Imperial College London

DrLauraMartinez Gili

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Research Fellow
 
 
 
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Contact

 

+44 (0)20 7594 2896l.martinez-gili

 
 
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Location

 

Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
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32 results found

Mullish BH, Martinez-Gili L, Chekmeneva E, Correia GDS, Lewis MRR, Horneffer-Van Der Sluis V, McDonald JAK, Pechlivanis A, Walters JRF, McClure E, Marchesi JR, Allegretti JRet al., 2022, Fecal bile acid profiles predict recurrence in patients with primary Clostridioides difficile infection

<jats:p>Background: Factors that influence recurrence risk in primary Clostridioides difficile infection (CDI) are poorly understood, and tools to predict recurrence are lacking. Perturbations in microbial-derived bile acids (BAs) contribute to CDI pathogenesis and may be relevant to primary disease prognosis.Aims: To define stool bile acid profiles and microbial bile-metabolising functionality in primary CDI patients, and explore signatures predicting recurrence.Methods: Weekly stool samples were collected from primary CDI patients from the last day of anti-CDI therapy until recurrence, or through eight weeks post-completion otherwise. Ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) was used to profile bile acids, and bacterial bile salt hydrolase (BSH) activity was measured to determine primary BA deconjugation capacity. Multivariate and univariate models were used to define differential BA trajectories in recurrers versus non-recurrers, and assess fecal bile acids as predictive markers for recurrence. Results: Twenty (36%) out of 56 patients (median age 57, 64% male) recurred, with 80% of recurrence occurring within the first nine days post-antibiotic treatment. Principal component analysis (PCA) of stool bile acid profiles demonstrated clustering of samples by recurrence status and post-treatment time point. Longitudinal fecal bile acid trajectories in non-recurrers showed a recovery of secondary bile acids and their derivatives in non-recurring patients that was not observed in recurrers. BSH activity increased over time amongst patients who did not relapse (beta=0.056; likelihood ratio test p=0.018). A joint longitudinal-survival model identified five stool bile acids with AUROC &gt; 0.73 for prediction of recurrence within nine days post-CDI treatment.Conclusions: Gut bile acid metabolism dynamics differ in primary CDI patients between those who develop recurrence versus those who do not. Individual bile acids show pr

Journal article

Martinez-Gili L, Gordon H, Blad W, McDonald JAK, Holmes E, Marchesi JR, Harbord Met al., 2022, Gut bacteria composition and familiality echo Inflammatory Bowel Disease type and pathological spectrum, 17th Congress of ECCO, Publisher: Oxford University Press, Pages: I601-I602, ISSN: 1873-9946

BackgroundInflammatory bowel disease (IBD) aetiology encompasses genetic and environmental factors. Twin studies provide valuable insights to the familial degree (shared genetics and environment) of observed phenotypes. We characterised the gut bacterial composition of twins with IBD to find taxa associated with disease and estimate their familiality.MethodsFaecal samples were collected from 88 monozygotic (MZ) and dizygotic (DZ) twin pairs concordant or discordant for Crohn’s disease (CD; 26 MZ; 19 DZ) or ulcerative colitis (UC; 16 MZ; 27 DZ). The 16S rRNA gene was sequenced and amplicon sequence variants (ASV) generated. ANCOM software was used to assess differences in IBD vs. non-IBD, stratifying by disease type (CD/UC) and adjusting for age, gender and smoking. Twin pair and zygosity were added as random effects to estimate familiality, defined as percentage of variation due to common environment and genetics. IBD-affected twins were used for differences in disease location or treatment. Participants reporting antibiotic/probiotic treatment within the last 3 months or with a stoma/pouch were not included. In UC, surgery-naive patients were compared to an excluded subset who underwent ileostomy or pouch surgery without any recent antibiotic courses.ResultsDisease concordance in MZ twins was higher in CD (54%) than UC (19%). Alpha diversity was lower in CD, but not UC, and in ileostomy and pouch vs. surgery-naive UC. Principal component analysis showed that CD-affected twins clustered apart from non-IBD ones (Figure 1A). Familiality was lower in CD, with 5% of ASVs having familiality > 50%, compared to 17% in UC (Figure 1B). Two Lachnospirales order ASVs were less abundant in UC, while 15 ASVs from Clostridia, Bacteroidia, Bacilli and Coriobacteriia classes differentiated CD from non-IBD. Firmicutes were higher in CD (β= 0.95; 95%CI [0.34,1.56]), while no phyla changed in UC. Veillonella, Barnesiella, Faecalimonas and Holdemania genera had opposite t

