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Herrera-Marcos LV, Martínez-Beamonte R, Arnal C, Barranquero C, Puente-Lanzarote JJ, Lou-Bonafonte JM, Gonzalo-Romeo G, Mocciaro G, Jenkins B, Surra JC, Rodríguez-Yoldi MJ, Alastrué-Vera V, Letosa J, García-Gil A, Güemes A, Koulman A, Osada J. Lipidomic signatures discriminate subtle hepatic changes in the progression of porcine nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2024; 326:G411-G425. [PMID: 38375587 DOI: 10.1152/ajpgi.00264.2023] [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: 11/13/2023] [Revised: 02/05/2024] [Accepted: 02/11/2024] [Indexed: 02/21/2024]
Abstract
Recently, the development of nonalcoholic steatohepatitis (NASH) in common strains of pigs has been achieved using a diet high in saturated fat, fructose, cholesterol, and cholate and deficient in choline and methionine. The aim of the present work was to characterize the hepatic and plasma lipidomic changes that accompany the progression of NASH and its reversal by switching pigs back to a chow diet. One month of this extreme steatotic diet was sufficient to induce porcine NASH. The lipidomic platform using liquid chromatography-mass spectrometry analyzed 467 lipid species. Seven hepatic phospholipids [PC(30:0), PC(32:0), PC(33:0), PC(33:1), PC(34:0), PC(34:3) and PC(36:2)] significantly discriminated the time of dietary exposure, and PC(30:0), PC(33:0), PC(33:1) and PC(34:0) showed rapid adaptation in the reversion period. Three transcripts (CS, MAT1A, and SPP1) showed significant changes associated with hepatic triglycerides and PC(33:0). Plasma lipidomics revealed that these species [FA 16:0, FA 18:0, LPC(17:1), PA(40:5), PC(37:1), TG(45:0), TG(47:2) and TG(51:0)] were able to discriminate the time of dietary exposure. Among them, FA 16:0, FA 18:0, LPC(17:1) and PA(40:5) changed the trend in the reversion phase. Plasma LDL-cholesterol and IL12P40 were good parameters to study the progression of NASH, but their capacity was surpassed by hepatic [PC(33:0), PC(33:1), and PC(34:0)] or plasma lipid [FA 16:0, FA 18:0, and LPC(17:1)] species. Taken together, these lipid species can be used as biomarkers of metabolic changes in the progression and regression of NASH in this model. The lipid changes suggest that the development of NASH also affects peripheral lipid metabolism.NEW & NOTEWORTHY A NASH stage was obtained in crossbred pigs. Hepatic [PC(33:0), PC(33:1) and PC(34:0)] or plasma [FA 16:0, FA 18:0 and LPC(17:1)] species were sensitive parameters to detect subtle changes in development and regression of nonalcoholic steatohepatitis (NASH). These findings may delineate the liquid biopsy to detect subtle changes in progression or in treatments. Furthermore, phospholipid changes according to the insult-inducing NASH may play an important role in accepting or rejecting fatty livers in transplantation.
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Affiliation(s)
- Luis V Herrera-Marcos
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain
| | - Roberto Martínez-Beamonte
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Carmen Arnal
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain
- Departamento de Patología Animal, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Cristina Barranquero
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Juan J Puente-Lanzarote
- Servicio de Bioquímica Clínica, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - José M Lou-Bonafonte
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain
- Departamento de Farmacología, Fisiología, Medicina Legal y Forense, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Gonzalo Gonzalo-Romeo
- Servicio General de Apoyo a la Investigación, División de Experimentación Animal, Universidad de Zaragoza, Zaragoza, Spain
| | - Gabriele Mocciaro
- Core Metabolomics and Lipidomics Laboratory, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Benjamin Jenkins
- Core Metabolomics and Lipidomics Laboratory, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Joaquín C Surra
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain
- Departamento de Producción Animal y Ciencia de los Alimentos, Escuela Politécnica Superior de Huesca, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Huesca, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - María J Rodríguez-Yoldi
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain
- Departamento de Farmacología, Fisiología, Medicina Legal y Forense, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | | | - Jesús Letosa
- Industrial Zootécnica Aragonesa S.L. (INZAR, S.L.), Zaragoza, Spain
| | - Agustín García-Gil
- Departamento de Cirugía, Facultad de Medicina, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain
| | - Antonio Güemes
- Departamento de Cirugía, Facultad de Medicina, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain
| | - Albert Koulman
- Core Metabolomics and Lipidomics Laboratory, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Jesús Osada
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
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Askar ME, Ali SI, Younis NN, Shaheen MA, Zaher ME. Raspberry ketone ameliorates nonalcoholic fatty liver disease in rats by activating the AMPK pathway. Eur J Pharmacol 2023; 957:176001. [PMID: 37598925 DOI: 10.1016/j.ejphar.2023.176001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 08/08/2023] [Accepted: 08/17/2023] [Indexed: 08/22/2023]
Abstract
The current study aimed to investigate the effect of orally administered raspberry ketone (RK) on ameliorating nonalcoholic fatty liver disease (NAFLD) induced in rats by high-fat high-fructose diet (HFFD) in comparison to calorie restriction (CR) regimen. Thirty male Wistar rats were divided into two experimental groups; one was fed normal chow diet (NCD, n = 6) for 15 weeks to serve as normal control group and the other group was fed HFFD (n = 24) for 7 weeks to induce NAFLD. After induction, rats in the HFFD group were randomly allocated into four groups (n = 6 rats each). One group continued on HFFD feeding for 8 weeks (NAFLD control group). The remaining 3 groups received NCD, calorie-restricted diet, or NCD along with RK (55 mg/kg/day, orally) for 8 weeks. Like CR, RK effectively attenuated NAFLD and ameliorated the changes attained by HFFD. RK upregulated the expression of the phosphorylated AMP-activated protein kinase (P-AMPK) and fatty acid oxidation factors; peroxisome proliferator-activated receptor alpha (PPAR-α) and carnitine palmitoyltransferase-1 (CPT-1) and downregulated lipogenic factors; sterol regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) in the hepatic tissue. Also, RK improved lipid profile parameters, liver enzymes and both body and liver tissue weights. Altogether, these findings suggest that oral administration of RK, along with normal diet, ameliorated NAFLD in a way similar to CR. This approach could be an alternative to CR in the management of NAFLD, overcoming the poor compliance to long term CR regimen.
