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Article ; Online: Endoplasmic Reticulum Protein TXNDC5 Interacts with PRDX6 and HSPA9 to Regulate Glutathione Metabolism and Lipid Peroxidation in the Hepatic AML12 Cell Line

Seyed Hesamoddin Bidooki / Javier Sánchez-Marco / Roberto Martínez-Beamonte / Tania Herrero-Continente / María A. Navarro / María J. Rodríguez-Yoldi / Jesús Osada

International Journal of Molecular Sciences, Vol 24, Iss 24, p

2023 Volume 17131

Abstract: Non-alcoholic fatty liver disease or steatosis is an accumulation of fat in the liver. Increased amounts of non-esterified fatty acids, calcium deficiency, or insulin resistance may disturb endoplasmic reticulum (ER) homeostasis, which leads to the ... ...

Abstract	Non-alcoholic fatty liver disease or steatosis is an accumulation of fat in the liver. Increased amounts of non-esterified fatty acids, calcium deficiency, or insulin resistance may disturb endoplasmic reticulum (ER) homeostasis, which leads to the abnormal accumulation of misfolded proteins, activating the unfolded protein response. The ER is the primary location site for chaperones like thioredoxin domain-containing 5 (TXNDC5). Glutathione participates in cellular oxidative stress, and its interaction with TXNDC5 in the ER may decrease the disulfide bonds of this protein. In addition, glutathione is utilized by glutathione peroxidases to inactivate oxidized lipids. To characterize proteins interacting with TXNDC5, immunoprecipitation and liquid chromatography–mass spectrometry were used. Lipid peroxidation, reduced glutathione, inducible phospholipase A 2 (iPLA 2 ) and hepatic transcriptome were assessed in the AML12 and TXNDC5-deficient AML12 cell lines. The results showed that HSPA9 and PRDX6 interact with TXNDC5 in AML12 cells. In addition, TXNDC5 deficiency reduced the protein levels of PRDX6 and HSPA9 in AML12. Moreover, lipid peroxidation, glutathione and iPLA 2 activities were significantly decreased in TXNDC5-deficient cells, and to find the cause of the PRDX6 protein reduction, proteasome suppression revealed no considerable effect on it. Finally, hepatic transcripts connected to PRDX6 and HSPA9 indicated an increase in the Dnaja3 , Mfn2 and Prdx5 and a decrease in Npm1 , Oplah , Gstp3 , Gstm6 , Gstt1 , Serpina1a , Serpina1b , Serpina3m , Hsp90aa1 and Rps14 mRNA levels in AML12 KO cells. In conclusion, the lipid peroxidation system and glutathione mechanism in AML12 cells may be disrupted by the absence of TXNDC5, a novel protein–protein interacting partner of PRDX6 and HSPA9.
Keywords	protein interaction ; TXNDC5 ; endoplasmic reticulum ; PRDX6 ; HSPA9 ; glutathione ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Squalene through Its Post-Squalene Metabolites Is a Modulator of Hepatic Transcriptome in Rabbits

Roubi Abuobeid / Javier Sánchez-Marco / María J. Felices / Carmen Arnal / Juan Carlos Burillo / Roberto Lasheras / Rebeca Busto / Miguel A. Lasunción / María Jesús Rodríguez-Yoldi / Roberto Martínez-Beamonte / Jesús Osada

International Journal of Molecular Sciences, Vol 23, Iss 4172, p

2022 Volume 4172

Abstract: Squalene is a natural bioactive triterpene and an important intermediate in the biosynthesis of sterols. To assess the effect of this compound on the hepatic transcriptome, RNA-sequencing was carried out in two groups of male New Zealand rabbits fed ... ...

Abstract	Squalene is a natural bioactive triterpene and an important intermediate in the biosynthesis of sterols. To assess the effect of this compound on the hepatic transcriptome, RNA-sequencing was carried out in two groups of male New Zealand rabbits fed either a diet enriched with 1% sunflower oil or the same diet with 0.5% squalene for 4 weeks. Hepatic lipids, lipid droplet area, squalene, and sterols were also monitored. The Squalene administration downregulated 9 transcripts and upregulated 13 transcripts. The gene ontology of transcripts fitted into the following main categories: transporter of proteins and sterols, lipid metabolism, lipogenesis, anti-inflammatory and anti-cancer properties. When the results were confirmed by RT-qPCR, rabbits receiving squalene displayed significant hepatic expression changes of LOC100344884 ( PNPLA3 ), GCK , TFCP2L1 , ASCL1 , ACSS2 , OST4 , FAM91A1 , MYH6 , LRRC39 , LOC108176846 , GLT1D1 and TREH . A squalene-enriched diet increased hepatic levels of squalene, lanosterol, dihydrolanosterol, lathosterol, zymostenol and desmosterol. Strong correlations were found among specific sterols and some squalene-changed transcripts. Incubation of the murine AML12 hepatic cell line in the presence of lanosterol, dihydrolanosterol, zymostenol and desmosterol reproduced the observed changes in the expressions of Acss2 , Fam91a1 and Pnpla3 . In conclusion, these findings indicate that the squalene and post-squalene metabolites play important roles in hepatic transcriptional changes required to protect the liver against malfunction.
Keywords	squalene ; virgin olive oil ; rabbits ; murine ; AML12 cell line ; lipid droplets ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	572
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Thioredoxin Domain Containing 5 Suppression Elicits Serum Amyloid A-Containing High-Density Lipoproteins

