Engineer Technology Research Center of Marine Biological Seed Industry, Guangzhou, China.,Guangdong Provincial Key Laboratory of Fishery Ecology and Environment, Guangzhou, China
| | - Bao-Suo Liu
- Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture and Rural Affairs - South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China.,Guangdong Provincial Engineer Technology Research Center of Marine Biological Seed Industry, Guangzhou, China.,Guangdong Provincial Key Laboratory of Fishery Ecology and Environment, Guangzhou, China
| | - Shi-Gui Jiang
- Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture and Rural Affairs - South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China.,Guangdong Provincial Engineer Technology Research Center of Marine Biological Seed Industry, Guangzhou, China.,Guangdong Provincial Key Laboratory of Fishery Ecology and Environment, Guangzhou, China
| | - Dian-Chang Zhang
- Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture and Rural Affairs - South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China.,Guangdong Provincial Engineer Technology Research Center of Marine Biological Seed Industry, Guangzhou, China.,Guangdong Provincial Key Laboratory of Fishery Ecology and Environment, Guangzhou, China
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47
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Ormazabal V, Nair S, Elfeky O, Aguayo C, Salomon C, Zuñiga FA. Association between insulin resistance and the development of cardiovascular disease. Cardiovasc Diabetol 2018; 17:122. [PMID: 30170598 PMCID: PMC6119242 DOI: 10.1186/s12933-018-0762-4] [Citation(s) in RCA: 1165] [Impact Index Per Article: 166.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 08/20/2018] [Indexed: 12/14/2022] Open
Abstract
For many years, cardiovascular disease (CVD) has been the leading cause of death around the world. Often associated with CVD are comorbidities such as obesity, abnormal lipid profiles and insulin resistance. Insulin is a key hormone that functions as a regulator of cellular metabolism in many tissues in the human body. Insulin resistance is defined as a decrease in tissue response to insulin stimulation thus insulin resistance is characterized by defects in uptake and oxidation of glucose, a decrease in glycogen synthesis, and, to a lesser extent, the ability to suppress lipid oxidation. Literature widely suggests that free fatty acids are the predominant substrate used in the adult myocardium for ATP production, however, the cardiac metabolic network is highly flexible and can use other substrates, such as glucose, lactate or amino acids. During insulin resistance, several metabolic alterations induce the development of cardiovascular disease. For instance, insulin resistance can induce an imbalance in glucose metabolism that generates chronic hyperglycemia, which in turn triggers oxidative stress and causes an inflammatory response that leads to cell damage. Insulin resistance can also alter systemic lipid metabolism which then leads to the development of dyslipidemia and the well-known lipid triad: (1) high levels of plasma triglycerides, (2) low levels of high-density lipoprotein, and (3) the appearance of small dense low-density lipoproteins. This triad, along with endothelial dysfunction, which can also be induced by aberrant insulin signaling, contribute to atherosclerotic plaque formation. Regarding the systemic consequences associated with insulin resistance and the metabolic cardiac alterations, it can be concluded that insulin resistance in the myocardium generates damage by at least three different mechanisms: (1) signal transduction alteration, (2) impaired regulation of substrate metabolism, and (3) altered delivery of substrates to the myocardium. The aim of this review is to discuss the mechanisms associated with insulin resistance and the development of CVD. New therapies focused on decreasing insulin resistance may contribute to a decrease in both CVD and atherosclerotic plaque generation.
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Affiliation(s)
- Valeska Ormazabal
- Faculty of Biological Sciences, Pharmacology Department, University of Concepcion, Concepción, Chile
| | - Soumyalekshmi Nair
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine + Biomedical Sciences, The University of Queensland, Brisbane, Australia
| | - Omar Elfeky
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine + Biomedical Sciences, The University of Queensland, Brisbane, Australia
| | - Claudio Aguayo
- Faculty of Pharmacy, Department of Clinical Biochemistry and Immunology, University of Concepcion, Concepción, Chile
| | - Carlos Salomon
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine + Biomedical Sciences, The University of Queensland, Brisbane, Australia. .,Faculty of Pharmacy, Department of Clinical Biochemistry and Immunology, University of Concepcion, Concepción, Chile. .,Department of Obstetrics and Gynecology, Ochsner Baptist Hospital, New Orleans, Louisiana, USA.
| | - Felipe A Zuñiga
- Faculty of Pharmacy, Department of Clinical Biochemistry and Immunology, University of Concepcion, Concepción, Chile
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48
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Gan Z, Fu T, Kelly DP, Vega RB. Skeletal muscle mitochondrial remodeling in exercise and diseases. Cell Res 2018; 28:969-980. [PMID: 30108290 DOI: 10.1038/s41422-018-0078-7] [Citation(s) in RCA: 166] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Accepted: 07/27/2018] [Indexed: 12/18/2022] Open
Abstract
Skeletal muscle fitness and plasticity is an important determinant of human health and disease. Mitochondria are essential for maintaining skeletal muscle energy homeostasis by adaptive re-programming to meet the demands imposed by a myriad of physiologic or pathophysiological stresses. Skeletal muscle mitochondrial dysfunction has been implicated in the pathogenesis of many diseases, including muscular dystrophy, atrophy, type 2 diabetes, and aging-related sarcopenia. Notably, exercise counteracts the effects of many chronic diseases on skeletal muscle mitochondrial function. Recent studies have revealed a finely tuned regulatory network that orchestrates skeletal muscle mitochondrial biogenesis and function in response to exercise and in disease states. In addition, increasing evidence suggests that mitochondria also serve to "communicate" with the nucleus and mediate adaptive genomic re-programming. Here we review the current state of knowledge relevant to the dynamic remodeling of skeletal muscle mitochondria in response to exercise and in disease states.
