|
1
|
Encarnacion J, Smith DM, Choi J, Scafidi J, Wolfgang MJ. Activating Transcription Factor 3 regulates hepatic Apolipoprotein A4 upon metabolic stress. J Biol Chem 2025:108468. [PMID: 40158856 DOI: 10.1016/j.jbc.2025.108468] [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: 02/02/2025] [Revised: 03/14/2025] [Accepted: 03/25/2025] [Indexed: 04/02/2025] Open
Abstract
The liver plays essential roles in maintaining systemic glucolipid homeostasis under ever changing metabolic stressors. Metabolic dysregulation can lead to both adaptive and maladaptive changes that impact systemic physiology. Here we examined disparate genetic and environmental metabolic stressors and identified Apolipoprotein A4 (ApoA4) as a circulating protein upregulated in liver-specific knockouts for Carnitine Palmitoyltransferase 2 and Pyruvate Carboxylase. We found this upregulation to be exacerbated by fasting and high fat or ketogenic diets. Unique among these models was a concomitant increase in Activating Transcription Factor 3 (Atf3). Liver-specific overexpression of Atf3 resulted in increased ApoA4 expression in a sex-dependent manner. To understand the requirement of Atf3 to metabolic stress, we generated liver-specific Atf3, Cpt2 double knockout mice. These experiments demonstrated the requirement for Atf3 in the induction of ApoA4 mRNA, ApoA4 protein, and serum triglycerides that were also sex dependent. These experiments reveal the roles of hepatic Atf3 and ApoA4 in response to metabolic stress in vivo.
Collapse
Affiliation(s)
- Jasmine Encarnacion
- Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Danielle M Smith
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Joseph Choi
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Joseph Scafidi
- Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.; The Michael V. Johnston Center for Developmental Neuroscience, Kennedy Krieger Institute, Baltimore, Maryland
| | - Michael J Wolfgang
- Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
| |
Collapse
|
|
2
|
Lin B, Wu T, Nasb M, Li Z, Chen N. Regular exercise alleviates metabolic dysfunction-associated steatohepatitis through rescuing mitochondrial oxidative stress and dysfunction in liver. Free Radic Biol Med 2025; 230:163-176. [PMID: 39954868 DOI: 10.1016/j.freeradbiomed.2025.02.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/20/2025] [Accepted: 02/13/2025] [Indexed: 02/17/2025]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by severe mitochondrial dysfunction, associated with the production of mitochondrial reactive oxygen species (mROS). The substantial generation of mROS in the MASH liver, resulting from lipid surplus and electron transport chain (ETC) overload, impairs mitochondrial structure and functionality, thereby contributing to the development of severe hepatic steatosis and inflammation. Regular exercise represents an effective strategy for the treatment of MASH. Understanding the effects of exercise on oxidative stress and mitochondrial function is essential for effective treatment of MASH. This article reviews the pathological alterations in mitochondrial β-oxidation, ETC efficiency and mROS production within MASH liver. Additionally, it discusses how exercise influences the redox state and mitochondrial quality control mechanisms-such as biogenesis, mitophagy, fusion, and fission-within the MASH liver. The article emphasizes the importance of in-depth studies on exercise-induced MASH mitigation through the enhancement of mitochondrial redox balance, quality control, and function. Exploring the relationship between exercise and hepatic mitochondria could provide valuable insights into identifying potential therapeutic targets for MASH.
Collapse
Affiliation(s)
- Baoxuan Lin
- Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Sports Medicine, Wuhan Sports University, Wuhan, China
| | - Tong Wu
- Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Sports Medicine, Wuhan Sports University, Wuhan, China
| | - Mohammad Nasb
- Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Sports Medicine, Wuhan Sports University, Wuhan, China
| | - Zeyun Li
- Department of Rehabilitation Medicine, Xiangtan Central Hospital, Xiangtan, China.
| | - Ning Chen
- Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Sports Medicine, Wuhan Sports University, Wuhan, China.
| |
Collapse
|
|
3
|
Zeballos L, García-Peral C, Ledesma MM, Auzmendi J, Lazarowski A, López DE. Changes in the Proteomic Profile After Audiogenic Kindling in the Inferior Colliculus of the GASH/Sal Model of Epilepsy. Int J Mol Sci 2025; 26:2331. [PMID: 40076950 PMCID: PMC11900993 DOI: 10.3390/ijms26052331] [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: 01/22/2025] [Revised: 02/27/2025] [Accepted: 03/02/2025] [Indexed: 03/14/2025] Open
Abstract
Epilepsy is a multifaceted neurological disorder characterized by recurrent seizures and associated with molecular and immune alterations in key brain regions. The GASH/Sal (Genetic Audiogenic Seizure Hamster, Salamanca), a genetic model for audiogenic epilepsy, provides a powerful tool to study seizure mechanisms and resistance in predisposed individuals. This study investigates the proteomic and immune responses triggered by audiogenic kindling in the inferior colliculus, comparing non-responder animals exhibiting reduced seizure severity following repeated stimulation versus GASH/Sal naïve hamsters. To assess auditory pathway functionality, Auditory Brainstem Responses (ABRs) were recorded, revealing reduced neuronal activity in the auditory nerve of non-responders, while central auditory processing remained unaffected. Cytokine profiling demonstrated increased levels of proinflammatory markers, including IL-1 alpha (Interleukin-1 alpha), IL-10 (Interleukin-10), and TGF-beta (Transforming Growth Factor beta), alongside decreased IGF-1 (Insulin-like Growth Factor 1) levels, highlighting systemic inflammation and its interplay with neuroprotection. Building on these findings, a proteomic analysis identified 159 differentially expressed proteins (DEPs). Additionally, bioinformatic approaches, including Gene Set Enrichment Analysis (GSEA) and Weighted Gene Co-expression Network Analysis (WGCNA), revealed disrupted pathways related to metabolic and inflammatory epileptic processes and a module potentially linked to a rise in the threshold of seizures, respectively. Differentially expressed genes, identified through bioinformatic and statistical analyses, were validated by RT-qPCR. This confirmed the upregulation of six genes (Gpc1-Glypican-1; Sdc3-Syndecan-3; Vgf-Nerve Growth Factor Inducible; Cpne5-Copine 5; Agap2-Arf-GAP with GTPase domain, ANK repeat, and PH domain-containing protein 2; and Dpp8-Dipeptidyl Peptidase 8) and the downregulation of two (Ralb-RAS-like proto-oncogene B-and S100b-S100 calcium-binding protein B), aligning with reduced seizure severity. This study may uncover key proteomic and immune mechanisms underlying seizure susceptibility, providing possible novel therapeutic targets for refractory epilepsy.
Collapse
Affiliation(s)
- Laura Zeballos
- Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, 37007 Salamanca, Spain; (L.Z.); (C.G.-P.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
- Departamento de Biología Celular y Patología, Facultad de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Carlos García-Peral
- Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, 37007 Salamanca, Spain; (L.Z.); (C.G.-P.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
- Departamento de Biología Celular y Patología, Facultad de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Martín M. Ledesma
- Unidad de Conocimiento Traslacional, Hospital de Alta Complejidad del Bicentenario Esteban Echeverría, Monte Grande B1842, Argentina;
- Hospital de Alta Complejidad en Red El Cruce Dr. N. C. Kirchner SAMIC, Florencio Varela B1888, Argentina
| | - Jerónimo Auzmendi
- Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires C1417, Argentina; (J.A.); (A.L.)
- Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Godoy Cruz M2290, Argentina
| | - Alberto Lazarowski
- Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires C1417, Argentina; (J.A.); (A.L.)
| | - Dolores E. López
- Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, 37007 Salamanca, Spain; (L.Z.); (C.G.-P.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
- Departamento de Biología Celular y Patología, Facultad de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| |
Collapse
|
|
4
|
Smith DM, Choi J, Wolfgang MJ. Tissue specific roles of fatty acid oxidation. Adv Biol Regul 2025; 95:101070. [PMID: 39672726 PMCID: PMC11832339 DOI: 10.1016/j.jbior.2024.101070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 12/03/2024] [Indexed: 12/15/2024]
Abstract
Mitochondrial long chain fatty acid β-oxidation is a critical central carbon catabolic process. The importance of fatty acid oxidation is made evident by the life-threatening disease associated with diverse inborn errors in the pathway. While inborn errors show multisystemic requirements for fatty acid oxidation, it is not clear from the clinical presentation of these enzyme deficiencies what the tissue specific roles of the pathway are compared to secondary systemic effects. To understand the cell or tissue specific contributions of fatty acid oxidation to systemic physiology, conditional knockouts in mice have been employed to determine the requirements of fatty acid oxidation in disparate cell types. This has produced a host of surprising results that sometimes run counter to the canonical view of this metabolic pathway. The rigor of conditional knockouts has also provided clarity over previous research utilizing cell lines in vitro or small molecule inhibitors with dubious specificity. Here we will summarize current research using mouse models of Carnitine Palmitoyltransferases to determine the tissue specific roles and requirements of long chain mitochondrial fatty acid β-oxidation.
Collapse
Affiliation(s)
- Danielle M Smith
- Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Joseph Choi
- Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael J Wolfgang
- Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| |
Collapse
|
|
5
|
Choi J, Smith DM, Scafidi S, Riddle RC, Wolfgang MJ. Carnitine palmitoyltransferase 1 facilitates fatty acid oxidation in a non-cell-autonomous manner. Cell Rep 2024; 43:115006. [PMID: 39671290 PMCID: PMC11726389 DOI: 10.1016/j.celrep.2024.115006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 09/18/2024] [Accepted: 11/06/2024] [Indexed: 12/15/2024] Open
Abstract
Mitochondrial fatty acid oxidation is facilitated by the combined activities of carnitine palmitoyltransferase 1 (Cpt1) and Cpt2, which generate and utilize acylcarnitines, respectively. We compare the response of mice with liver-specific deficiencies in the liver-enriched Cpt1a or the ubiquitously expressed Cpt2 and discover that they display unique metabolic, physiological, and molecular phenotypes. The loss of Cpt1a or Cpt2 results in the induction of the muscle-enriched isoenzyme Cpt1b in hepatocytes in a Pparα-dependent manner. However, hepatic Cpt1b does not contribute substantively to hepatic fatty acid oxidation when Cpt1a is absent. Liver-specific double knockout of Cpt1a and Cpt1b or Cpt2 eliminates the mitochondrial oxidation of non-esterified fatty acids. However, Cpt1a/Cpt1b double knockout mice retain fatty acid oxidation by utilizing extracellular long-chain acylcarnitines that are dependent on Cpt2. These data demonstrate the non-cell-autonomous intercellular metabolism of fatty acids in hepatocytes.
Collapse
Affiliation(s)
- Joseph Choi
- Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Danielle M Smith
- Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Susanna Scafidi
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ryan C Riddle
- Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD, USA; Research and Development Service, Baltimore VA Medical Center, Baltimore, MD, USA
| | - Michael J Wolfgang
- Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| |
Collapse
|
|
6
|
Wang LL, Lu YM, Wang YH, Wang YF, Fang RF, Sai WL, Yao DF, Yao M. Carnitine palmitoyltransferase-II inactivity promotes malignant progression of metabolic dysfunction-associated fatty liver disease via liver cancer stem cell activation. World J Gastroenterol 2024; 30:5055-5069. [PMID: 39713165 PMCID: PMC11612864 DOI: 10.3748/wjg.v30.i47.5055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 10/06/2024] [Accepted: 11/05/2024] [Indexed: 11/26/2024] Open
Abstract
BACKGROUND Metabolic dysfunction-associated fatty liver disease (MAFLD) is one of the main chronic liver diseases. However, the roles of mitochondrial carnitine palmitoyl transferase-II (CPT-II) downregulation and liver cancer stem cell (LCSC) activation remain to be identified. AIM To investigate the dynamic alterations in CPT-II inactivity and LCSC activation during the malignant progression of MAFLD. METHODS Dynamic models of mouse MAFLD were generated via the consumption of a high-fat diet or the addition of 2-fluorenylacetamide for hepatocarcinogenesis. The mice were divided into groups on the basis of hematoxylin and eosin staining. Biochemistries, CPT-II, intrahepatic T cells, and LCSCs were determined and confirmed in clinical samples. The mitochondrial membrane potential (MMP) was analyzed. Differentially expressed genes were screened via RNA sequencing and enriched in KEGG pathways or GO functions. RESULTS Dynamic models of MAFLD malignant transformation were successfully generated on the basis of pathological examination. Hepatic lipid accumulation was associated with the loss of mitochondrial CPT-II activity and alterations in the MMP, with decreases in liver CD3+ or CD4+ T cells and increased AFP levels. In the lipid accumulation microenvironment, mitochondrial CPT-II was inactivated, followed by aberrant activation of CD44+ or CD24+ LCSCs, as validated in MAFLD or hepatocellular carcinoma patient samples. In terms of mechanism, the biological process category focused mainly on the metabolic regulation of cells in response to external stimuli. The enriched molecular functions included protein binding, cell apoptosis, and cell proliferation. CONCLUSION CPT-II inactivity promotes the malignant progression of MAFLD via the loss of innate immune function and abnormal LCSC activation.