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Affiliation(s)
- Mervat E Askar
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, 44519, Egypt
| | - Sousou I Ali
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, 44519, Egypt
| | - Nahla N Younis
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, 44519, Egypt.
| | - Mohamed A Shaheen
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Zagazig University, 44519, Egypt
| | - Mahmoud E Zaher
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, 44519, Egypt
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Herrera-Marcos LV, Martínez-Beamonte R, Arnal C, Barranquero C, Puente-Lanzarote JJ, Herrero-Continente T, Lou-Bonafonte JM, Gonzalo-Romeo G, Mocciaro G, Jenkins B, Surra JC, Rodríguez-Yoldi MJ, Burillo JC, Lasheras R, García-Gil A, Güemes A, Koulman A, Osada J. Dietary squalene supplementation decreases triglyceride species and modifies phospholipid lipidomic profile in the liver of a porcine model of non-alcoholic steatohepatitis. J Nutr Biochem 2023; 112:109207. [PMID: 36402249 DOI: 10.1016/j.jnutbio.2022.109207] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 09/07/2022] [Accepted: 11/03/2022] [Indexed: 11/19/2022]
Abstract
Squalene is a key minor component of virgin olive oil, the main source of fat in the Mediterranean diet, and had shown to improve the liver metabolism in rabbits and mice. The present research was carried out to find out whether this effect was conserved in a porcine model of hepatic steatohepatitis and to search for the lipidomic changes involved. The current study revealed that a 0.5% squalene supplementation to a steatotic diet for a month led to hepatic accumulation of squalene and decreased triglyceride content as well as area of hepatic lipid droplets without influencing cholesterol content or fiber areas. However, ballooning score was increased and associated with the hepatic squalene content. Of forty hepatic transcripts related to lipid metabolism and hepatic steatosis, only citrate synthase and a non-coding RNA showed decreased expressions. The hepatic lipidome, assessed by liquid chromatography-mass spectrometry in a platform able to analyze 467 lipids, revealed that squalene supplementation increased ceramide, Cer(36:2), and phosphatidylcholine (PC[32:0], PC[33:0] and PC[34:0]) species and decreased cardiolipin, CL(69:5), and triglyceride (TG[54:2], TG[55:0] and TG[55:2]) species. Plasma levels of interleukin 12p40 increased in pigs receiving the squalene diet. The latter also modified plasma lipidome by increasing TG(58:12) and decreasing non-esterified fatty acid (FA 14:0, FA 16:1 and FA 18:0) species without changes in total NEFA levels. Together this shows that squalene-induced changes in hepatic and plasma lipidomic profiles, non-coding RNA and anti-inflammatory interleukin are suggestive of an alleviation of the disease despite the increase in the ballooning score.