Javier Sánchez-Marco / Roberto Martínez-Beamonte / Alicia De Diego / Tania Herrero-Continente / Cristina Barranquero / Carmen Arnal / Joaquín Surra / María A. Navarro / Jesús Osada

Biomedicines, Vol 10, Iss 709, p

2022 Volume 709

Abstract: Thioredoxin domain containing 5 (TXNDC5) is a protein disulfide isomerase involved in several diseases related to oxidative stress, energy metabolism and cellular inflammation. In a previous manuscript, a negative association between fatty liver ... ...

Abstract	Thioredoxin domain containing 5 (TXNDC5) is a protein disulfide isomerase involved in several diseases related to oxidative stress, energy metabolism and cellular inflammation. In a previous manuscript, a negative association between fatty liver development and hepatic Txndc5 expression was observed. To study the role of TXNDC5 in the liver, we generated Txndc5 -deficient mice. The absence of the protein caused an increased metabolic need to gain weight along with a bigger and fatter liver. RNAseq was performed to elucidate the putative mechanisms, showing a substantial liver overexpression of serum amyloid genes ( Saa1 , Saa2 ) with no changes in hepatic protein, but discrete plasma augmentation by the gene inactivation. Higher levels of malonyldialdehyde, apolipoprotein A1 and platelet activating factor-aryl esterase activity were also found in serum from Txndc5 -deficient mice. However, no difference in the distribution of high-density lipoproteins (HDL)-mayor components and SAA was found between groups, and even the reactive oxygen species decreased in HDL coming from Txndc5 -deficient mice. These results confirm the relation of this gene with hepatic steatosis and with a fasting metabolic derive remedying an acute phase response. Likewise, they pose a new role in modulating the nature of HDL particles, and SAA-containing HDL particles are not particularly oxidized.
Keywords	thioredoxin domain containing 5 ; TXNDC5 ; serum amyloid ; HDL ; SAA ; Saa1 ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Dietary Erythrodiol Modifies Hepatic Transcriptome in Mice in a Sex and Dose-Dependent Way

Roubi Abuobeid / Luis Herrera-Marcos / María A. Navarro / Carmen Arnal / Roberto Martínez-Beamonte / Joaquín Surra / Jesús Osada

International Journal of Molecular Sciences, Vol 21, Iss 7331, p

2020 Volume 7331

Abstract: Erythrodiol is a terpenic compound found in a large number of plants. To test the hypotheses that its long-term administration may influence hepatic transcriptome and this could be influenced by the presence of APOA1-containing high-density lipoproteins ( ...

Abstract	Erythrodiol is a terpenic compound found in a large number of plants. To test the hypotheses that its long-term administration may influence hepatic transcriptome and this could be influenced by the presence of APOA1-containing high-density lipoproteins (HDL), Western diets containing 0.01% of erythrodiol (10 mg/kg dose) were provided to Apoe - and Apoa1 -deficient mice. Hepatic RNA-sequencing was carried out in male Apoe -deficient mice fed purified Western diets differing in the erythrodiol content. The administration of this compound significantly up- regulated 68 and down-regulated 124 genes at the level of 2-fold change. These genes belonged to detoxification processes, protein metabolism and nucleic acid related metabolites. Gene expression changes of 21 selected transcripts were verified by RT-qPCR. Ccl19-ps2 , Cyp2b10 , Rbm14-rbm4 , Sec61g , Tmem81 , Prtn3 , Amy2a5 , Cyp2b9 and Mup1 showed significant changes by erythrodiol administration. When Cyp2b10 , Dmbt1 , Cyp2b13 , Prtn3 and Cyp2b9 were analyzed in female Apoe -deficient mice, no change was observed. Likewise, no significant variation was observed in Apoa1 - or in Apoe- deficient mice receiving doses ranging from 0.5 to 5 mg/kg erythrodiol. Our results give evidence that erythrodiol exerts a hepatic transcriptional role, but this is selective in terms of sex and requires a threshold dose. Furthermore, it requires an APOA1-containing HDL.
Keywords	erythrodiol ; mice ; liver ; apolipoprotein E ; olive oil ; transcriptome ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Hepatic galectin-3 is associated with lipid droplet area in non-alcoholic steatohepatitis in a new swine model