Collapse
Affiliation(s)
- Ling-Ling Wang
- Department of Immunology, Medical School, Nantong University, Nantong 226001, Jiangsu Province, China
| | - Yu-Ming Lu
- Department of Immunology, Medical School, Nantong University, Nantong 226001, Jiangsu Province, China
| | - Yi-Han Wang
- Department of Immunology, Medical School, Nantong University, Nantong 226001, Jiangsu Province, China
| | - Yi-Fan Wang
- Department of Immunology, Medical School, Nantong University, Nantong 226001, Jiangsu Province, China
| | - Rong-Fei Fang
- Department of Gastroenterology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Wen-Li Sai
- Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Deng-Fu Yao
- Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Min Yao
- Department of Immunology, Medical School, Nantong University, Nantong 226001, Jiangsu Province, China
| |
Collapse
|
|
7
|
Zhao H, Shi D, Gui W, Lin X, Chen J, Yu W. Profiling of Metabolome in the Plasma Following a circH19 Knockdown Intervention in Diet-Induced Obese Mice. Metabolites 2024; 14:603. [PMID: 39590839 PMCID: PMC11596236 DOI: 10.3390/metabo14110603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 10/13/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
The circular RNA circH19 has been implicated in the regulation of gene expression and various biological processes, including obesity. Objectives: This study aimed to elucidate the metabolic changes in plasma after circH19 knockdown in a diet-induced obese (DIO) mouse model. Methods: Plasma samples were collected following the intervention and subjected to non-targeted metabolomics analysis using liquid chromatography-mass spectrometry (LC-MS). Metabolic profiling was performed to identify and quantify metabolites, followed by multivariate statistical analysis to discern differential metabolic signatures. Results: A total of 1250 features were quantified, resulting in the upregulation of 564 metabolites and the downregulation of 686 metabolites in the circH19 knockdown group compared to the control mice. Metabolic pathway analysis revealed disruptions in lipid metabolism, amino acid turnover, and energy production pathways. Notably, the intervention led to a substantial decrease in circulating lipids and alterations in the plasma amino acid profile, indicative of an impact on protein catabolism and anabolic processes. The observed shifts in lipid and amino acid metabolism suggest potential therapeutic avenues for obesity and related metabolic disorders. Conclusions: The circH19 knockdown in DIO mice led to significant alterations in plasma metabolites, highlighting its potential role in the regulation of obesity and metabolic disorders.
Collapse
Affiliation(s)
- Hanxin Zhao
- Department of Endocrinology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; (H.Z.); (W.G.); (X.L.)
| | - Dike Shi
- Department of Gastroenterology Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China;
| | - Weiwei Gui
- Department of Endocrinology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; (H.Z.); (W.G.); (X.L.)
| | - Xihua Lin
- Department of Endocrinology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; (H.Z.); (W.G.); (X.L.)
| | - Jionghuang Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China
| | - Weihua Yu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China
| |
Collapse
|
|
8
|
Babcock SJ, Houten SM, Gillingham MB. A review of fatty acid oxidation disorder mouse models. Mol Genet Metab 2024; 142:108351. [PMID: 38430613 PMCID: PMC11073919 DOI: 10.1016/j.ymgme.2024.108351] [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: 11/22/2023] [Revised: 02/20/2024] [Accepted: 02/21/2024] [Indexed: 03/05/2024]
Abstract
Fatty acid oxidation disorders (FAODs) are a family of rare, genetic disorders that affect any part of the fatty acid oxidation pathway. Patients present with severe phenotypes, such as hypoketotic hypoglycemia, cardiomyopathy, and rhabdomyolysis, and currently manage these symptoms by the avoidance of fasting and maintaining a low-fat, high-carbohydrate diet. Because knowledge about FAODs is limited due to the small number of patients, rodent models have been crucial in learning more about these disorders, particularly in studying the molecular mechanisms involved in different phenotypes and in evaluating treatments for patients. The purpose of this review is to present the different FAOD mouse models and highlight the benefits and limitations of using these models. Specifically, we discuss the phenotypes of the available FAOD mouse models, the potential molecular causes of prominent FAOD phenotypes that have been studied using FAOD mouse models, and how FAOD mouse models have been used to evaluate treatments for patients.
Collapse
Affiliation(s)
- Shannon J Babcock
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
| | - Sander M Houten
- Deparment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Melanie B Gillingham
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
| |
Collapse
|
|
9
|
Zheng Q, Wang F, Nie C, Zhang K, Sun Y, Al-Ansi W, Wu Q, Wang L, Du J, Li Y. Elevating the significance of legume intake: A novel strategy to counter aging-related mitochondrial dysfunction and physical decline. Compr Rev Food Sci Food Saf 2024; 23:e13342. [PMID: 38634173 DOI: 10.1111/1541-4337.13342] [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: 01/09/2024] [Revised: 03/11/2024] [Accepted: 03/19/2024] [Indexed: 04/19/2024]
Abstract
Mitochondrial dysfunction increasingly becomes a target for promoting healthy aging and longevity. The dysfunction of mitochondria with age ultimately leads to a decline in physical functions. Among them, biogenesis dysfunction and the imbalances in the metabolism of reactive oxygen species and mitochondria as signaling organelles in the aging process have aroused our attention. Dietary intervention in mitochondrial dysfunction and physical decline during aging processes is essential, and greater attention should be directed toward healthful legume intake. Legumes are constantly under investigation for their nutritional and bioactive properties, and their consumption may yield antiaging and mitochondria-protecting benefits. This review summarizes mitochondrial dysfunction with age, discusses the benefits of legumes on mitochondrial function, and introduces the potential role of legumes in managing aging-related physical decline. Additionally, it reveals the benefits of legume intake for the elderly and offers a viable approach to developing legume-based functional food.
Collapse
Affiliation(s)
- Qingwei Zheng
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Feijie Wang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Chenzhipeng Nie
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Kuiliang Zhang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Yujie Sun
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Waleed Al-Ansi
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Qiming Wu
- Nutrilite Health Institute, Shanghai, China
| | - Li Wang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Jun Du
- Nutrilite Health Institute, Shanghai, China
| | - Yan Li
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China
| |
Collapse
|
|
10
|
Dong J, Chen L, Ye F, Tang J, Liu B, Lin J, Zhou PH, Lu B, Wu M, Lu JH, He JJ, Engelender S, Meng Q, Song Z, He H. Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease. Nat Commun 2024; 15:168. [PMID: 38168065 PMCID: PMC10762189 DOI: 10.1038/s41467-023-44057-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 11/28/2023] [Indexed: 01/05/2024] Open
Abstract
Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.
Collapse
Affiliation(s)
- Jun Dong
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Li Chen
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
- Department of pathology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fei Ye
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Junhui Tang
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Bing Liu
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Jiacheng Lin
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Pang-Hu Zhou
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Bin Lu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Min Wu
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Jia-Hong Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Jing-Jing He
- Department of Pediatric Intensive Care Unit, Anhui Provincial Children's Hospital, Hefei, Anhui, China
| | - Simone Engelender
- Department of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Qingtao Meng
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Zhiyin Song
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China.
- Department of pathology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - He He
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China.
- Department of pathology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| |
Collapse
|
|
11
|
Syed-Abdul MM. Lipid Metabolism in Metabolic-Associated Steatotic Liver Disease (MASLD). Metabolites 2023; 14:12. [PMID: 38248815 PMCID: PMC10818604 DOI: 10.3390/metabo14010012] [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: 11/23/2023] [Revised: 12/20/2023] [Accepted: 12/21/2023] [Indexed: 01/23/2024] Open
Abstract
Metabolic-associated steatotic liver disease (MASLD) is a cluster of pathological conditions primarily developed due to the accumulation of ectopic fat in the hepatocytes. During the severe form of the disease, i.e., metabolic-associated steatohepatitis (MASH), accumulated lipids promote lipotoxicity, resulting in cellular inflammation, oxidative stress, and hepatocellular ballooning. If left untreated, the advanced form of the disease progresses to fibrosis of the tissue, resulting in irreversible hepatic cirrhosis or the development of hepatocellular carcinoma. Although numerous mechanisms have been identified as significant contributors to the development and advancement of MASLD, altered lipid metabolism continues to stand out as a major factor contributing to the disease. This paper briefly discusses the dysregulation in lipid metabolism during various stages of MASLD.
Collapse
Affiliation(s)
- Majid Mufaqam Syed-Abdul
- Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada
| |
Collapse
|
|
12
|
Nurjanah S, Gerding A, Vieira-Lara MA, Evers B, Langelaar-Makkinje M, Spiekerkoetter U, Bakker BM, Tucci S. Heptanoate Improves Compensatory Mechanism of Glucose Homeostasis in Mitochondrial Long-Chain Fatty Acid Oxidation Defect. Nutrients 2023; 15:4689. [PMID: 37960342 PMCID: PMC10649308 DOI: 10.3390/nu15214689] [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: 09/22/2023] [Revised: 10/31/2023] [Accepted: 11/01/2023] [Indexed: 11/15/2023] Open
Abstract
Defects in mitochondrial fatty acid β-oxidation (FAO) impair metabolic flexibility, which is an essential process for energy homeostasis. Very-long-chain acyl-CoA dehydrogenase (VLCADD; OMIM 609575) deficiency is the most common long-chain mitochondrial FAO disorder presenting with hypoglycemia as a common clinical manifestation. To prevent hypoglycemia, triheptanoin-a triglyceride composed of three heptanoates (C7) esterified with a glycerol backbone-can be used as a dietary treatment, since it is metabolized into precursors for gluconeogenesis. However, studies investigating the effect of triheptanoin on glucose homeostasis are limited. To understand the role of gluconeogenesis in the pathophysiology of long-chain mitochondrial FAO defects, we injected VLCAD-deficient (VLCAD-/-) mice with 13C3-glycerol in the presence and absence of heptanoate (C7). The incorporation of 13C3-glycerol into blood glucose was higher in VLCAD-/- mice than in WT mice, whereas the difference disappeared in the presence of C7. The result correlates with 13C enrichment of liver metabolites in VLCAD-/- mice. In contrast, the C7 bolus significantly decreased the 13C enrichment. These data suggest that the increased contribution of gluconeogenesis to the overall glucose production in VLCAD-/- mice increases the need for gluconeogenesis substrate, thereby avoiding hypoglycemia. Heptanoate is a suitable substrate to induce glucose production in mitochondrial FAO defect.
Collapse
Affiliation(s)
- Siti Nurjanah
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Centre, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany (U.S.)
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Albert Gerding
- Laboratory of Pediatrics, Systems Medicine of Metabolism and Signaling, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands (M.L.-M.)
- Laboratory of Metabolic Diseases, Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
| | - Marcel A. Vieira-Lara
- Laboratory of Pediatrics, Systems Medicine of Metabolism and Signaling, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands (M.L.-M.)
| | - Bernard Evers
- Laboratory of Pediatrics, Systems Medicine of Metabolism and Signaling, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands (M.L.-M.)
| | - Miriam Langelaar-Makkinje
- Laboratory of Pediatrics, Systems Medicine of Metabolism and Signaling, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands (M.L.-M.)
| | - Ute Spiekerkoetter
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Centre, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany (U.S.)
| | - Barbara M. Bakker
- Laboratory of Pediatrics, Systems Medicine of Metabolism and Signaling, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands (M.L.-M.)
| | - Sara Tucci
- Pharmacy, Medical Center, University of Freiburg, 79106 Freiburg, Germany
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Prosthetic Dentistry, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| |
Collapse
|
|
13
|
Heiserman JP, Minhas Z, Nikpayam E, Cheon DJ. Targeting Heat Shock Protein 27 and Fatty Acid Oxidation Augments Cisplatin Treatment in Cisplatin-Resistant Ovarian Cancer Cell Lines. Int J Mol Sci 2023; 24:12638. [PMID: 37628819 PMCID: PMC10454186 DOI: 10.3390/ijms241612638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/04/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Most ovarian cancer patients develop recurrent cancers which are often resistant to commonly employed chemotherapy agents, such as cisplatin. We have previously shown that the inhibition of heat shock protein 27 (HSP27) or fatty acid oxidation (FAO) sensitizes cisplatin-resistant ovarian cancer cell lines to cisplatin and dual inhibition of both HSP27 and FAO induces substantial cell death in vitro. However, it is unclear how HSP27 and FAO promote cisplatin resistance, and if dual inhibition of both HSP27 and FAO would augment cisplatin treatment in vivo. Here we showed that HSP27 knockdown in two cisplatin-resistant ovarian cancer cell lines (A2780CIS and PEO4) resulted in more ROS production upon cisplatin treatment. HSP27-knockdown cancer cells exhibited decreased levels of reduced glutathione (GSH) and glucose6phosphate dehydrogenase (G6PD), a crucial pentose phosphate pathway enzyme. ROS depletion with the compound N-acetyl cysteine (NAC) attenuated cisplatin-induced upregulation of HSP27, FAO, and markers of apoptosis and ferroptosis in cisplatin-resistant ovarian cancer cell lines. Finally, inhibition of HSP27 and FAO with ivermectin and perhexiline enhanced the cytotoxic effect of cisplatin in A2780CIS xenograft tumors in vivo. Our results suggest that two different cisplatin-resistant ovarian cancer cell lines upregulate HSP27 and FAO to deplete cisplatin-induced ROS to attenuate cisplatin's cytotoxic effect.