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Affiliation(s)
- Luis V Herrera-Marcos
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain; Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain
| | - Roberto Martínez-Beamonte
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain; Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Spain
| | - Carmen Arnal
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain; Departamento de Patología Animal, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Spain
| | - Cristina Barranquero
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain; Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Spain
| | - Juan J Puente-Lanzarote
- Servicio de Bioquímica Clínica. Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - Tania Herrero-Continente
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain
| | - José M Lou-Bonafonte
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain; Departamento de Farmacología, Fisiología, Medicina Legal y Forense, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Spain
| | - Gonzalo Gonzalo-Romeo
- Servicio General de Apoyo a la Investigación. División de Experimentación Animal, Universidad de Zaragoza, Zaragoza, Spain
| | - Gabriele Mocciaro
- NIHR BRC Core Metabolomics and Lipidomics Laboratory, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Benjamin Jenkins
- NIHR BRC Core Metabolomics and Lipidomics Laboratory, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Joaquín C Surra
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain; Departamento de Producción Animal y Ciencia de los Alimentos, Escuela Politécnica Superior de Huesca, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Huesca, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Spain
| | - María J Rodríguez-Yoldi
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain; Departamento de Farmacología, Fisiología, Medicina Legal y Forense, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Spain
| | - Juan Carlos Burillo
- Laboratorio Agroambiental, Servicio de Seguridad Agroalimentaria de la Dirección General de Alimentación y Fomento Agroalimentario, Zaragoza, Spain
| | - Roberto Lasheras
- Laboratorio Agroambiental, Servicio de Seguridad Agroalimentaria de la Dirección General de Alimentación y Fomento Agroalimentario, Zaragoza, Spain
| | - Agustín García-Gil
- Departamento de Cirugía, Facultad de Medicina, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain
| | - Antonio Güemes
- Departamento de Cirugía, Facultad de Medicina, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain
| | - Albert Koulman
- NIHR BRC Core Metabolomics and Lipidomics Laboratory, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Jesús Osada
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain; Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Spain.
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Herrera-Marcos LV, Martínez-Beamonte R, Macías-Herranz M, Arnal C, Barranquero C, Puente-Lanzarote JJ, Gascón S, Herrero-Continente T, Gonzalo-Romeo G, Alastrué-Vera V, Gutiérrez-Blázquez D, Lou-Bonafonte JM, Surra JC, Rodríguez-Yoldi MJ, García-Gil A, Güemes A, Osada J. Hepatic galectin-3 is associated with lipid droplet area in non-alcoholic steatohepatitis in a new swine model. Sci Rep 2022; 12:1024. [PMID: 35046474 PMCID: PMC8770509 DOI: 10.1038/s41598-022-04971-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 12/29/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently a growing epidemic disease that can lead to cirrhosis and hepatic cancer when it evolves into non-alcoholic steatohepatitis (NASH), a gap not well understood. To characterize this disease, pigs, considered to be one of the most similar to human experimental animal models, were used. To date, all swine-based settings have been carried out using rare predisposed breeds or long-term experiments. Herein, we fully describe a new experimental swine model for initial and reversible NASH using cross-bred animals fed on a high saturated fat, fructose, cholesterol, cholate, choline and methionine-deficient diet. To gain insight into the hepatic transcriptome that undergoes steatosis and steatohepatitis, we used RNA sequencing. This process significantly up-regulated 976 and down-regulated 209 genes mainly involved in cellular processes. Gene expression changes of 22 selected transcripts were verified by RT-qPCR. Lipid droplet area was positively associated with CD68, GPNMB, LGALS3, SLC51B and SPP1, and negatively with SQLE expressions. When these genes were tested in a second experiment of NASH reversion, LGALS3, SLC51B and SPP1 significantly decreased their expression. However, only LGALS3 was associated with lipid droplet areas. Our results suggest a role for LGALS3 in the transition of NAFLD to NASH.
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Affiliation(s)
- Luis V Herrera-Marcos
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Miguel Servet, 177, 50013, Zaragoza, Spain.,Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain
| | - Roberto Martínez-Beamonte
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Miguel Servet, 177, 50013, Zaragoza, Spain.,Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain.,CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Manuel Macías-Herranz
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Miguel Servet, 177, 50013, Zaragoza, Spain
| | - Carmen Arnal
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain.,Departamento de Patología Animal, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain.,CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Cristina Barranquero
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Miguel Servet, 177, 50013, Zaragoza, Spain.,Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain.,CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Juan J Puente-Lanzarote
- Servicio de Bioquímica Clínica. Hospital, Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - Sonia Gascón
- Departamento de Farmacología, Fisiología, Medicina Legal y Forense, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain.,CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Tania Herrero-Continente
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Miguel Servet, 177, 50013, Zaragoza, Spain
| | - Gonzalo Gonzalo-Romeo
- Servicio General de Apoyo a la Investigación. División de Experimentación Animal, Universidad de Zaragoza, Zaragoza, Spain
| | | | | | - José M Lou-Bonafonte
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain.,Departamento de Farmacología, Fisiología, Medicina Legal y Forense, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain.,CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Joaquín C Surra
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain.,Departamento de Producción Animal y Ciencia de los Alimentos, Escuela Politécnica Superior de Huesca, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Huesca, Spain.,CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - María J Rodríguez-Yoldi
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain.,Departamento de Farmacología, Fisiología, Medicina Legal y Forense, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain.,CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Agustín García-Gil
- Departamento de Cirugía, Facultad de Medicina, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain
| | - Antonio Güemes
- Departamento de Cirugía, Facultad de Medicina, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain
| | - Jesús Osada
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Miguel Servet, 177, 50013, Zaragoza, Spain. .,Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain. .,CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.