Luis V. Herrera-Marcos / Roberto Martínez-Beamonte / Manuel Macías-Herranz / Carmen Arnal / Cristina Barranquero / Juan J. Puente-Lanzarote / Sonia Gascón / Tania Herrero-Continente / Gonzalo Gonzalo-Romeo / Víctor Alastrué-Vera / Dolores Gutiérrez-Blázquez / José M. Lou-Bonafonte / Joaquín C. Surra / María J. Rodríguez-Yoldi / Agustín García-Gil / Antonio Güemes / Jesús Osada

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 17

Abstract: 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, ... ...

Abstract	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.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Current Insights into the Biological Action of Squalene

Lou‐Bonafonte, José M / Carmen Arnal / Javier Sanchez‐Marco / Jesús Osada / Joaquín C. Surra / Luis V. Herrera‐Marcos / Roberto Martínez‐Beamonte / Teresa Sanclemente

Molecular nutrition & food research. 2018 Aug., v. 62, no. 15

2018

Abstract: Squalene is a triterpenic compound found in a large number of plants and other sources with a long tradition of research since it was first reported in 1926. Herein a systematic review of studies concerning squalene published in the last 8 years is ... ...

Abstract	Squalene is a triterpenic compound found in a large number of plants and other sources with a long tradition of research since it was first reported in 1926. Herein a systematic review of studies concerning squalene published in the last 8 years is presented. These studies have provided further support for its antioxidant, anti‐inflammatory, and anti‐atherosclerotic properties in vivo and in vitro. Moreover, an antineoplastic effect in nutrigenetic‐type treatments, which depends on the failing metabolic pathway of tumors, has also been reported. The bioavailability of squalene in cell cultures, animal models, and in humans has been well established, and further progress has been made in regard to the intracellular transport of this lipophilic molecule. Squalene accumulates in the liver and decreases hepatic cholesterol and triglycerides, with these actions being exerted via a complex network of changes in gene expression at both transcriptional and post‐transcriptional levels. Its presence in different biological fluids has also been studied. The combination of squalene with other bioactive compounds has been shown to enhance its pleiotropic properties and might lead to the formulation of functional foods and nutraceuticals to control oxidative stress and, therefore, numerous age‐related diseases in human and veterinary medicine.
Keywords	animal models ; antioxidants ; bioactive compounds ; bioavailability ; biochemical pathways ; cell culture ; cholesterol ; functional foods ; gene expression regulation ; lipophilicity ; liver ; neoplasms ; oxidative stress ; physiological transport ; squalene ; systematic review ; transcription (genetics) ; triacylglycerols ; veterinary medicine
Language	English
Dates of publication	2018-08
Size	p. e1800136.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	REVIEW
ZDB-ID	2160372-8
ISSN	1613-4133 ; 1613-4125
ISSN (online)	1613-4133
ISSN	1613-4125
DOI	10.1002/mnfr.201800136
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Sphingomyelin in High-Density Lipoproteins

Jesús Osada / María V. Martínez-Gracia / Roberto Martínez-Beamonte / Jose M. Lou-Bonafonte

International Journal of Molecular Sciences, Vol 14, Iss 4, Pp 7716-

Structural Role and Biological Function

2013 Volume 7741

Abstract: High-density lipoprotein (HDL) levels are an inverse risk factor for cardiovascular diseases, and sphingomyelin (SM) is the second most abundant phospholipid component and the major sphingolipid in HDL. Considering the marked presence of SM, the present ... ...

Abstract	High-density lipoprotein (HDL) levels are an inverse risk factor for cardiovascular diseases, and sphingomyelin (SM) is the second most abundant phospholipid component and the major sphingolipid in HDL. Considering the marked presence of SM, the present review has focused on the current knowledge about this phospholipid by addressing its variable distribution among HDL lipoparticles, how they acquire this phospholipid, and the important role that SM plays in regulating their fluidity and cholesterol efflux from different cells. In addition, plasma enzymes involved in HDL metabolism such as lecithin–cholesterol acyltransferase or phospholipid transfer protein are inhibited by HDL SM content. Likewise, HDL SM levels are influenced by dietary maneuvers (source of protein or fat), drugs (statins or diuretics) and modified in diseases such as diabetes, renal failure or Niemann–Pick disease. Furthermore, increased levels of HDL SM have been shown to be an inverse risk factor for coronary heart disease. The complexity of SM species, described using new lipidomic methodologies, and their distribution in different HDL particles under many experimental conditions are promising avenues for further research in the future.
Keywords	high-density lipoproteins ; phospholipids ; sphingomyelin ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2013-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Dietary squalene increases high density lipoprotein-cholesterol and paraoxonase 1 and decreases oxidative stress in mice.