Collapse
Affiliation(s)
| | | | | | - Dong-Joo Cheon
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA; (J.P.H.); (E.N.)
| |
Collapse
|
|
14
|
Wang L, Donahue G, Zhang C, Havas A, Lei X, Xu C, Wang W, Vahedi G, Adams PD, Berger SL. Dynamic enhancer interactome promotes senescence and aging. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.22.541769. [PMID: 37292952 PMCID: PMC10245931 DOI: 10.1101/2023.05.22.541769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Gene expression programs are regulated by enhancers which act in a context-specific manner, and can reside at great distances from their target genes. Extensive three-dimensional (3D) genome reorganization occurs in senescence, but how enhancer interactomes are reconfigured during this process is just beginning to be understood. Here we generated high-resolution contact maps of active enhancers and their target genes, assessed chromatin accessibility, and established one-dimensional maps of various histone modifications and transcription factors to comprehensively understand the regulation of enhancer configuration during senescence. Hyper-connected enhancer communities/cliques formed around genes that are highly expressed and within essential gene pathways in each cell state. In addition, motif analysis indicates the involvement of specific transcription factors in hyper-connected regulatory elements in each condition; importantly, MafK, a bZIP family transcription factor, was upregulated in senescence, and reduced expression of MafK ameliorated the senescence phenotypes. Because the accumulation of senescent cells is a key feature of aging, we further investigated enhancer connectomes in the liver of young and aged mice. Hyper-connected enhancer communities were identified during aging, which regulate essential genes that maintain cell differentiation and homeostasis. These findings reveal that hyper-connected enhancer communities correlate with high gene expression in senescence and aging and provide potential hotspots for therapeutic intervention in aging and age-associated diseases.
Collapse
|
|
15
|
Yao M, Zhou P, Qin YY, Wang L, Yao DF. Mitochondrial carnitine palmitoyltransferase-II dysfunction: A possible novel mechanism for nonalcoholic fatty liver disease in hepatocarcinogenesis. World J Gastroenterol 2023; 29:1765-1778. [PMID: 37032731 PMCID: PMC10080702 DOI: 10.3748/wjg.v29.i12.1765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/04/2022] [Accepted: 03/13/2023] [Indexed: 03/28/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) or metabolic-associated fatty liver disease has been characterized by the lipid accumulation with injury of hepatocytes and has become one of the most common chronic liver diseases in the world. The complex mechanisms of NAFLD formation are still under identification. Carnitine palmitoyltransferase-II (CPT-II) on inner mitochondrial membrane (IMM) regulates long chain fatty acid β-oxidation, and its abnormality has had more and more attention paid to it by basic and clinical research in NAFLD. The sequences of its peptide chain and DNA nucleotides have been identified, and the catalytic activity of CPT-II is affected on its gene mutations, deficiency, enzymatic thermal instability, circulating carnitine level and so on. Recently, the CPT-II dysfunction has been discovered in models of liver lipid accumulation. Meanwhile, the malignant transformation of hepatocyte-related CD44+ stem T cell activation, high levels of tumor-related biomarkers (AFP, GPC3) and abnormal activation of Wnt3a expression as a key signal molecule of the Wnt/β-catenin pathway run parallel to the alterations of hepatocyte pathology. This review focuses on some of the progress of CPT-II inactivity on IMM with liver fatty accumulation as a possible novel pathogenesis for NAFLD in hepatocarcinogenesis.
Collapse
Affiliation(s)
- Min Yao
- Department of Medical Immunology, Medical School of Nantong University & Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Ping Zhou
- Department of Medical Immunology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Yan-Yan Qin
- Department of Medical Immunology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Li Wang
- Research Center for Intelligent Information Technology, Nantong University, Nantong 226019, Jiangsu Province, China
| | - Deng-Fu Yao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| |
Collapse
|
|
16
|
Fu L, Wang Y, Hu YQ. Causal effects of B vitamins and homocysteine on obesity and musculoskeletal diseases: A Mendelian randomization study. Front Nutr 2022; 9:1048122. [PMID: 36505230 PMCID: PMC9731309 DOI: 10.3389/fnut.2022.1048122] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 10/24/2022] [Indexed: 11/25/2022] Open
Abstract
Objectives Although homocysteine (Hcy) increases the risk of cardiovascular diseases, its effects on obesity and musculoskeletal diseases remain unclear. We performed a Mendelian randomization study to estimate the associations between Hcy and B vitamin concentrations and their effects on obesity and musculoskeletal-relevant diseases in the general population. Methods We selected independent single nucleotide polymorphisms of Hcy (n = 44,147), vitamin B12 (n = 45,576), vitamin B6 (n = 1864), and folate (n = 37,465) at the genome-wide significance level as instruments and applied them to the studies of summary-level data for fat and musculoskeletal phenotypes from the UK Biobank study (n = 331,117), the FinnGen consortium (n = 218,792), and other consortia. Two-sample Mendelian randomization (MR) approaches were utilized in this study. The inverse variance weighting (IVW) was adopted as the main analysis. MR-PRESSO, MR-Egger, the weighted median estimate, bidirectional MR, and multivariable MR were performed as sensitivity methods. Results Higher Hcy concentrations were robustly associated with an increased risk of knee osteoarthritis [odds ratio (OR) 1.119; 95% confidence interval (CI) 1.032-1.214; P = 0.007], hospital-diagnosed osteoarthritis (OR 1.178; 95% CI 1.012-1.37; P = 0.034), osteoporosis with pathological fracture (OR 1.597; 95% CI 1.036-2.46; P = 0.034), and soft tissue disorder (OR 1.069; 95% CI 1.001-1.141; P = 0.045) via an inverse variance weighting method and other MR approaches. Higher vitamin B12 levels were robustly associated with decreased body fat percentage and its subtypes (all P < 0.05). Bidirectional analyses showed no reverse causation. Multivariable MR analyses and other sensitivity analyses showed directionally similar results. Conclusions There exist significant causal effects of vitamin B12 in the serum and Hcy in the blood on fat and musculoskeletal diseases, respectively. These findings may have an important insight into the pathogenesis of obesity and musculoskeletal diseases and other possible future therapies.
Collapse
Affiliation(s)
- Liwan Fu
- Center for Non-Communicable Disease Management, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China,*Correspondence: Liwan Fu
| | - Yuquan Wang
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, Institute of Biostatistics, School of Life Sciences, Fudan University, Shanghai, China
| | - Yue-Qing Hu
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, Institute of Biostatistics, School of Life Sciences, Fudan University, Shanghai, China,Shanghai Center for Mathematical Sciences, Fudan University, Shanghai, China,Yue-Qing Hu
| |
Collapse
|
|
17
|
Selen ES, Rodriguez S, Cavagnini KS, Kim HB, Na CH, Wolfgang MJ. Requirement of hepatic pyruvate carboxylase during fasting, high fat, and ketogenic diet. J Biol Chem 2022; 298:102648. [PMID: 36441025 PMCID: PMC9694104 DOI: 10.1016/j.jbc.2022.102648] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 10/18/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022] Open
Abstract
Pyruvate has two major fates upon entry into mitochondria, the oxidative decarboxylation to acetyl-CoA via the pyruvate decarboxylase complex or the biotin-dependent carboxylation to oxaloacetate via pyruvate carboxylase (Pcx). Here, we have generated mice with a liver-specific KO of pyruvate carboxylase (PcxL-/-) to understand the role of Pcx in hepatic mitochondrial metabolism under disparate physiological states. PcxL-/- mice exhibited a deficit in hepatic gluconeogenesis and enhanced ketogenesis as expected but were able to maintain systemic euglycemia following a 24 h fast. Feeding a high-fat diet to PcxL-/- mice resulted in animals that were resistant to glucose intolerance without affecting body weight. However, we found that PcxL-/- mice fed a ketogenic diet for 1 week became severely hypoglycemic, demonstrating a requirement for hepatic Pcx for long-term glycemia under carbohydrate-limited diets. Additionally, we determined that loss of Pcx was associated with an induction in the abundance of lysine-acetylated proteins in PcxL-/- mice regardless of physiologic state. Furthermore, liver acetyl-proteomics revealed a biased induction in mitochondrial lysine-acetylated proteins. These data show that Pcx is important for maintaining the proper balance of pyruvate metabolism between oxidative and anaplerotic pathways.
Collapse
Affiliation(s)
- Ebru S. Selen
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Susana Rodriguez
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kyle S. Cavagnini
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Han-Byeol Kim
- Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Chan Hyun Na
- Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael J. Wolfgang
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA,For correspondence: Michael J. Wolfgang
| |
Collapse
|
|
18
|
Yang X, Jiang J, Wang Q, Duan J, Chen N, Wu D, Xia Y. Gender difference in hepatic AMPK pathway activated lipid metabolism induced by aged polystyrene microplastics exposure. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 245:114105. [PMID: 36155338 DOI: 10.1016/j.ecoenv.2022.114105] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 06/16/2023]
Abstract
Microplastics (MPs) pollution becomes an increasing concern and researchers keep exploring the health effects caused by MPs exposure. The ageing process in the environment significantly alters the physicochemical characteristics of MPs and subsequently affects their toxicities. The health effects of aged MPs exposure and the mechanism underlying are worthy of exploration. Polystyrene microplastics (PS-MPs) (with size less than 50 µm) were obtained by grinding and screening polystyrene materials. PS-MPs continued to be aged by ozone treatment (0.4 mg/min, 9 h). Both male and female C57BL/6 mice were orally exposed to 0 or 2 mg/kg/d aged PS-MPs for 28 days. Results showed that PS-MPs were found in liver, ovary and spleen of females and liver, testis and spleen of males in the aged PS-MPs group. Exposure to aged PS-MPs significantly decreased abdominal fat/body coefficient, the adipocyte size and the serum LDL-C level in females. Compared to the control, serum estradiol (E2) level, the mRNA expression levels of genes regulating E2 production (17β-hsd, 3β-hsd and Star) in ovary and the protein expression levels of E2 receptors (ERα, ERβ), AMPKα and p-AMPKα1 in liver increased significantly, and the mRNA expression levels of AMP-activated protein kinase (AMPK) downstream genes (Srebp-1c, Fas and Scd1) in liver decreased significantly in the female aged PS-MPs group. Liver metabolomic profiling showed that differential metabolites between female aged PS-MPs group and female control group were enriched in biotin metabolism and the level of biotin increased significantly in the female aged PS-MPs group. However, no significant changes were detected in males. These results indicated that aged PS-MPs exposure increased ovarian E2 production and activated the AMPK pathway in the liver which might inhibit liver lipid synthesis only in females. Our findings provide new insights into the potential sex-specific health effects of environmental MPs pollution.