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Hepatic Synaptotagmin 1 is involved in the remodelling of liver plasma- membrane lipid composition and gene expression in male Apoe-deficient mice consuming a Western diet. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158790. [PMID: 32771460 DOI: 10.1016/j.bbalip.2020.158790] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 07/28/2020] [Accepted: 08/02/2020] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND AIMS The molecular mechanisms by which the liver develops steatotic disease still remain unclear. Previous studies using nutritional and genetic models of hepatic steatosis in mice showed that liver synaptotagmin 1 (Syt1) expression was associated with lipid droplet area. Hepatic Syt1 overexpression was used as a tool to explore its effect on hepatic and plasma lipids. METHODS AND RESULTS To find out a cause-effect, hepatic mouse Syt1 mRNA was cloned into a vector driving hepatocyte-specific expression and administered by hydrodynamic injection to male Apoe-deficient mice fed on a Western diet, the latter as a model of rapid spontaneous steatosis development. Hepatic microsomal, large vesicle, lysosomal and plasma membrane fractions were enriched in SYT1 protein following gene overexpression. In these conditions, very low density lipoprotein esterified cholesterol increased. Likewise, the transgene caused an alteration in lipid droplet surface and a positive correlation between Syt1 expression and hepatic total cholesterol content. A lipidomic approach evidenced a decrease in lysophosphatidylcholine, phosphatidylcholine and triglycerides in isolated plasma membrane fraction. Expressions of genes involved in biosynthesis of bile acids, fatty acid metabolism, lipoprotein dynamics and vesicular transport were modified by the increased SYT1 expression. CONCLUSIONS These results indicate that this protein is involved in hepatic management of lipids and in the regulation of genes involved in lipid metabolism.
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Catalpol Attenuates Hepatic Steatosis by Regulating Lipid Metabolism via AMP-Activated Protein Kinase Activation. BIOMED RESEARCH INTERNATIONAL 2020; 2020:6708061. [PMID: 32420361 PMCID: PMC7201822 DOI: 10.1155/2020/6708061] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 03/12/2020] [Accepted: 04/04/2020] [Indexed: 12/18/2022]
Abstract
The increased prevalence of nonalcoholic fatty liver disease (NAFLD), which develops from hepatic steatosis, represents a public health challenge. Catalpol, a natural component extracted from the roots of Radix Rehmanniae, has several pharmacological activities. The present study is aimed at examining whether catalpol prevents hepatic steatosis in cell and animal experiments and elucidating the possible mechanisms. HepG2 cells were treated with 300 μM palmitate (PA) and/or catalpol for 24 h in vitro, and male C57BL/6J mice fed a high-fat diet (HFD) were administered catalpol for 18 weeks in vivo. The results revealed that catalpol significantly decreased lipid accumulation in PA-treated HepG2 cells. Moreover, catalpol drastically reduced body weight and lipid accumulation in the liver, whereas it ameliorated hepatocyte steatosis in HFD-fed mice. Notably, catalpol remarkably promoted the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase. Subsequently, catalpol repressed the expressions of lipogenesis-associated genes such as sterol regulatory element-binding protein 1c and fatty acid synthase but promoted the expressions of genes associated with fatty acid β-oxidation such as peroxisome proliferator-activated receptor α together with its target genes carnitine palmitoyltransferase 1 and acyl-CoA oxidase 1 (ACOX1). However, the preincubation of the HepG2 cells with compound C (10 μM), an AMPK inhibitor, prevented catalpol-mediated beneficial effects. These findings suggest that catalpol ameliorates hepatic steatosis by suppressing lipogenesis and enhancing fatty acid β-oxidation in an AMPK-dependent manner. Therefore, catalpol has potential as a novel agent in the treatment of NAFLD.
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Zhang X, Xie X, Heckmann BL, Saarinen AM, Gu H, Zechner R, Liu J. Identification of an intrinsic lysophosphatidic acid acyltransferase activity in the lipolytic inhibitor G 0/G 1 switch gene 2 (G0S2). FASEB J 2019; 33:6655-6666. [PMID: 30802154 PMCID: PMC6463910 DOI: 10.1096/fj.201802502r] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 01/28/2019] [Indexed: 12/16/2022]
Abstract
G0/G1 switch gene 2 (G0S2) is a specific inhibitor of adipose triglyceride lipase (ATGL), the rate-limiting enzyme for intracellular lipolysis. Recent studies show that G0S2 plays a critical role in promoting triacylglycerol (TG) accumulation in the liver, and its encoding gene is a direct target of a major lipogenic transcription factor liver X receptor (LXR)α. Here we sought to investigate a lipolysis-independent role of G0S2 in hepatic triglyceride synthesis. Knockdown of G0S2 decreased hepatic TG content in mice with ATGL ablation. Conversely, overexpression of G0S2 promoted fatty acid incorporation into TGs and diacylglycerols in both wild-type and ATGL-deficient hepatocytes. Biochemical characterization showed that G0S2 mediates phosphatidic acid synthesis from lysophosphatidic acid (LPA) and acyl-coenzyme A. In response to a high-sucrose lipogenic diet, G0S2 is up-regulated via LXRα and required for the increased TG accumulation in liver. Furthermore, deletion of a distinct 4-aa motif necessary for the LPA-specific acyltransferase (LPAAT) activity impaired G0S2's ability to mediate TG synthesis both in vitro and in vivo. These studies identify G0S2 as a dual-function regulator of lipid metabolism as well as a novel mechanism whereby hepatic TG storage is promoted in response to lipogenic stimulation. In addition to its role as a lipolytic inhibitor, G0S2 is capable of directly promoting TG synthesis by acting as a lipid-synthesizing enzyme.-Zhang, X., Xie, X., Heckmann, B. L., Saarinen, A. M., Gu, H., Zechner, R., Liu, J. Identification of an intrinsic lysophosphatidic acid acyltransferase activity in the lipolytic inhibitor G0/G1 switch gene 2 (G0S2).