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Affiliation(s)
- Zhenji Gan
- The State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Department of Spine Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, 210061, Nanjing, China.
| | - Tingting Fu
- The State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Department of Spine Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, 210061, Nanjing, China
| | - Daniel P Kelly
- Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
| | - Rick B Vega
- Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL, 32804, USA.
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Chen JW, Kong ZL, Tsai ML, Lo CY, Ho CT, Lai CS. Tetrahydrocurcumin ameliorates free fatty acid-induced hepatic steatosis and improves insulin resistance in HepG2 cells. J Food Drug Anal 2018; 26:1075-1085. [PMID: 29976400 PMCID: PMC9303024 DOI: 10.1016/j.jfda.2018.01.005] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 01/05/2018] [Accepted: 01/10/2018] [Indexed: 01/07/2023] Open
Abstract
Elevated levels of free fatty acids (FFAs) in the liver, resulting from either increased lipolysis or imbalanced FFAs flux, is a key pathogenic factor of hepatic steatosis. This study was conducted to examine the therapeutic effect of tetrahydrocurcumin (THC), a naturally occurring curcuminoid and a metabolite of curcumin, on oleic acid (OA)-induced steatosis in human hepatocellular carcinoma cells and to elucidate the underlying mechanism. HepG2 cells were incubated with OA to induce steatosis, and then treated with various concentrations of THC. The results showed that THC treatment significantly decreased lipid accumulation in OA-treated HepG2 cells, possibly, by inhibiting the expression of the lipogenic proteins, sterol regulatory element-binding protein 1 (SREBP-1c), peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FAS), and fatty acid-binding protein 4 (FABP4). Moreover, THC attenuated OA-induced hepatic lipogenesis in an adenosine monophosphate–activated protein kinase (AMPK)-dependent manner, which was reversed by pretreatment with an AMPK inhibitor. THC promoted lipolysis and upregulated the expression of genes involved in β-oxidation. Glucose uptake and insulin signaling impaired in HepG2 cells incubated with OA were abated by THC treatment, including phosphorylation of the insulin receptor substrate 1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Akt and downstream signaling pathways, forkhead box protein O1 (FOXO1) and glycogen synthase kinase 3 β (GSK3β), which are involved in gluconeogenesis and glycogen synthesis, respectively. Altogether, these results demonstrated the novel therapeutic benefit of THC against hepatic steatosis and, consequently, a potential treatment for non-alcoholic fatty liver disease (NAFLD).
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50
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The Involvement of PPARs in the Peculiar Energetic Metabolism of Tumor Cells. Int J Mol Sci 2018; 19:ijms19071907. [PMID: 29966227 PMCID: PMC6073339 DOI: 10.3390/ijms19071907] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 06/10/2018] [Accepted: 06/24/2018] [Indexed: 12/13/2022] Open
Abstract
Energy homeostasis is crucial for cell fate, since all cellular activities are strongly dependent on the balance between catabolic and anabolic pathways. In particular, the modulation of metabolic and energetic pathways in cancer cells has been discussed in some reports, but subsequently has been neglected for a long time. Meanwhile, over the past 20 years, a recovery of the study regarding cancer metabolism has led to an increasing consideration of metabolic alterations in tumors. Cancer cells must adapt their metabolism to meet their energetic and biosynthetic demands, which are associated with the rapid growth of the primary tumor and colonization of distinct metastatic sites. Cancer cells are largely dependent on aerobic glycolysis for their energy production, but are also associated with increased fatty acid synthesis and increased rates of glutamine consumption. In fact, emerging evidence has shown that therapeutic resistance to cancer treatment may arise from the deregulation of glucose metabolism, fatty acid synthesis, and glutamine consumption. Cancer cells exhibit a series of metabolic alterations induced by mutations that lead to a gain-of-function of oncogenes, and a loss-of-function of tumor suppressor genes, including increased glucose consumption, reduced mitochondrial respiration, an increase of reactive oxygen species, and cell death resistance; all of these are responsible for cancer progression. Cholesterol metabolism is also altered in cancer cells and supports uncontrolled cell growth. In this context, we discuss the roles of peroxisome proliferator-activated receptors (PPARs), which are master regulators of cellular energetic metabolism in the deregulation of the energetic homeostasis, which is observed in cancer. We highlight the different roles of PPAR isotypes and the differential control of their transcription in various cancer cells.
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