Collapse
Affiliation(s)
- Xiaona Yang
- State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Jin Jiang
- State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Qing Wang
- State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Jiawei Duan
- State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Na Chen
- State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Di Wu
- State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
| | - Yankai Xia
- State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| |
Collapse
|
|
19
|
Hughey CC, Puchalska P, Crawford PA. Integrating the contributions of mitochondrial oxidative metabolism to lipotoxicity and inflammation in NAFLD pathogenesis. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159209. [DOI: 10.1016/j.bbalip.2022.159209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 06/25/2022] [Accepted: 07/27/2022] [Indexed: 11/28/2022]
|
|
20
|
Grigorova N, Ivanova Z, Bjørndal B, Berge RK, Vachkova E, Milanova A, Penchev G, Georgiev IP. Diet restriction alone improves glucose tolerance and insulin sensitivity than its coadministration with krill or fish oil in a rabbit model of castration‐induced obesity. J Anim Physiol Anim Nutr (Berl) 2022; 106:1396-1407. [DOI: 10.1111/jpn.13742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 04/27/2022] [Accepted: 05/17/2022] [Indexed: 11/27/2022]
Affiliation(s)
- Natalia Grigorova
- Department of Pharmacology, Animal Physiology and Physiological Chemistry, Faculty of Veterinary Medicine Trakia University Stara Zagora Bulgaria
| | - Zhenya Ivanova
- Department of Pharmacology, Animal Physiology and Physiological Chemistry, Faculty of Veterinary Medicine Trakia University Stara Zagora Bulgaria
| | - Bodil Bjørndal
- Department of Clinical Science University of Bergen Bergen Norway
- Department of Sports, Food, and Natural Sciences Western Norway University of Applied Sciences Bergen Norway
| | - Rolf Kristian Berge
- Department of Clinical Science University of Bergen Bergen Norway
- Department of Heart Disease Haukeland University Hospital Bergen Norway
| | - Ekaterina Vachkova
- Department of Pharmacology, Animal Physiology and Physiological Chemistry, Faculty of Veterinary Medicine Trakia University Stara Zagora Bulgaria
| | - Aneliya Milanova
- Department of Pharmacology, Animal Physiology and Physiological Chemistry, Faculty of Veterinary Medicine Trakia University Stara Zagora Bulgaria
| | - Georgi Penchev
- Department of Veterinary Anatomy, Histology and Embryology, Faculty of Veterinary Medicine Trakia University Stara Zagora Bulgaria
| | - Ivan Penchev Georgiev
- Department of Pharmacology, Animal Physiology and Physiological Chemistry, Faculty of Veterinary Medicine Trakia University Stara Zagora Bulgaria
| |
Collapse
|
|
21
|
Sun S, Luo J, Du H, Liu G, Liu M, Wang J, Han S, Che H. Widely Targeted Lipidomics and Transcriptomics Analysis Revealed Changes of Lipid Metabolism in Spleen Dendritic Cells in Shrimp Allergy. Foods 2022; 11:foods11131882. [PMID: 35804699 PMCID: PMC9265612 DOI: 10.3390/foods11131882] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/09/2022] [Accepted: 06/23/2022] [Indexed: 02/01/2023] Open
Abstract
Shrimp allergy (SA) is pathological type 2 inflammatory immune responses against harmless shrimp protein allergen, which is caused by complex interactions between dendritic cells (DCs) and other immune cells. Lipid metabolism in different DCs states are significantly changed. However, the lipid metabolism of spleen DCs in SA remain ambiguous. In this study, we established a BALB/c mouse shrimp protein extract-induced allergy model to determine the lipid profile of spleen DCs in SA, and the molecular mechanism between lipid metabolism and immune inflammation was preliminarily studied. Spleen DCs were sorted by fluorescence-activated cell sorting, and then widely targeted lipidomics and transcriptomics analysis were performed. Principal component analysis presented the lipidome alterations in SA. The transcriptomic data showed that Prkcg was involved in lipid metabolism, immune system, and inflammatory signaling pathway. In the correlation analysis, the results suggested that Prkcg was positively correlated with triacylglycerol (Pearson correlation coefficient = 0.917, p = 0.01). The lipidomics and transcriptomics integrated pathway analysis indicated the activated metabolic conversion from triacylglycerol to 1,2-diacyl-sn-glycerol and the transmission of lipid metabolism to immune inflammation (from triacylglycerol and ceramide to Prkcg) in SA spleen DCs, and cellular experiments in vitro showed that glyceryl trioleate and C16 ceramide treatment induced immune function alteration in DCs.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Huilian Che
- Correspondence: ; Tel.: +86-10-6273-7244; Fax: +86-10-6232-3465
| |
Collapse
|
|
22
|
Görigk S, Ouwens DM, Kuhn T, Altenhofen D, Binsch C, Damen M, Khuong JMA, Kaiser K, Knebel B, Vogel H, Schürmann A, Chadt A, Al-Hasani H. Nudix hydrolase NUDT19 regulates mitochondrial function and ATP production in murine hepatocytes. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159153. [PMID: 35367353 DOI: 10.1016/j.bbalip.2022.159153] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/14/2022] [Accepted: 03/17/2022] [Indexed: 02/04/2023]
Abstract
Changes in intracellular CoA levels are known to contribute to the development of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes (T2D) in human and rodents. However, the underlying genetic basis is still poorly understood. Due to their diverse susceptibility towards metabolic diseases, mouse inbred strains have been proven to serve as powerful tools for the identification of novel genetic factors that underlie the pathophysiology of NAFLD and diabetes. Transcriptome analysis of mouse liver samples revealed the nucleoside diphosphate linked moiety X-type motif Nudt19 as novel candidate gene responsible for NAFLD and T2D development. Knockdown (KD) of Nudt19 increased mitochondrial and glycolytic ATP production rates in Hepa 1-6 cells by 41% and 10%, respectively. The enforced utilization of glutamine or fatty acids as energy substrate reduced uncoupled respiration by 41% and 47%, respectively, in non-target (NT) siRNA transfected cells. This reduction was prevented upon Nudt19 KD. Furthermore, incubation with palmitate or oleate respectively increased mitochondrial ATP production by 31% and 20%, and uncoupled respiration by 23% and 30% in Nudt19 KD cells, but not in NT cells. The enhanced fatty acid oxidation in Nudt19 KD cells was accompanied by a 1.3-fold increased abundance of Pdk4. This study is the first to describe Nudt19 as regulator of hepatic lipid metabolism and potential mediator of NAFLD and T2D development.
Collapse
Affiliation(s)
- Sarah Görigk
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany
| | - D Margriet Ouwens
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany; Department of Endocrinology, Ghent University Hospital, Ghent, Belgium
| | - Tanja Kuhn
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany
| | - Delsi Altenhofen
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany
| | - Christian Binsch
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Mareike Damen
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Jenny Minh-An Khuong
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany
| | - Katharina Kaiser
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany
| | - Birgit Knebel
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany
| | - Heike Vogel
- German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany; Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, D-14558 Nuthetal, Germany; Research Group Genetics of Obesity, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), 14558 Nuthetal, Germany; Research Group Molecular and Clinical Life Science of Metabolic Diseases, Faculty of Health Sciences Brandenburg, University of Potsdam, Brandenburg, Germany
| | - Annette Schürmann
- German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany; Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, D-14558 Nuthetal, Germany
| | - Alexandra Chadt
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany; Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
| | - Hadi Al-Hasani
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany; Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| |
Collapse
|
|
23
|
Albhaisi S, Sanyal AJ. Pharmacology of NASH. COMPREHENSIVE PHARMACOLOGY 2022:214-238. [DOI: 10.1016/b978-0-12-820472-6.00121-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
24
|
Pan Z, Miao W, Wang C, Tu W, Jin C, Jin Y. 6:2 Cl-PFESA has the potential to cause liver damage and induce lipid metabolism disorders in female mice through the action of PPAR-γ. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2021; 287:117329. [PMID: 34022685 DOI: 10.1016/j.envpol.2021.117329] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 05/03/2021] [Accepted: 05/05/2021] [Indexed: 05/14/2023]
Abstract
6:2 Cl-PFESA is a polyfluoroalkyl ether with high environmental persistence that has been confirmed to have significant adverse effects on animals. In this study, 6-week-old female C57BL/6 mice were exposed to 0, 1, 3 and 10 μg/L 6:2 Cl-PFESA for 10 weeks to estimate the hepatotoxicity of 6:2 Cl-PFESA and explore its underlying molecular mechanism. The results indicated that 6:2 Cl-PFESA preferentially bioaccumulated in the liver and induced hepatic cytoplasmic vacuolation and hepatomegaly in mice. In addition, serum metabolic profiling showed that 6:2 Cl-PFESA exposure caused an abnormal increase in amino acids and an abnormal decrease in acyl-carnitine, which interfered with fatty acid transport and increased the risk of metabolic diseases. Further experiments showed that 6:2 Cl-PFESA formed more hydrogen bonds with PPAR-γ than PFOS, Rosi and GW9662, and the binding affinity of 6:2 Cl-PFESA toward PPAR-γ was the highest among the ligands. 6:2 Cl-PFESA promoted the differentiation of 3T3-L1 cells by increasing PPAR-γ expression. Therefore, our results showed that 6:2 Cl-PFESA has the potential to induce liver damage and dysfunction in female mice, and this effect was achieved through PPAR-γ. This study is the first to reveal the hepatic toxicity of 6:2 Cl-PFESA in female mammals and provides new insights for subsequent in-depth research.
Collapse
Affiliation(s)
- Zihong Pan
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310032, China
| | - Wenyu Miao
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310032, China
| | - Caiyun Wang
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310032, China
| | - Wenqing Tu
- Research Institute of Poyang Lake, Jiangxi Academy of Sciences, Nanchang, 330029, China
| | - Cuiyuan Jin
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310032, China
| | - Yuanxiang Jin
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310032, China.
| |
Collapse
|
|
25
|
Abstract
Ketone bodies play significant roles in organismal energy homeostasis, serving as oxidative fuels, modulators of redox potential, lipogenic precursors, and signals, primarily during states of low carbohydrate availability. Efforts to enhance wellness and ameliorate disease via nutritional, chronobiological, and pharmacological interventions have markedly intensified interest in ketone body metabolism. The two ketone body redox partners, acetoacetate and D-β-hydroxybutyrate, serve distinct metabolic and signaling roles in biological systems. We discuss the pleiotropic roles played by both of these ketones in health and disease. While enthusiasm is warranted, prudent procession through therapeutic applications of ketogenic and ketone therapies is also advised, as a range of metabolic and signaling consequences continue to emerge. Organ-specific and cell-type-specific effects of ketone bodies are important to consider as prospective therapeutic and wellness applications increase.
Collapse
Affiliation(s)
- Patrycja Puchalska
- Department of Medicine, Division of Molecular Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA; ,
| | - Peter A Crawford
- Department of Medicine, Division of Molecular Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA; , .,Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA
| |
Collapse
|
|
26
|
Eder K, Gessner DK, Ringseis R. Fibroblast growth factor 21 in dairy cows: current knowledge and potential relevance. J Anim Sci Biotechnol 2021; 12:97. [PMID: 34517929 PMCID: PMC8439079 DOI: 10.1186/s40104-021-00621-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 07/12/2021] [Indexed: 12/28/2022] Open
Abstract
Fibroblast growth factor 21 (FGF21) has been identified as an important regulator of carbohydrate and lipid metabolism, which plays an important role for metabolic regulation, particularly under conditions of energy deprivation or stress conditions. Dairy cows are subjected to a negative energy balance and various kinds of stress particularly during the periparturient phase and during early lactation. It has been shown that the plasma concentration of FGF21 in dairy cows is dramatically increased at parturition and remains high during the first weeks of lactation. This finding suggests that FGF21 might exert similar functions in dairy cows than in other species, such as mice or humans. However, the role of FGF21 in dairy cows has been less investigated so far. Following a brief summary of the previous findings about the function of FGF21 in humans and mice, the present review aims to present the current state of knowledge about the role of FGF21 in dairy cows. The first part of the review deals with the tissue localization of FGF21 and with conditions leading to an upregulation of FGF21 expression in the liver of dairy cows. In the second part, the influence of nutrition on FGF21 expression and the role of FGF21 for metabolic diseases in dairy cows is addressed. In the third part, findings of exogenous FGF21 application on metabolism in dairy cows are reported. Finally, the potential relevance of FGF21 in dairy cows is discussed. It is concluded that FGF21 might be of great importance for metabolic adaptation to negative energy balance and stress conditions in dairy cows. However, further studies are needed for a better understanding of the functions of FGF21 in dairy cows.