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Affiliation(s)
- Xiaodong Zhang
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Xitao Xie
- Department of Chemical Engineering, Arizona State University, Tempe, Arizona, USA
| | - Bradlee L. Heckmann
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Alicia M. Saarinen
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Haiwei Gu
- Center for Metabolic and Vascular Biology, College of Health Solutions, Arizona State University, Scottsdale, Arizona, USA
| | - Rudolf Zechner
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Jun Liu
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
- Division of Endocrinology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
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The Crosstalk between Fat Homeostasis and Liver Regional Immunity in NAFLD. J Immunol Res 2019; 2019:3954890. [PMID: 30719457 PMCID: PMC6335683 DOI: 10.1155/2019/3954890] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Revised: 11/11/2018] [Accepted: 12/09/2018] [Indexed: 12/14/2022] Open
Abstract
The liver is well known as the center of glucose and lipid metabolism in the human body. It also functions as an immune organ. Previous studies have suggested that liver nonparenchymal cells are crucial in the progression of NAFLD. In recent years, NAFLD's threat to human health has been becoming a global issue. And by far, there is no effective treatment for NAFLD. Liver nonparenchymal cells are stimulated by lipid antigens, adipokines, or other factors, and secreted immune factors can alter the expression of key proteins such as SREBP-1c, ChREBP, and PPARγ to regulate lipid metabolism, thus affecting the pathological process of NAFLD. Interestingly, some ncRNAs (including miRNAs and lncRNAs) participate in the pathological process of NAFLD by changing body fat homeostasis. And even some ncRNAs could regulate the activity of HSCs, thereby affecting the progression of inflammation and fibrosis in the course of NAFLD. In conclusion, immunotherapy could be an effective way to treat NAFLD.
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Jiang GZ, Zhou M, Zhang DD, Li XF, Liu WB. The mechanism of action of a fat regulator: Glycyrrhetinic acid (GA) stimulating fatty acid transmembrane and intracellular transport in blunt snout bream (Megalobrama amblycephala). Comp Biochem Physiol A Mol Integr Physiol 2018; 226:83-90. [PMID: 30193864 DOI: 10.1016/j.cbpa.2018.08.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 08/16/2018] [Accepted: 08/27/2018] [Indexed: 02/07/2023]
Abstract
High-fat diets are associated with fatty liver and aberrant hepatic lipid metabolism, and glycyrrhetinic acid (GA) has been shown to exert a beneficial effect on lipolysis and fat deposition in fish. In the present study, we evaluated the effect of GA on the growth performance and expression of hepatic lipid transport related genes in blunt snout bream (Megalobrama amblycephala) fed a high fat diet. Two hundred and sixteen fish (average body weight: 45.57 g ± 0.98 g) were fed three experimental diets (6% fat/L6 group, control, 11% fat/L11 group, and 11% fat with 0.3 mg kg-1 GA/L11GA group) for 8 weeks. Compared to the control group, the weight gain and specific growth rate of high-fat fed group at the end of the trialwere significantly improved (P < .05).However, GA showed no effect on animals' growth performance(P > .05). Dietary supplementation with 0.3 mg kg-1 GA significantly decreased the hepatosomatic index, viscera/body ratio, and intraperitoneal fat ratio (P < .05), and up-regulated the expression levels of fatty acids transport protein (FATP), fatty acids binding protein (FABP), fatty acid translocase (CD36), carnitine palmitoyl transferase I (CPT1) and peroxisome proliferators-activated receptors α (PPARα) compared to both the L6 group and L11 group (P < .05). However, no significant difference was observed in fatty acid synthetase (FAS), acetyl-CoA carboxylase α (ACCα), or lipoprotein lipase (LPL) between groups (P > .05). In conclusion, GA significantly rescued high-fat diet induced hepatic lipid accumulation and metabolism dysfunction in M. amblycephalaby stimulating hepatic fatty acid transport and β-oxidation. Dietary GA may be used as a promising supplement to alleviate high-fat diet induced side effects on M. amblycephala.
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Affiliation(s)
- Guang-Zhen Jiang
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No.1 Weigang Road, Nanjing 210095, People's Republic of China
| | - Man Zhou
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No.1 Weigang Road, Nanjing 210095, People's Republic of China
| | - Ding-Dong Zhang
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No.1 Weigang Road, Nanjing 210095, People's Republic of China
| | - Xiang-Fei Li
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No.1 Weigang Road, Nanjing 210095, People's Republic of China
| | - Wen-Bin Liu
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No.1 Weigang Road, Nanjing 210095, People's Republic of China.