Clara Gabás-Rivera / Cristina Barranquero / Roberto Martínez-Beamonte / María A Navarro / Joaquín C Surra / Jesús Osada

PLoS ONE, Vol 9, Iss 8, p e

2014 Volume 104224

Abstract: BACKGROUND AND PURPOSE: Squalene, the main hydrocarbon in the unsaponifiable fraction of virgin olive oil, is involved in cholesterol synthesis and it has been reported to own antiatherosclerotic and antiesteatosic effects. However, the squalene's role ... ...

Abstract	BACKGROUND AND PURPOSE: Squalene, the main hydrocarbon in the unsaponifiable fraction of virgin olive oil, is involved in cholesterol synthesis and it has been reported to own antiatherosclerotic and antiesteatosic effects. However, the squalene's role on lipid plasma parameters and the influence of genotype on this effect need to be addressed. EXPERIMENTAL APPROACHES: Three male mouse models (wild-type, Apoa1- and Apoe- deficient) were fed chow semisynthetic diets enriched in squalene to provide a dose of 1 g/kg during 11 weeks. After this period, their plasma parameters and lipoprotein profiles were analyzed. KEY RESULTS: Squalene administration at a dose of 1 g/kg showed decreased reactive oxygen species in lipoprotein fractions independently of the animal background and caused an specific increase in high density lipoprotein (HDL)-cholesterol levels, accompanied by an increase in phosphatidylcholine and paraoxonase 1 and no changes in apolipoproteins A1 and A4 in wild-type mice. In these mice, the cholesterol increase was due to its esterified form and associated with an increased hepatic expression of Lcat. These effects were not observed in absence of apolipoprotein A1. The increases in HDL- paraoxonase 1 were translated into decreased plasma malondialdehyde levels depending on the presence of Apolipoprotein A1. CONCLUSIONS AND IMPLICATIONS: Dietary squalene promotes changes in HDL- cholesterol and paraoxonase 1 and decreases reactive oxygen species in lipoproteins and plasma malondialdehyde levels, providing new benefits of its intake that might contribute to explain the properties of virgin olive oil, although the phenotype related to apolipoproteins A1 and E may be particularly relevant.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Postprandial changes in high density lipoproteins in rats subjected to gavage administration of virgin olive oil.

Roberto Martínez-Beamonte / María A Navarro / Sergio Acin / Natalia Guillén / Cristina Barranquero / Carmen Arnal / Joaquín Surra / Jesus Osada

PLoS ONE, Vol 8, Iss 1, p e

2013 Volume 55231

Abstract: Background and aims The present study was designed to verify the influence of acute fat loading on high density lipoprotein (HDL) composition, and the involvement of liver and different segments of small intestine in the changes observed. Methods and ... ...

Abstract	Background and aims The present study was designed to verify the influence of acute fat loading on high density lipoprotein (HDL) composition, and the involvement of liver and different segments of small intestine in the changes observed. Methods and results To address these issues, rats were administered a bolus of 5-ml of extra-virgin olive oil and sacrificed 4 and 8 hours after feeding. In these animals, lipoproteins were analyzed and gene expressions of apolipoprotein and HDL enzymes were assessed in duodenum, jejunum, ileum and liver. Using this experimental design, total plasma and HDL phospholipids increased at the 8-hour-time-point due to increased sphingomyelin content. An increase in apolipoprotein A4 was also observed mainly in lipid-poor HDL. Increased expression of intestinal Apoa1, Apoa4 and Sgms1 mRNA was accompanied by hepatic decreases in the first two genes in liver. Hepatic expression of Abcg1, Apoa1bp, Apoa2, Apoe, Ptlp, Pon1 and Scarb1 decreased significantly following fat gavage, while no changes were observed for Abca1, Lcat or Pla2g7. Significant associations were also noted for hepatic expression of apolipoproteins and Pon1. Manipulation of postprandial triglycerides using an inhibitor of microsomal transfer protein -CP-346086- or of lipoprotein lipase -tyloxapol- did not influence hepatic expression of Apoa1 or Apoa4 mRNA. Conclusion All these data indicate that dietary fat modifies the phospholipid composition of rat HDL, suggesting a mechanism of down-regulation of hepatic HDL when intestine is the main source of those particles and a coordinated regulation of hepatic components of these lipoproteins at the mRNA level, independently of plasma postprandial triglycerides.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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