Collapse
Affiliation(s)
- Klaus Eder
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany
| | - Denise K. Gessner
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany
| | - Robert Ringseis
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany
| |
Collapse
|
|
27
|
Pewan SB, Otto JR, Kinobe RT, Adegboye OA, Malau-Aduli AEO. Nutritional Enhancement of Health Beneficial Omega-3 Long-Chain Polyunsaturated Fatty Acids in the Muscle, Liver, Kidney, and Heart of Tattykeel Australian White MARGRA Lambs Fed Pellets Fortified with Omega-3 Oil in a Feedlot System. BIOLOGY 2021; 10:biology10090912. [PMID: 34571789 PMCID: PMC8465306 DOI: 10.3390/biology10090912] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/08/2021] [Accepted: 09/10/2021] [Indexed: 01/09/2023]
Abstract
Simple Summary The problem addressed in this research was the possibility of enhancing the nutritional value and health beneficial omega-3 long-chain fatty acid content of lamb and its edible components. The aims and objectives were to evaluate the omega-3 contents of muscle, liver, kidney, and heart of lot-fed Tattykeel Australian White lambs of the MARGRA brand, in response to dietary supplementation with or without omega-3 oil fortified pellets. The findings demonstrate that the inclusion of omega-3 oil in feedlot diets of lambs enhances the human health beneficial omega-3 long-chain polyunsaturated fatty acid profiles of edible muscle tissue and organs without compromising meat quality or shelf life. These results are valuable to society because of increased functionality, health benefits, micro-marbling, tender, mouth-melting taste, and high-end eating quality experience of MARGRA lamb tissues and organs. Abstract The aim of this research was to evaluate the nutritional enhancement of omega-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA) composition of edible lamb Longissimus thoracis et lumborum muscle, heart, kidney, and liver in response to dietary supplementation of lot-fed lambs with or without omega-3 oil fortified pellets. The hypothesis tested was that fortifying feedlot pellets with omega-3 oil will enhance the human health beneficial n-3 LC-PUFA composition of edible lamb muscle tissue and organs. Seventy-five Tattykeel Australian White lambs exclusive to the MARGRA brand, with an average body weight of 30 kg at six months of age, were randomly assigned to the following three dietary treatments of 25 lambs each, and lot-fed as a cohort for 47 days in a completely randomized experimental design: (1) Control grain pellets without oil plus hay; (2) Omega-3 oil fortified grain pellets plus hay; and (3) Commercial whole grain pellets plus hay. All lambs had ad libitum access to the basal hay diet and water. Post-slaughter fatty acid composition of the Longissimus thoracis et lumborum muscle, liver, kidney, and heart were determined using thee gas chromatography–mass spectrophotometry technique. Results indicated significant variations (p < 0.05) in fatty acid profiles between tissues and organs. Omega-3 oil fortified pellets significantly (p < 0.05) increased ≥C20 n-3 LC-PUFA (C20:5n-3 eicosapentaenoate, EPA + C22:5n3 docosapentaenoate, DPA + C22:6n3 docosahexanoate DHA); C18:3n-3 alpha-linolenate, ALA; C18:2 conjugated linoleic acid, CLA; total monounsaturated fatty acids, MUFA; polyunsaturated fatty acids, PUFA contents; and reduced the ratio of omega-6 to omega-3 fatty acids in all lamb organs and tissues without impacting shelf-life. The findings demonstrate that the inclusion of omega-3 oil in feedlot diets of lambs enhances the human health beneficial omega-3 long-chain polyunsaturated fatty acid profiles of edible muscle tissue and organs without compromising meat quality.
Collapse
Affiliation(s)
- Shedrach Benjamin Pewan
- Animal Genetics and Nutrition, Veterinary Sciences Discipline, College of Public Health, Medical and Veterinary Sciences, Division of Tropical Health and Medicine, James Cook University, Townsville, QLD 4811, Australia; (S.B.P.); (J.R.O.); (R.T.K.)
- National Veterinary Research Institute, Private Mail Bag 01 Vom, Plateau State, Nigeria
| | - John Roger Otto
- Animal Genetics and Nutrition, Veterinary Sciences Discipline, College of Public Health, Medical and Veterinary Sciences, Division of Tropical Health and Medicine, James Cook University, Townsville, QLD 4811, Australia; (S.B.P.); (J.R.O.); (R.T.K.)
| | - Robert Tumwesigye Kinobe
- Animal Genetics and Nutrition, Veterinary Sciences Discipline, College of Public Health, Medical and Veterinary Sciences, Division of Tropical Health and Medicine, James Cook University, Townsville, QLD 4811, Australia; (S.B.P.); (J.R.O.); (R.T.K.)
| | - Oyelola Abdulwasiu Adegboye
- Public Health and Tropical Medicine Discipline, College of Public Health, Medical and Veterinary Sciences, Division of Tropical Health and Medicine, James Cook University, Townsville, QLD 4811, Australia;
| | - Aduli Enoch Othniel Malau-Aduli
- Animal Genetics and Nutrition, Veterinary Sciences Discipline, College of Public Health, Medical and Veterinary Sciences, Division of Tropical Health and Medicine, James Cook University, Townsville, QLD 4811, Australia; (S.B.P.); (J.R.O.); (R.T.K.)
- Correspondence: ; Tel.: +61-747-815-339
| |
Collapse
|
|
28
|
Effects of Fatty Acid Oxidation and Its Regulation on Dendritic Cell-Mediated Immune Responses in Allergies: An Immunometabolism Perspective. J Immunol Res 2021; 2021:7483865. [PMID: 34423053 PMCID: PMC8376428 DOI: 10.1155/2021/7483865] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 07/08/2021] [Accepted: 07/27/2021] [Indexed: 12/25/2022] Open
Abstract
Type 1 allergies, involve a complex interaction between dendritic cells and other immune cells, are pathological type 2 inflammatory immune responses against harmless allergens. Activated dendritic cells undergo extensive phenotypic and functional changes to exert their functions. The activation, differentiation, proliferation, migration, and mounting of effector reactions require metabolic reprogramming. Dendritic cells are important upstream mediators of allergic responses and are therefore an important effector of allergies. Hence, a better understanding of the underlying metabolic mechanisms of functional changes that promote allergic responses of dendritic cells could improve the prevention and treatment of allergies. Metabolic changes related to dendritic cell activation have been extensively studied. This review briefly outlines the basis of fatty acid oxidation and its association with dendritic cell immune responses. The relationship between immune metabolism and effector function of dendritic cells related to allergic diseases can better explain the induction and maintenance of allergic responses. Further investigations are warranted to improve our understanding of disease pathology and enable new treatment strategies.
Collapse
|
|
29
|
Godsday OU, Kingsley NE, Chukwuebuka NB, Ephraim C, Emmanuel E, Ejime AC, Chukwuka IJ. Isometric Handgrip Exercise Training Improves Spirometric Parameters and Pulmonary Capacity. PATHOPHYSIOLOGY 2021; 28:328-338. [PMID: 35366278 PMCID: PMC8830447 DOI: 10.3390/pathophysiology28030022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 06/28/2021] [Accepted: 07/15/2021] [Indexed: 12/02/2022] Open
Abstract
Decline in normal physiological pulmonary function has been attributed to premorbid conditions such as prehypertension. Research evidence suggests that physical activity reduces age-related decline in pulmonary function and improves the efficiency of the lungs in prehypertensive patients. However, there is a scarcity of data evidence relating to isometric exercise and pulmonary function. Furthermore, the interrelationship between the intensity and duration of isometric exercise and pulmonary function in these patients is still uncertain. Therefore, this study was undertaken to investigate the effect of isometric handgrip exercise on pulmonary function capacity in adults with prehypertension. To determine the effectiveness of isometric handgrip exercise on pulmonary function capacity in adults with prehypertension. A quasi experiment using a pre- and post-exercise method was carried out in two out-patients hospital settings. The sample comprised 192 sedentary pre-hypertensive subjects, aged between 30-50 years, that were randomly distributed into three groups of 64 participants each. The subjects performed, for 24 consecutive days, an isometric handgrip exercise at 30% Maximum Voluntary Contraction (M.V.C.). At the end of the 24 days, group one (GP1) discontinued, while group two (GP2) continued the exercise protocol for another 24 consecutive days and group three (GP3) continued with the exercise protocol for another 24 consecutive days but at 50% M.V.C. Determinants of lung function (outcomes) were Forced Expiratory Volume in 1 s (FEV1), Forced Vital Capacity (FVC), FEV1/FVC Ratio and Peak Expiratory Flow Rate (PEFR). The study shows that there was no statistically significant difference in the pre- and post-exercise outcomes for FEV1, FVC, FEV1/FVC Ratio and PEFR after 24 days for group 1. In group 2, there was a statistically significant difference in the FVC [(mean = 0.12 ± 0.12), (p = 0.002)], FEV1 [(mean = 0.15 ± 0.17), (p = 0.003)] and PEF [(mean = 0.85 ± 0.35), (p = 0.001)] after 48 days. In group 3, there was a statistically significant difference (p = 0.001) in all the outcomes assessed after 48 days. There was a between groups difference in favour of group 2 compared with group 1 for outcomes of FEV1 [(mean = 0.142 ± 0.68), (p = 0.005)] and PEF [(mean = 0.83 ± 0.19), (p = 0.0031)]. There was statistically significant difference in favour of group 3 compared to group 2, by increasing the exercise intensity from 30% to 50% M.V.C., for outcomes of FVC [mean change = 0.10 ± 0.052), (p = 0.005)], FEV1/FVC [mean change = 3.18 ± 0.75), (p = 0.017)] and PEF [(mean change = 0.86 ± 0.35), (p = 0.001)] after 48 days. Isometric handgrip exercise (after 48 days at 30% to 50% M.V.C.) improves outcomes of pulmonary function capacity in adults with prehypertension. Meanwhile, duration and/or increase in intensity of the isometric effort significantly contributed to the affects attained.
Collapse
Affiliation(s)
- Ogbutor Udoji Godsday
- Department of Physiotherapy, Federal Medical Centre Asaba, Asaba PMB 1033, Nigeria; (O.U.G.); (C.E.); (E.E.)
| | - Nwangwa Eze Kingsley
- Department of Human Physiology, Faculty of Basic Medical Sciences, Delta State University, Abraka PMB 1, Nigeria; (N.E.K.); (A.-C.E.); (I.J.C.)
| | | | - Chukwuemeka Ephraim
- Department of Physiotherapy, Federal Medical Centre Asaba, Asaba PMB 1033, Nigeria; (O.U.G.); (C.E.); (E.E.)
| | - Ezunu Emmanuel
- Department of Physiotherapy, Federal Medical Centre Asaba, Asaba PMB 1033, Nigeria; (O.U.G.); (C.E.); (E.E.)
| | - Agbonifo-Chijiokwu Ejime
- Department of Human Physiology, Faculty of Basic Medical Sciences, Delta State University, Abraka PMB 1, Nigeria; (N.E.K.); (A.-C.E.); (I.J.C.)
| | - Igweh John Chukwuka
- Department of Human Physiology, Faculty of Basic Medical Sciences, Delta State University, Abraka PMB 1, Nigeria; (N.E.K.); (A.-C.E.); (I.J.C.)
| |
Collapse
|
|
30
|
Mitochondrial Lipid Homeostasis at the Crossroads of Liver and Heart Diseases. Int J Mol Sci 2021; 22:ijms22136949. [PMID: 34203309 PMCID: PMC8268967 DOI: 10.3390/ijms22136949] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/19/2021] [Accepted: 06/25/2021] [Indexed: 12/16/2022] Open
Abstract
The prevalence of NAFLD (non-alcoholic fatty liver disease) is a rapidly increasing problem, affecting a huge population around the globe. However, CVDs (cardiovascular diseases) are the most common cause of mortality in NAFLD patients. Atherogenic dyslipidemia, characterized by plasma hypertriglyceridemia, increased small dense LDL (low-density lipoprotein) particles, and decreased HDL-C (high-density lipoprotein cholesterol) levels, is often observed in NAFLD patients. In this review, we summarize recent genetic evidence, proving the diverse nature of metabolic pathways involved in NAFLD pathogenesis. Analysis of available genetic data suggests that the altered operation of fatty-acid β-oxidation in liver mitochondria is the key process, connecting NAFLD-mediated dyslipidemia and elevated CVD risk. In addition, we discuss several NAFLD-associated genes with documented anti-atherosclerotic or cardioprotective effects, and current pharmaceutical strategies focused on both NAFLD treatment and reduction of CVD risk.