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10
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Hepatic subcellular distribution of squalene changes according to the experimental setting. J Physiol Biochem 2018; 74:531-538. [DOI: 10.1007/s13105-018-0616-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 02/14/2018] [Indexed: 02/07/2023]
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11
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Chen CC, Lee TY, Kwok CF, Hsu YP, Shih KC, Lin YJ, Ho LT. Using proteomics to discover novel biomarkers for fatty liver development and response to CB1R antagonist treatment in an obese mouse model. Proteomics 2017; 17. [DOI: 10.1002/pmic.201600292] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 11/23/2016] [Accepted: 11/25/2016] [Indexed: 12/12/2022]
Affiliation(s)
- Chin-Chang Chen
- Institute of Physiology; National Yang-Ming University; Taipei Taiwan
- Graduate Institute of Traditional Chinese Medicine; Chang Gung University; Taoyuan Taiwan
| | - Tzung-Yan Lee
- Graduate Institute of Traditional Chinese Medicine; Chang Gung University; Taoyuan Taiwan
| | - Ching-Fai Kwok
- Division of Endocrinology and Metabolism; Department of Medicine; Taipei Veterans General Hospital; Taipei Taiwan
| | - Yung-Pei Hsu
- Department of Medical Research; Taipei Veterans General Hospital; Taipei Taiwan
| | - Kuang-Chung Shih
- Department of Medicine-Metabolism; Cheng Hsin General Hospital; Taipei Taiwan
| | - Yan-Jie Lin
- Department of Research Planning and Development; National Health Research Institutes; Miaoli Taiwan
| | - Low-Tone Ho
- Institute of Physiology; National Yang-Ming University; Taipei Taiwan
- Division of Endocrinology and Metabolism; Department of Medicine; Taipei Veterans General Hospital; Taipei Taiwan
- Department of Medical Research; Taipei Veterans General Hospital; Taipei Taiwan
- School of Medicine; National Yang-Ming University; Taipei Taiwan
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12
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Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver. Sci Rep 2015; 5:12911. [PMID: 26246194 PMCID: PMC4526858 DOI: 10.1038/srep12911] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 07/09/2015] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) are important regulators and potential therapeutic targets of metabolic disease. In this study we show by in vivo administration of locked nucleic acid (LNA) inhibitors that suppression of endogenous miR-29 lowers plasma cholesterol levels by ~40%, commensurate with the effect of statins, and reduces fatty acid content in the liver by ~20%. Whole transcriptome sequencing of the liver reveals 883 genes dysregulated (612 down, 271 up) by inhibition of miR-29. The set of 612 down-regulated genes are most significantly over-represented in lipid synthesis pathways. Among the up-regulated genes are the anti-lipogenic deacetylase sirtuin 1 (Sirt1) and the anti-lipogenic transcription factor aryl hydrocarbon receptor (Ahr), the latter of which we demonstrate is a direct target of miR-29. In vitro radiolabeled acetate incorporation assays confirm that pharmacologic inhibition of miR-29 significantly reduces de novo cholesterol and fatty acid synthesis. Our findings indicate that miR-29 controls hepatic lipogenic programs, likely in part through regulation of Ahr and Sirt1, and therefore may represent a candidate therapeutic target for metabolic disorders such as dyslipidemia.
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Zhang D, Lu K, Jiang G, Liu W, Dong Z, Tian H, Li X. A global transcriptional analysis of Megalobrama amblycephala revealing the molecular determinants of diet-induced hepatic steatosis. Gene 2015; 570:255-63. [PMID: 26074088 DOI: 10.1016/j.gene.2015.06.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Revised: 03/19/2015] [Accepted: 06/09/2015] [Indexed: 02/07/2023]
Abstract
Blunt snout bream (Megalobrama amblycephala), a prevalent species in China's intensive polyculture systems, is highly susceptible to hepatic steatosis, resulting in considerable losses to the fish farming industry. Due to a lack of genomic resources, the molecular mechanisms of lipid metabolism in M. amblycephala are poorly understood. Here, a hepatic cDNA library was generated from equal amounts of mRNAs isolated from M. amblycephala fed normal-fat and high-fat diets. Sequencing of this library using the Illumina/Solexa platform produced approximately 51.87 million clean reads, which were assembled into 48,439 unigenes with an average length of 596 bp and an N50 value of 800 bp. These unigenes were searched against the nucleotide (NT), non-redundant (NR), Swiss-Prot, Cluster of Orthologous Groups (COG), and Kyoto Encyclopedia of Genes and Genome (KEGG) databases using the BLASTn or BLASTx algorithms (E-value ≤ 10(-5)). A total of 8602 unigenes and 22,155 unigenes were functionally classified into 25 COG categories and 259 KEGG pathways, respectively. Furthermore, 22,072 unigenes were grouped into 62 sub-categories belonging to three main Gene Ontology (GO) terms. Using a digital gene expression analysis and the M. amblycephala transcriptome as a reference, 477 genes (134 up-regulated and 343 down-regulated) were identified as differentially expressed in fish fed a high-fat diet versus a normal-fat diet. KEGG and GO functional enrichment analyses of the differentially expressed unigenes were performed and 12 candidate genes related to lipid metabolism were identified. This study provides a global survey of hepatic transcriptome profiles and identifies candidate genes that may be related to lipid metabolism in M. amblycephala. These findings will facilitate further investigations of the mechanisms underlying hepatic steatosis in M. amblycephala.