Collapse
|
|
31
|
Selen ES, Wolfgang MJ. mTORC1 activation is not sufficient to suppress hepatic PPARα signaling or ketogenesis. J Biol Chem 2021; 297:100884. [PMID: 34146544 PMCID: PMC8294577 DOI: 10.1016/j.jbc.2021.100884] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/04/2021] [Accepted: 06/15/2021] [Indexed: 11/18/2022] Open
Abstract
The mechanistic target of rapamycin (mTOR) is often referred to as a master regulator of the cellular metabolism that can integrate the growth factor and nutrient signaling. Fasting suppresses hepatic mTORC1 activity via the activity of the tuberous sclerosis complex (TSC), a negative regulator of mTORC1, to suppress anabolic metabolism. The loss of TSC1 in the liver locks the liver in a constitutively anabolic state even during fasting, which was suggested to regulate peroxisome proliferator-activated receptor alpha (PPARα) signaling and ketogenesis, but the molecular determinants of this regulation are unknown. Here, we examined if the activation of the mTORC1 complex in mice by the liver-specific deletion of TSC1 (TSC1L−/−) is sufficient to suppress PPARα signaling and therefore ketogenesis in the fasted state. We found that the activation of mTORC1 in the fasted state is not sufficient to repress PPARα-responsive genes or ketogenesis. Furthermore, we examined whether the activation of the anabolic program mediated by mTORC1 complex activation in the fasted state could suppress the robust catabolic programming and enhanced PPARα transcriptional response of mice with a liver-specific defect in mitochondrial long-chain fatty acid oxidation using carnitine palmitoyltransferase 2 (Cpt2L−/−) mice. We generated Cpt2L−/−; Tsc1L−/− double-KO mice and showed that the activation of mTORC1 by deletion of TSC1 could not suppress the catabolic PPARα-mediated phenotype of Cpt2L−/− mice. These data demonstrate that the activation of mTORC1 by the deletion of TSC1 is not sufficient to suppress a PPARα transcriptional program or ketogenesis after fasting.
Collapse
Affiliation(s)
- Ebru S Selen
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Michael J Wolfgang
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
| |
Collapse
|
|
32
|
Townsend LK, Weber AJ, Day EA, Shamshoum H, Shaw SJ, Perry CGR, Kemp BE, Steinberg GR, Wright DC. AMPK mediates energetic stress-induced liver GDF15. FASEB J 2021; 35:e21218. [PMID: 33337559 DOI: 10.1096/fj.202000954r] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 10/30/2020] [Accepted: 11/10/2020] [Indexed: 12/11/2022]
Abstract
Growth differentiating factor-15 (GDF15) is an emerging target for the treatment of obesity and metabolic disease partly due to its ability to suppress food intake. GDF15 expression and secretion are thought to be regulated by a cellular integrated stress response, which involves endoplasmic reticulum (ER) stress. AMPK is another cellular stress sensor, but the relationship between AMPK, ER stress, and GDF15 has not been assessed in vivo. Wildtype (WT), AMPK β1 deficient (AMPKβ1-/- ), and CHOP-/- mice were treated with three distinct AMPK activators; AICAR, which is converted to ZMP mimicking the effects of AMP on the AMPKγ isoform, R419, which indirectly activates AMPK through inhibition of mitochondrial respiration, or A769662, a direct AMPK activator which binds the AMPKβ1 isoform ADaM site causing allosteric activation. Following treatments, liver Gdf15, markers of ER-stress, AMPK activity, adenine nucleotides, circulating GDF15, and food intake were assessed. AICAR and R419 caused ER and energetic stress, increased GDF15 expression and secretion, and suppressed food intake. Direct activation of AMPK β1 containing complexes by A769662 increased hepatic Gdf15 expression, circulating GDF15, and suppressed food intake, independent of ER stress. The effects of AICAR, R419, and A769662 on GDF15 were attenuated in AMPKβ1-/- mice. AICAR and A769662 increased GDF15 to a similar extent in WT and CHOP-/- mice. Herein, we provide evidence that AMPK plays a role in mediating the induction of GDF15 under conditions of energetic stress in mouse liver in vivo.
Collapse
Affiliation(s)
- Logan K Townsend
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada.,Centre for Metabolism, Obesity and Diabetes Research and Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Alyssa J Weber
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
| | - Emily A Day
- Centre for Metabolism, Obesity and Diabetes Research and Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Hesham Shamshoum
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
| | - Simon J Shaw
- Rigel Pharmaceuticals Inc., South San Francisco, CA, USA
| | - Christopher G R Perry
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, ON, Canada
| | - Bruce E Kemp
- Department of Medicine, St. Vincent's Institute, University of Melbourne, Melbourne, Vic, Australia.,Mary MacKillop Institute for Health Research, Australian Catholic University, Fitzroy, Victoria, Australia
| | - Gregory R Steinberg
- Centre for Metabolism, Obesity and Diabetes Research and Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - David C Wright
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
| |
Collapse
|
|
33
|
Kang SG, Choi MJ, Jung SB, Chung HK, Chang JY, Kim JT, Kang YE, Lee JH, Hong HJ, Jun SM, Ro HJ, Suh JM, Kim H, Auwerx J, Yi HS, Shong M. Differential roles of GDF15 and FGF21 in systemic metabolic adaptation to the mitochondrial integrated stress response. iScience 2021; 24:102181. [PMID: 33718833 PMCID: PMC7920832 DOI: 10.1016/j.isci.2021.102181] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 12/23/2020] [Accepted: 02/09/2021] [Indexed: 12/20/2022] Open
Abstract
Perturbation of mitochondrial proteostasis provokes cell autonomous and cell non-autonomous responses that contribute to homeostatic adaptation. Here, we demonstrate distinct metabolic effects of hepatic metabokines as cell non-autonomous factors in mice with mitochondrial OxPhos dysfunction. Liver-specific mitochondrial stress induced by a loss-of-function mutation in Crif1 (LKO) leads to aberrant oxidative phosphorylation and promotes the mitochondrial unfolded protein response. LKO mice are highly insulin sensitive and resistant to diet-induced obesity. The hepatocytes of LKO mice secrete large quantities of metabokines, including GDF15 and FGF21, which confer metabolic benefits. We evaluated the metabolic phenotypes of LKO mice with global deficiency of GDF15 or FGF21 and show that GDF15 regulates body and fat mass and prevents diet-induced hepatic steatosis, whereas FGF21 upregulates insulin sensitivity, energy expenditure, and thermogenesis in white adipose tissue. This study reveals that the mitochondrial integrated stress response (ISRmt) in liver mediates metabolic adaptation through hepatic metabokines.
Collapse
Affiliation(s)
- Seul Gi Kang
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon 35015, Republic of Korea.,Department of Medical Science, Chungnam National University School of Medicine, 266 Munhwaro, Daejeon 35015, Republic of Korea
| | - Min Jeong Choi
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon 35015, Republic of Korea.,Department of Medical Science, Chungnam National University School of Medicine, 266 Munhwaro, Daejeon 35015, Republic of Korea
| | - Saet-Byel Jung
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon 35015, Republic of Korea
| | - Hyo Kyun Chung
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon 35015, Republic of Korea
| | - Joon Young Chang
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon 35015, Republic of Korea.,Department of Medical Science, Chungnam National University School of Medicine, 266 Munhwaro, Daejeon 35015, Republic of Korea
| | - Jung Tae Kim
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon 35015, Republic of Korea.,Department of Medical Science, Chungnam National University School of Medicine, 266 Munhwaro, Daejeon 35015, Republic of Korea
| | - Yea Eun Kang
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon 35015, Republic of Korea.,Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Ju Hee Lee
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon 35015, Republic of Korea.,Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Hyun Jung Hong
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon 35015, Republic of Korea.,Department of Medical Science, Chungnam National University School of Medicine, 266 Munhwaro, Daejeon 35015, Republic of Korea
| | - Sang Mi Jun
- Center for Research Equipment, Korea Basic Science Institute, Cheongju 28119, Republic of Korea.,Convergent Research Center for Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
| | - Hyun-Joo Ro
- Center for Research Equipment, Korea Basic Science Institute, Cheongju 28119, Republic of Korea.,Convergent Research Center for Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
| | - Jae Myoung Suh
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
| | - Hail Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
| | - Johan Auwerx
- Laboratory for Integrative Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, Lausanne 1015, Switzerland
| | - Hyon-Seung Yi
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon 35015, Republic of Korea.,Department of Medical Science, Chungnam National University School of Medicine, 266 Munhwaro, Daejeon 35015, Republic of Korea.,Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Minho Shong
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon 35015, Republic of Korea.,Department of Medical Science, Chungnam National University School of Medicine, 266 Munhwaro, Daejeon 35015, Republic of Korea.,Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| |
Collapse
|
|
34
|
Wu Y, Ding R, Zhang X, Zhang J, Huang Q, Liu L, Shen H. Meet-in-metabolite analysis: A novel strategy to identify connections between arsenic exposure and male infertility. ENVIRONMENT INTERNATIONAL 2021; 147:106360. [PMID: 33401174 DOI: 10.1016/j.envint.2020.106360] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 12/07/2020] [Accepted: 12/18/2020] [Indexed: 06/12/2023]
Abstract
BACKGROUND Despite a trend in the use of systems epidemiology to fill the knowledge gap between risk-factor exposure and adverse outcomes in the OMICS data, such as the metabolome, seriously hindrances need to be overcome for identifying molecular connections. OBJECTIVES Using male infertility phenotypes and arsenic exposure, we aimed to identify intermediate biomarkers that reflect both arsenic exposure and male infertility with a meet-in-metabolite analysis (MIMA). METHODS Urinary arsenic levels and metabolome were measured by using inductively coupled plasma-mass spectrometry (ICP-MS) and HPLC-quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS), respectively. To identify arsenic-related metabolic markers (A-MIMA), the intermediate markers were profiled by orthogonal projections to latent structures (OPLS-DA). To detect infertility-related metabolic markers (I-MIMA), the intermediate markers were investigated by weighted gene co-expression network analysis. The key node markers, related to both A-MIMA and I-MIMA, were determined by O2PLS and defined as MIMA markers. Finally, network analysis was used to construct the MIMA-related metabolic network. RESULTS Twelve markers each were defined through the significant associations with arsenic exposure (A-MIMA) and/or infertility (I-MIMA), respectively. Seven of them, including acetyl-N-formyl-5-methoxykynurenamine, carnitine, estrone, 2-oxo-4-methylthiobutanoic acid, malonic acid, valine, and LysoPC (10:0), were defined through the associations with both arsenic exposure and male infertility (MIMA markers). These intermediate markers were involved majorly in oxidative stress, one-carbon metabolism, steroid hormone homeostasis, and lipid metabolism pathways. The core correlation network analysis further highlighted that testosterone is a vital link between the effect of arsenic and male infertility. CONCLUSIONS From arsenic exposure to male infertility, the arsenic methylation that coupled one-carbon metabolism disruption with oxidation stress may have extended its effect to fatty acid oxidation and steroidogenesis dysfunction. Testosterone is at the hub between arsenic exposure and male infertility modules and, along with the related metabolic pathways, may service as a potential surrogate marker in risk assessment for male dysfunction due to arsenic exposure.
Collapse
Affiliation(s)
- Yan Wu
- Department of Health Inspection and Quarantine, The School of Public Health, Fujian Medical University, Fuzhou, Fujian 350122, PR China
| | - Rui Ding
- College of Environmental Science and Engineering, Fujian Normal University, Fuzhou, Fujian Province 350007, PR China
| | - Xi Zhang
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, PR China
| | - Jie Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, PR China; Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, PR China
| | - Qingyu Huang
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, PR China
| | - Liangpo Liu
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, PR China; School of Public Health, Shanxi Medical University, Taiyuan 030001, PR China
| | - Heqing Shen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, PR China; Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, PR China.
| |
Collapse
|
|
35
|
Selen ES, Choi J, Wolfgang MJ. Discordant hepatic fatty acid oxidation and triglyceride hydrolysis leads to liver disease. JCI Insight 2021; 6:135626. [PMID: 33491665 PMCID: PMC7934875 DOI: 10.1172/jci.insight.135626] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 12/09/2020] [Indexed: 12/14/2022] Open
Abstract
To extract energy from stored lipids, fatty acids must first be liberated from triglyceride before their β-oxidation in mitochondria in a coordinated and stepwise manner. To determine the independent and interdependent roles of hepatic triglyceride hydrolysis and fatty acid oxidation, mice were generated with a liver-specific defect in triglyceride hydrolysis (AtglL–/–), fatty acid oxidation (Cpt2L–/–), or both (double knockout). The loss of either gene resulted in the compensatory increase in the other, demonstrating their coordination. The loss of individual components of fatty acid catabolism (carnitine palmitoyl transferase 2 [Cpt2], adipose triglyceride lipase [Atgl], and Pparα) resulted in largely independent effects on hepatocyte morphology, intermediary metabolism, and gene expression in response to fasting. However, high-fat feeding revealed the interdependent role of Atgl and Cpt2, as the loss of only one of the genes resulted in steatosis (fatty liver) but the loss of both components resulted in significant steatohepatitis (inflammation and fibrosis). Lipolysis and β-oxidation are intimately linked within a continuous pathway, and disruption of their coordination leads to unique cellular and molecular phenotypes that ultimately result in liver disease.
Collapse
Affiliation(s)
| | | | - Michael J Wolfgang
- Department of Biological Chemistry and.,Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
|
36
|
Badakhshi Y, Jin T. Current understanding and controversies on the clinical implications of fibroblast growth factor 21. Crit Rev Clin Lab Sci 2020; 58:311-328. [PMID: 33382006 DOI: 10.1080/10408363.2020.1864278] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Metabolic functions of the hepatic hormone fibroblast growth factor 21 (FGF21) have been recognized for more than a decade in studying the responses of human subjects and rodent models to nutritional stresses such as fasting, high-fat diet or ketogenic diet consumption, and ethanol intake. Our interest in the beneficial metabolic effects of FGF21 has risen due to its potential ability to serve as a therapeutic agent for various metabolic disorders, including type 2 diabetes, obesity, and fatty liver diseases, as well as its potential to act as a diagnostic or prognostic biomarker for metabolic and other disorders. Here, we briefly review the FGF21 gene and protein structures, its expression pattern, and cellular signaling cascades that mediate FGF21 production and function. We mainly focus on discussing experimental and clinical literature pertaining to FGF21 as a therapeutic agent. Furthermore, we present several lines of investigation, including a few studies conducted by our team, suggesting that FGF21 expression and function can be regulated by dietary polyphenol interventions. Finally, we discuss the literature debating FGF21 as a potential biomarker in various disorders.
Collapse
Affiliation(s)
- Yasaman Badakhshi
- Division of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.,Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada.,Banting and Best Diabetes Center, Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Tianru Jin
- Division of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.,Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada.,Banting and Best Diabetes Center, Faculty of Medicine, University of Toronto, Toronto, Canada
| |
Collapse
|
|
37
|
The Effect of Probiotics Supplementation on Gut Microbiota After Helicobacter pylori Eradication: A Multicenter Randomized Controlled Trial. Infect Dis Ther 2020; 10:317-333. [PMID: 33270205 PMCID: PMC7955021 DOI: 10.1007/s40121-020-00372-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 11/11/2020] [Indexed: 02/08/2023] Open
Abstract
Introduction Helicobacter pylori eradication therapy may lead to the perturbation of gut microbiota. We aim to investigate the impact of probiotics on eradication rate and gut microbiota during eradication therapy. Methods A total of 162 patients receiving bismuth quadruple therapy were enrolled and randomly assigned to groups given probiotics (n = 83) or placebo (n = 79) for 4 weeks. Fecal samples were collected before treatment and 2, 4, 6, and 8 weeks after eradication therapy. Gut microbiota was analyzed by 16S rRNA high-throughput sequencing. Results The eradication rates in the placebo and probiotics group were 82.43% and 87.01%, respectively (P > 0.05). Compared with baseline, alpha and beta diversity was significantly altered 2 weeks after eradication in both groups, which was restored at week 8. There were no significant differences in diversity between the two groups. H. pylori eradication therapy resulted in enrichment of some detrimental bacteria taxa such as Shigella, Klebsiella, and Streptococcus, while probiotics supplementation could rapidly restore these taxa levels after eradication and increase the taxa of Bacillus and Lactobacillales. Functional analysis revealed that lipopolysaccharide biosynthesis and polymyxin resistance pathways were significantly enriched after eradication, while probiotics supplementation mainly enriched the cofactors and vitamins metabolism pathways. Increased relative abundances of Roseburia and Dialister were associated with the positive eradication outcome. Conclusions Probiotics supplementation might help to construct a beneficial profile of gut microbiota after eradication therapy. Specific bacteria taxa are associated with H. pylori eradication outcome. These findings may be of value in rational use of probiotics during H. pylori eradication. Trial Registration Chinese Clinical Trial Registry, ChiCTR1900022116. Electronic supplementary material The online version of this article (10.1007/s40121-020-00372-9) contains supplementary material, which is available to authorized users.
Collapse
|
|
38
|
Zhang Y, Ge S, Yang Z, Li Z, Gong X, Zhang Q, Dong W, Dong C. Disturbance of di-(2-ethylhexyl) phthalate in hepatic lipid metabolism in rats fed with high fat diet. Food Chem Toxicol 2020; 146:111848. [DOI: 10.1016/j.fct.2020.111848] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/16/2020] [Accepted: 11/02/2020] [Indexed: 01/05/2023]
|
|
39
|
Hsu JY, Lin HH, Wang ZH, Chen JH. Aqueous extract from Pepino (Solanum muricatum Ait.) leaves ameliorated insulin resistance, hyperlipidemia, and hyperglycemia in mice with metabolic syndrome. J Food Biochem 2020; 44:e13518. [PMID: 33047354 DOI: 10.1111/jfbc.13518] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/30/2020] [Accepted: 09/24/2020] [Indexed: 12/14/2022]
Abstract
Solanum muricatum Ait. (Pepino) is a plant food commonly cultivated in the Penghu Island, Taiwan. This present study aimed to investigate the protective effects of aqueous extract of Pepino leaves (AEPL) in mice with metabolic syndrome. Metabolic syndrome animal model was induced by continuous high-fat diet feeding and low-dose streptozotocin (40 mg/ml) for 5 days. A 1% AEPL or metformin were given for 6 weeks after streptozotocin injection. The results revealed that 1% AEPL effectively reduced fasting blood glucose, insulin resistance, and hyperlipidemia in metabolic syndrome mice. Histologic examination revealed lipid accumulation in liver decreased by 1% AEPL treatment. Further, western blot analysis revealed 1% AEPL treatment managed enzymes related to lipid synthesis and oxidation pathways and hepatic glucose production. Besides, 1% AEPL treatment increased liver antioxidant activities to against oxidative stress. These results concluded that AEPL treatment attenuated insulin resistance, hyperlipidemia, and hyperglycemia of metabolic syndrome. PRACTICAL APPLICATIONS: Metabolic syndrome (MS) is a multifactorial chronic disease which is characterized by dyslipidemia, insulin resistance, and hyperglycemia. However, there is no single drug or defined medication for MS so far. The present study revealed that AEPL treatment was able to regulate lipid metabolism and glycemic control at the molecular level to alleviate MS. AEPL has the potential to be a novo complementary medication for metabolic syndrome.
Collapse
Affiliation(s)
- Jen-Ying Hsu
- Department of Nutrition, Chung Shan Medical University, Taichung City, Taiwan
| | - Hui-Hsuan Lin
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung City, Taiwan
| | - Zhi-Hong Wang
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung City, Taiwan
| | - Jing-Hsien Chen
- Department of Nutrition, Chung Shan Medical University, Taichung City, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung City, Taiwan
| |
Collapse
|
|
40
|
Li LY, Li JM, Ning LJ, Lu DL, Luo Y, Ma Q, Limbu SM, Li DL, Chen LQ, Lodhi IJ, Degrace P, Zhang ML, Du ZY. Mitochondrial Fatty Acid β-Oxidation Inhibition Promotes Glucose Utilization and Protein Deposition through Energy Homeostasis Remodeling in Fish. J Nutr 2020; 150:2322-2335. [PMID: 32720689 PMCID: PMC7690763 DOI: 10.1093/jn/nxaa187] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 05/02/2020] [Accepted: 06/11/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Fish cannot use carbohydrate efficiently and instead utilize protein for energy supply, thus limiting dietary protein storage. Protein deposition is dependent on protein turnover balance, which correlates tightly with cellular energy homeostasis. Mitochondrial fatty acid β-oxidation (FAO) plays a crucial role in energy metabolism. However, the effect of remodeled energy homeostasis caused by inhibited mitochondrial FAO on protein deposition in fish has not been intensively studied. OBJECTIVES This study aimed to identify the regulatory role of mitochondrial FAO in energy homeostasis maintenance and protein deposition by studying lipid, glucose, and protein metabolism in fish. METHODS Carnitine-depleted male Nile tilapia (initial weight: 4.29 ± 0.12 g; 3 mo old) were established by feeding them with mildronate diets (1000 mg/kg/d) for 6 wk. Zebrafish deficient in the carnitine palmitoyltransferase 1b gene (cpt1b) were produced by using CRISPR/Cas9 gene-editing technology, and their males (154 ± 3.52 mg; 3 mo old) were used for experiments. Normal Nile tilapia and wildtype zebrafish were used as controls. We assessed nutrient metabolism and energy homeostasis-related biochemical and molecular parameters, and performed 14C-labeled nutrient tracking and transcriptomic analyses. RESULTS The mitochondrial FAO decreased by 33.1-88.9% (liver) and 55.6-68.8% (muscle) in carnitine-depleted Nile tilapia and cpt1b-deficient zebrafish compared with their controls (P < 0.05). Notably, glucose oxidation and muscle protein deposition increased by 20.5-24.4% and 6.40-8.54%, respectively, in the 2 fish models compared with their corresponding controls (P < 0.05). Accordingly, the adenosine 5'-monophosphate-activated protein kinase/protein kinase B-mechanistic target of rapamycin (AMPK/AKT-mTOR) signaling was significantly activated in the 2 fish models with inhibited mitochondrial FAO (P < 0.05). CONCLUSIONS These data show that inhibited mitochondrial FAO in fish induces energy homeostasis remodeling and enhances glucose utilization and protein deposition. Therefore, fish with inhibited mitochondrial FAO could have high potential to utilize carbohydrate. Our results demonstrate a potentially new approach for increasing protein deposition through energy homeostasis regulation in cultured animals.
Collapse
Affiliation(s)
- Ling-Yu Li
- LANEH, School of Life Sciences, East China Normal University, Shanghai, China
| | - Jia-Min Li
- LANEH, School of Life Sciences, East China Normal University, Shanghai, China
- Fisheries College, Ocean University of China, Qingdao, China
| | - Li-Jun Ning
- College of Marine Sciences, South China Agricultural University, Guangzhou, China
| | - Dong-Liang Lu
- LANEH, School of Life Sciences, East China Normal University, Shanghai, China
| | - Yuan Luo
- LANEH, School of Life Sciences, East China Normal University, Shanghai, China
| | - Qiang Ma
- LANEH, School of Life Sciences, East China Normal University, Shanghai, China
| | - Samwel Mchele Limbu
- LANEH, School of Life Sciences, East China Normal University, Shanghai, China
- Department of Aquatic Sciences and Fisheries Technology, University of Dar es Salaam, Dar es Salaam, Tanzania
| | - Dong-Liang Li
- LANEH, School of Life Sciences, East China Normal University, Shanghai, China
| | - Li-Qiao Chen
- LANEH, School of Life Sciences, East China Normal University, Shanghai, China
| | - Irfan J Lodhi
- Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, Saint Louis, MO, USA
| | - Pascal Degrace
- Team Pathophysiology of Dyslipidemia, INSERM UMR1231 Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France
| | - Mei-Ling Zhang
- 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
| |
Collapse
|
|
41
|
Chen Y, Liao C, Huang Y, Chen M, Huang C, Chen W, Chiu Y. Proteome and microbiota analysis highlight Lactobacillus plantarum TWK10 supplementation improves energy metabolism and exercise performance in mice. Food Sci Nutr 2020; 8:3525-3534. [PMID: 32724615 PMCID: PMC7382123 DOI: 10.1002/fsn3.1635] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 04/19/2020] [Accepted: 04/20/2020] [Indexed: 12/13/2022] Open
Abstract
Lactobacillus plantarum TWK10 (LP10) is a probiotic known to improve endurance exercise performance. Here, we analyze the proteomics and metagenomic changes in a LP10 supplemented mouse model. Male ICR mice were divided into two groups (n = 8) to receive by oral gavage either vehicle or of LP10 for 6 weeks. Proteins changes by LP10 treatment were subjected to the Ingenuity Pathway Analysis (IPA) to provide corroborative evidence for differential regulation of molecular and cellular functions affecting metabolic processes. Fecal samples were obtained from each mouse, and the microbial community profile analyzed by pyrosequencing of the 16S rRNA genes. Of the 880 identified proteins, 25 proteins were significantly downregulated and 44 proteins were significantly upregulated in the LP10 treated compared to vehicle group. LP10 supplementation shift in the gut microbiota to butyrate-producing members and provided from lipid oxidation since peroxisomal fatty acid oxidation in liver.