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Affiliation(s)
- Dingdong Zhang
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Kangle Lu
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Guangzhen Jiang
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Wenbin Liu
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
| | - Zaijie Dong
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China.
| | - Hongyan Tian
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Xiangfei Li
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
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Pazienza V, Borghesan M, Mazza T, Sheedfar F, Panebianco C, Williams R, Mazzoccoli G, Andriulli A, Nakanishi T, Vinciguerra M. SIRT1-metabolite binding histone macroH2A1.1 protects hepatocytes against lipid accumulation. Aging (Albany NY) 2014; 6:35-47. [PMID: 24473773 PMCID: PMC3927808 DOI: 10.18632/aging.100632] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Non-alcoholic-fatty-liver-disease (NAFLD) encompasses conditions associated to fat deposition in the liver, which are generally deteriorated during the aging process. MacroH2A1, a variant of histone H2A, is a key transcriptional regulator involved in tumorigenic processes and cell senescence, and featuring two alternatively splicing isoforms, macroH2A1.1 and macroH2A1.2. MacroH2A1.1 binds with high affinity O-acetyl ADP ribose, a small metabolite produced by the reaction catalysed by NAD+-dependent deacetylase SIRT1, whereas macroH2A1.2 is unable to do so. The functional significance of this binding is unknown. We previously reported that the hepatic levels of macroH2A1.1 and macroH2A1.2 are differentially expressed in mice models of NAFLD. Here we show that over-expression of macroH2A1.1, but not of macroH2A1.2, is able to protect hepatocytes against lipid accumulation. MacroH2A1.1 over-expressing cells display ameliorated glucose metabolism, reduced expression of lipidogenic genes and fatty acids content. SIRT1/macroH2A1.1-dependent epigenetic regulation of lipid metabolism may be relevant to NAFLD development.
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Affiliation(s)
- Valerio Pazienza
- Department of Medical Sciences, Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy
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Ferramosca A, Zara V. Modulation of hepatic steatosis by dietary fatty acids. World J Gastroenterol 2014; 20:1746-1755. [PMID: 24587652 PMCID: PMC3930973 DOI: 10.3748/wjg.v20.i7.1746] [Citation(s) in RCA: 135] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Revised: 10/03/2013] [Accepted: 11/05/2013] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) describes a range of conditions caused by fat deposition within liver cells. Liver fat content reflects the equilibrium between several metabolic pathways involved in triglyceride synthesis and disposal, such as lipolysis in adipose tissue and de novo lipogenesis, triglyceride esterification, fatty acid oxidation and very-low-density lipoprotein synthesis/secretion in hepatic tissue. In particular, it has been demonstrated that hepatic de novo lipogenesis plays a significant role in NAFLD pathogenesis. It is widely known that the fatty acid composition of the diet influences hepatic lipogenesis along with other metabolic pathways. Therefore, dietary fat may not only be involved in the pathogenesis of hepatic steatosis, but may also prevent and/or reverse hepatic fat accumulation. In this review, major data from the literature about the role of some dietary fats as a potential cause of hepatic fat accumulation or as a potential treatment for NAFLD are described. Moreover, biochemical mechanisms responsible for an increase or decrease in hepatic lipid content are critically analyzed. It is noteworthy that both quantitative and qualitative aspects of dietary fat influence triglyceride deposition in the liver. A high-fat diet or the dietary administration of conjugated linoleic acids induced hepatic steatosis. In contrast, supplementation of the diet with krill oil or pine nut oil helped in the prevention and/or in the treatment of steatotic liver. Quite interesting is the “case” of olive oil, since several studies have often provided different and⁄or conflicting results in animal models.