Collapse
Affiliation(s)
- Yi‐Ming Chen
- College of physical educationHubei Normal UniversityHuangshiChina
| | - Chen‐Chung Liao
- Proteomics Research CenterNational Yang‐Ming UniversityTaipeiTaiwan
| | - Yen‐Chun Huang
- Institute of Biochemistry and Molecular BiologyNational Yang‐Ming UniversityTaipeiTaiwan
| | - Ming‐Yi Chen
- General Education CenterNational Taipei University of Nursing and Health SciencesTaipeiTaiwan
| | - Chi‐Chang Huang
- Graduate Institute of Sports ScienceNational Taiwan Sport UniversityTaoyuanTaiwan
| | - Wen‐Chyuan Chen
- Center for General EducationChang Gung University of Science and TechnologyTaoyuanTaiwan
- Department of Otorhinolaryngology‐Head and Neck SurgerySleep CenterLinkou‐Chang Gung Memorial HospitalTaoyuanTaiwan
| | - Yen‐Shuo Chiu
- Department of OrthopedicsShuang Ho HospitalTaipei Medical UniversityTaipeiTaiwan
- School of Nutrition and Health SciencesCollege of NutritionTaipei Medical UniversityTaipeiTaiwan
| |
Collapse
|
|
42
|
Stotland AB, Spivia W, Orosco A, Andres AM, Gottlieb RA, Van Eyk JE, Parker SJ. MitoPlex: A targeted multiple reaction monitoring assay for quantification of a curated set of mitochondrial proteins. J Mol Cell Cardiol 2020; 142:1-13. [PMID: 32234390 PMCID: PMC7347090 DOI: 10.1016/j.yjmcc.2020.03.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 03/23/2020] [Accepted: 03/24/2020] [Indexed: 12/21/2022]
Abstract
Mitochondria are the major source of cellular energy (ATP), as well as critical mediators of widespread functions such as cellular redox balance, apoptosis, and metabolic flux. The organelles play an especially important role in the maintenance of cardiac homeostasis; their inability to generate ATP following impairment due to ischemic damage has been directly linked to organ failure. Methods to quantify mitochondrial content are limited to low throughput immunoassays, measurement of mitochondrial DNA, or relative quantification by untargeted mass spectrometry. Here, we present a high throughput, reproducible and quantitative mass spectrometry multiple reaction monitoring based assay of 37 proteins critical to central carbon chain metabolism and overall mitochondrial function termed 'MitoPlex'. We coupled this protein multiplex with a parallel analysis of the central carbon chain metabolites (219 metabolite assay) extracted in tandem from the same sample, be it cells or tissue. In tests of its biological applicability in cells and tissues, "MitoPlex plus metabolites" indicated profound effects of HMG-CoA Reductase inhibition (e.g., statin treatment) on mitochondria of i) differentiating C2C12 skeletal myoblasts, as well as a clear opposite trend of statins to promote mitochondrial protein expression and metabolism in heart and liver, while suppressing mitochondrial protein and ii) aspects of metabolism in the skeletal muscle obtained from C57Bl6 mice. Our results not only reveal new insights into the metabolic effect of statins in skeletal muscle, but present a new high throughput, reliable MS-based tool to study mitochondrial dynamics in both cell culture and in vivo models.
Collapse
Affiliation(s)
- Aleksandr B Stotland
- Molecular Cardiobiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
| | - Weston Spivia
- Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
| | - Amanda Orosco
- Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
| | - Allen M Andres
- Molecular Cardiobiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
| | - Roberta A Gottlieb
- Molecular Cardiobiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
| | - Jennifer E Van Eyk
- Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
| | - Sarah J Parker
- Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
| |
Collapse
|
|
43
|
White CJ, Lee J, Choi J, Chu T, Scafidi S, Wolfgang MJ. Determining the Bioenergetic Capacity for Fatty Acid Oxidation in the Mammalian Nervous System. Mol Cell Biol 2020; 40:e00037-20. [PMID: 32123009 PMCID: PMC7189099 DOI: 10.1128/mcb.00037-20] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 02/16/2020] [Indexed: 12/15/2022] Open
Abstract
The metabolic state of the brain can greatly impact neurologic function. Evidence of this includes the therapeutic benefit of a ketogenic diet in neurologic diseases, including epilepsy. However, brain lipid bioenergetics remain largely uncharacterized. The existence, capacity, and relevance of mitochondrial fatty acid β-oxidation (FAO) in the brain are highly controversial, with few genetic tools available to evaluate the question. We have provided evidence for the capacity of brain FAO using a pan-brain-specific conditional knockout (KO) mouse incapable of FAO due to the loss of carnitine palmitoyltransferase 2, the product of an obligate gene for FAO (CPT2B-/-). Loss of central nervous system (CNS) FAO did not result in gross neuroanatomical changes or systemic differences in metabolism. Loss of CPT2 in the brain did not result in robustly impaired behavior. We demonstrate by unbiased and targeted metabolomics that the mammalian brain oxidizes a substantial quantity of long-chain fatty acids in vitro and in vivo Loss of CNS FAO results in robust accumulation of long-chain acylcarnitines in the brain, suggesting that the mammalian brain mobilizes fatty acids for their oxidation, irrespective of diet or metabolic state. Together, these data demonstrate that the mammalian brain oxidizes fatty acids under normal circumstances with little influence from or on peripheral tissues.
Collapse
Affiliation(s)
- Cory J White
- Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Jieun Lee
- Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Joseph Choi
- Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Tiffany Chu
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Susanna Scafidi
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Michael J Wolfgang
- Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
- Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
|
44
|
Joshi PR, Zierz S. Muscle Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Conceptual Approach. Molecules 2020; 25:molecules25081784. [PMID: 32295037 PMCID: PMC7221885 DOI: 10.3390/molecules25081784] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 04/08/2020] [Accepted: 04/11/2020] [Indexed: 11/16/2022] Open
Abstract
Carnitine palmitoyltransferase (CPT) catalyzes the transfer of long- and medium-chain fatty acids from cytoplasm into mitochondria, where oxidation of fatty acids takes place. Deficiency of CPT enzyme is associated with rare diseases of fatty acid metabolism. CPT is present in two subforms: CPT I at the outer mitochondrial membrane and carnitine palmitoyltransferase II (CPT II) inside the mitochondria. Deficiency of CPT II results in the most common inherited disorder of long-chain fatty acid oxidation affecting skeletal muscle. There is a lethal neonatal form, a severe infantile hepato-cardio-muscular form, and a rather mild myopathic form characterized by exercise-induced myalgia, weakness, and myoglobinuria. Total CPT activity (CPT I + CPT II) in muscles of CPT II-deficient patients is generally normal. Nevertheless, in some patients, not detectable to reduced total activities are also reported. CPT II protein is also shown in normal concentration in patients with normal CPT enzymatic activity. However, residual CPT II shows abnormal inhibition sensitivity towards malonyl-CoA, Triton X-100 and fatty acid metabolites in patients. Genetic studies have identified a common p.Ser113Leu mutation in the muscle form along with around 100 different rare mutations. The biochemical consequences of these mutations have been controversial. Hypotheses include lack of enzymatically active protein, partial enzyme deficiency and abnormally regulated enzyme. The recombinant enzyme experiments that we recently conducted have shown that CPT II enzyme is extremely thermoliable and is abnormally inhibited by different emulsifiers and detergents such as malonyl-CoA, palmitoyl-CoA, palmitoylcarnitine, Tween 20 and Triton X-100. Here, we present a conceptual overview on CPT II deficiency based on our own findings and on results from other studies addressing clinical, biochemical, histological, immunohistological and genetic aspects, as well as recent advancements in diagnosis and therapeutic strategies in this disorder.
Collapse
|
|
45
|
Protective effect of metformin against palmitate-induced hepatic cell death. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165621. [DOI: 10.1016/j.bbadis.2019.165621] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 10/31/2019] [Accepted: 11/21/2019] [Indexed: 12/12/2022]
|
|
46
|
Roles of galectin-3 in metabolic disorders and tumor cell metabolism. Int J Biol Macromol 2020; 142:463-473. [DOI: 10.1016/j.ijbiomac.2019.09.118] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/03/2019] [Accepted: 09/16/2019] [Indexed: 12/12/2022]
|
|
47
|
Tillman EJ, Rolph T. FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases. Front Endocrinol (Lausanne) 2020; 11:601290. [PMID: 33381084 PMCID: PMC7767990 DOI: 10.3389/fendo.2020.601290] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 11/12/2020] [Indexed: 12/13/2022] Open
Abstract
The rising global prevalence of obesity, metabolic syndrome, and type 2 diabetes has driven a sharp increase in non-alcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in the liver. Approximately one-sixth of the NAFLD population progresses to non-alcoholic steatohepatitis (NASH) with liver inflammation, hepatocyte injury and cell death, liver fibrosis and cirrhosis. NASH is one of the leading causes of liver transplant, and an increasingly common cause of hepatocellular carcinoma (HCC), underscoring the need for intervention. The complex pathophysiology of NASH, and a predicted prevalence of 3-5% of the adult population worldwide, has prompted drug development programs aimed at multiple targets across all stages of the disease. Currently, there are no approved therapeutics. Liver-related morbidity and mortality are highest in more advanced fibrotic NASH, which has led to an early focus on anti-fibrotic approaches to prevent progression to cirrhosis and HCC. Due to limited clinical efficacy, anti-fibrotic approaches have been superseded by mechanisms that target the underlying driver of NASH pathogenesis, namely steatosis, which drives hepatocyte injury and downstream inflammation and fibrosis. Among this wave of therapeutic mechanisms targeting the underlying pathogenesis of NASH, the hormone fibroblast growth factor 21 (FGF21) holds considerable promise; it decreases liver fat and hepatocyte injury while suppressing inflammation and fibrosis across multiple preclinical studies. In this review, we summarize preclinical and clinical data from studies with FGF21 and FGF21 analogs, in the context of the pathophysiology of NASH and underlying metabolic diseases.
Collapse
|
|
48
|
Zhang J, Zhao Y, Ren D, Yang X. Effect of okra fruit powder supplementation on metabolic syndrome and gut microbiota diversity in high fat diet-induced obese mice. Food Res Int 2019; 130:108929. [PMID: 32156377 DOI: 10.1016/j.foodres.2019.108929] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 11/29/2019] [Accepted: 12/17/2019] [Indexed: 02/08/2023]
Abstract
This study aimed to explore a novel strategy for dietary okra fruit powder (OFP) consumption on attenuation of non-alcohol fatty liver damage, lipid metabolic disorder and gut microbiota dysbiosis and associated mechanisms in high-fat diet (HFD)-induced obese mice. C57BL/6J mice were fed a normal diet and HFD feeds supplemented with or without OFP (2.5%, 5% and 10%, n = 10) for 12 weeks. The results showed that supplementation of OFP caused strong inhibition on HFD-caused high blood glucose, body weight gain and liver fat accumulation, as well as dyslipidemia involved in a dose-dependent modulation of hepatic FAS and CD36 expressions of obese mice. The hepatic LXR-α energy metabolism and PPAR-α pathway were also doubly activated by OFP to alleviate lipogenesis, obesity and metabolic syndrome. Malonaldehyde production was effectively antagonized, and glutathione peroxidase and superoxide dismutase activities were elevated by OFP supplementation in HFD-fed mice. OFP also significantly improved colonic SCFAs (acetic acid, propionic acid and butyrate acid) formation, especially for butyrate production via increasing the proportion of selected butyrate-producing bacteria. OFP also dramatically modified the gut microbial species at the family level with suppressing an increase in Proteobacteria, Actinobacteria and F/B ratio, and the decrease in Bacteroidetes caused by HFD. These findings support that dietary OFP consumption is a novel strategy to prevent obesity, metabolic syndrome and gut microbiota imbalance.
Collapse
Affiliation(s)
- Jin Zhang
- Key Laboratory of Ministry of Education for Medicinal Resource and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, Xi'an 710062, China
| | - Yan Zhao
- Key Laboratory of Ministry of Education for Medicinal Resource and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, Xi'an 710062, China.
| | - Daoyuan Ren
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, and Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710062, China
| | - Xingbin Yang
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, and Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710062, China.
| |
Collapse
|
|
49
|
Nonalcoholic Fatty Liver Disease: A Challenge from Mechanisms to Therapy. J Clin Med 2019; 9:jcm9010015. [PMID: 31861591 PMCID: PMC7019297 DOI: 10.3390/jcm9010015] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 12/05/2019] [Accepted: 12/16/2019] [Indexed: 12/11/2022] Open
Abstract
Focusing on previously published mechanisms of non-alcoholic fatty liver disease (NAFLD), their uncertainty does not always permit a clear elucidation of the grassroot alterations that are at the basis of the wide-spread illness, and thus curing it is still a challenge. There is somehow exceptional progress, but many controversies persist in NAFLD research and clinical investigation. It is likely that hidden mechanisms will be brought to light in the near future. Hereby, the authors present, with some criticism, classical mechanisms that stand at the basis of NAFLD, and consider contextually different emerging processes. Without ascertaining these complex interactions, investigators have a long way left ahead before finding an effective therapy for NAFLD beyond diet and exercise.
Collapse
|
|
50
|
|