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Rappa F, Greco A, Podrini C, Cappello F, Foti M, Bourgoin L, Peyrou M, Marino A, Scibetta N, Williams R, Mazzoccoli G, Federici M, Pazienza V, Vinciguerra M. Immunopositivity for histone macroH2A1 isoforms marks steatosis-associated hepatocellular carcinoma. PLoS One 2013; 8:e54458. [PMID: 23372727 PMCID: PMC3553099 DOI: 10.1371/journal.pone.0054458] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Accepted: 12/11/2012] [Indexed: 02/07/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Prevention and risk reduction are important and the identification of specific biomarkers for early diagnosis of HCC represents an active field of research. Increasing evidence indicates that fat accumulation in the liver, defined as hepatosteatosis, is an independent and strong risk factor for developing an HCC. MacroH2A1, a histone protein generally associated with the repressed regions of chromosomes, is involved in hepatic lipid metabolism and is present in two alternative spliced isoforms, macroH2A1.1 and macroH2A1.2. These isoforms have been shown to predict lung and colon cancer recurrence but to our knowledge, their role in fatty-liver associated HCC has not been investigated previously. Methods We examined macroH2A1.1 and macroH2A1.2 protein expression levels in the liver of two murine models of fat-associated HCC, the high fat diet/diethylnistrosamine (DEN) and the phosphatase and tensin homolog (PTEN) liver specific knock-out (KO) mouse, and in human liver samples of subjects with steatosis or HCC, using immunoblotting and immunohistochemistry. Results Protein levels for both macroH2A1 isoforms were massively upregulated in HCC, whereas macroH2A1.2 was specifically upregulated in steatosis. In addition, examination of human liver samples showed a significant difference (p<0.01) in number of positive nuclei in HCC (100% of tumor cells positive for either macroH2A1.1 or macroH2A1.2), when compared to steatosis (<2% of hepatocytes positive for either isoform). The steatotic areas flanking the tumors were highly immunopositive for macroH2A1.1 and macroH2A1.2. Conclusions These data obtained in mice and humans suggest that both macroH2A1 isoforms may play a role in HCC pathogenesis and moreover may be considered as novel diagnostic markers for human HCC.
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Affiliation(s)
- Francesca Rappa
- Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy, University of Palermo, Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
| | - Azzura Greco
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
| | - Christine Podrini
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
| | - Francesco Cappello
- Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy, University of Palermo, Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
- Istituto “Paolo Sotgiu, Libera Università degli Studi di Scienze Umane e Tecnologiche, Lugano, Switzerland
| | - Michelangelo Foti
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Lucie Bourgoin
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Marion Peyrou
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Arianna Marino
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | | | - Roger Williams
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
| | - Gianluigi Mazzoccoli
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy
| | - Massimo Federici
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Valerio Pazienza
- Division and Laboratory of Gastroenterology, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy
| | - Manlio Vinciguerra
- Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
- * E-mail:
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Zingg JM, Hasan ST, Meydani M. Molecular mechanisms of hypolipidemic effects of curcumin. Biofactors 2013; 39:101-21. [PMID: 23339042 DOI: 10.1002/biof.1072] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Accepted: 10/19/2012] [Indexed: 12/14/2022]
Abstract
Recent evidence suggests potential benefits from phytochemicals and micronutrients in reducing the elevated oxidative and lipid-mediated stress associated with inflammation, obesity, and atherosclerosis. These compounds may either directly scavenge reactive oxygen or nitrogen species or they may modulate the activity of signal transduction enzymes leading to changes in the expression of antioxidant genes. Alternatively, they may reduce plasma lipid levels by modulating lipid metabolic genes in tissues and thus reduce indirectly lipid-mediated oxidative and endoplasmic reticulum stress through their hypolipidemic effect. Here we review the proposed molecular mechanisms by which curcumin, a polyphenol present in the rhizomes of turmeric (Curcuma longa) spice, influences oxidative and lipid-mediated stress in the vascular system. At the molecular level, mounting experimental evidence suggests that curcumin may act chemically as scavenger of free radicals and/or influences signal transduction (e.g., Akt, AMPK) and modulates the activity of specific transcription factors (e.g., FOXO1/3a, NRF2, SREBP1/2, CREB, CREBH, PPARγ, and LXRα) that regulate the expression of genes involved in free radicals scavenging (e.g., catalase, MnSOD, and heme oxygenase-1) and lipid homeostasis (e.g., aP2/FABP4, CD36, HMG-CoA reductase, and carnitine palmitoyltransferase-I (CPT-1)). At the cellular level, curcumin may induce a mild oxidative and lipid-metabolic stress leading to an adaptive cellular stress response by hormetic stimulation of these cellular antioxidant defense systems and lipid metabolic enzymes. The resulting lower oxidative and lipid-mediated stress may not only explain the beneficial effects of curcumin on inflammation, cardiovascular, and neurodegenerative disease, but may also contribute to the increase in maximum life-span observed in animal models.
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Affiliation(s)
- Jean-Marc Zingg
- Vascular Biology Laboratory, Jean Mayer USDA-Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA.
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Proteomics and gene expression analyses of squalene-supplemented mice identify microsomal thioredoxin domain-containing protein 5 changes associated with hepatic steatosis. J Proteomics 2012; 77:27-39. [DOI: 10.1016/j.jprot.2012.07.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Revised: 06/28/2012] [Accepted: 07/01/2012] [Indexed: 11/18/2022]
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Ramírez-Torres A, Barceló-Batllori S, Fernández-Vizarra E, Navarro MA, Arnal C, Guillén N, Acín S, Osada J. Proteomics and gene expression analyses of mitochondria from squalene-treated apoE-deficient mice identify short-chain specific acyl-CoA dehydrogenase changes associated with fatty liver amelioration. J Proteomics 2012; 75:2563-75. [DOI: 10.1016/j.jprot.2012.02.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Revised: 02/06/2012] [Accepted: 02/20/2012] [Indexed: 02/07/2023]
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