Conference paper

Belda E, Voland L, Tremaroli V, Falony G, Adriouch S, Assmann KE, Prifiti E, Aron-Wisnewsky J, Debedat J, Le Roy T, Nielsen T, Amouyal C, Andre S, Andreelli F, Blueher M, Chakaroun R, Chilloux J, Coelho LP, Dao MC, Das P, Fellahi S, Forslund S, Galleron N, Hansen TH, Holmes B, Ji B, Pedersen HK, Phuong L, Le Chatelier E, Lewinter C, Manneras-Holm L, Marquet F, Myridakis A, Pelloux V, Pons N, Quinquis B, Rouault C, Roume H, Salem J-E, Sokolovska N, Sondertoft NB, Touch S, Vieira-Silva S, Galan P, Holst J, Gotze JP, Kober L, Vestergaard H, Hansen T, Hercberg S, Oppert J-M, Nielsen J, Letunic I, Dumas M-E, Stumvoll M, Pedersen OB, Bork P, Ehrlich SD, Zucker J-D, Baeckhed F, Raes J, Clement Ket al., 2022, Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism, GUT, ISSN: 0017-5749

Journal article

Forslund SK, Chakaroun R, Zimmermann-Kogadeeva M, Marko L, Aron-Wisnewsky J, Nielsen T, Moitinho-Silva L, Schmidt TSB, Falony G, Vieira-Silva S, Adriouch S, Alves RJ, Assmann K, Bastard J-P, Birkner T, Caesar R, Chilloux J, Coelho LP, Fezeu L, Galleron N, Helft G, Isnard R, Ji B, Kuhn M, Le Chatelier E, Myridakis A, Olsson L, Pons N, Prifti E, Quinquis B, Roume H, Salem J-E, Sokolovska N, Tremaroli V, Valles-Colomer M, Lewinter C, Sondertoft NB, Pedersen HK, Hansen TH, Gotze JP, Kober L, Vestergaard H, Hansen T, Zucker J-D, Hercberg S, Oppert J-M, Letunic I, Nielsen J, Backhed F, Ehrlich SD, Dumas M-E, Raes J, Pedersen O, Clement K, Stumvoll M, Bork Pet al., 2021, Combinatorial, additive and dose-dependent drug-microbiome associations, NATURE, Vol: 600, Pages: 500-+, ISSN: 0028-0836

Journal article

Nalpas N, Hoyles L, Anselm V, Ganief T, Martinez-Gili L, Grau C, Droste-Borel I, Davidovic L, Altafaj X, Dumas M-E, Macek Bet al., 2021, An integrated workflow for enhanced taxonomic and functional coverage of the mouse fecal metaproteome., Gut Microbes, Vol: 13, Pages: 1-23, ISSN: 1949-0976

Intestinal microbiota plays a key role in shaping host homeostasis by regulating metabolism, immune responses and behavior. Its dysregulation has been associated with metabolic, immune and neuropsychiatric disorders and is accompanied by changes in bacterial metabolic regulation. Although proteomics is well suited for analysis of individual microbes, metaproteomics of fecal samples is challenging due to the physical structure of the sample, presence of contaminating host proteins and coexistence of hundreds of taxa. Furthermore, there is a lack of consensus regarding preparation of fecal samples, as well as downstream bioinformatic analyses following metaproteomics data acquisition. Here we assess sample preparation and data analysis strategies applied to mouse feces in a typical mass spectrometry-based metaproteomic experiment. We show that subtle changes in sample preparation protocols may influence interpretation of biological findings. Two-step database search strategies led to significant underestimation of false positive protein identifications. Unipept software provided the highest sensitivity and specificity in taxonomic annotation of the identified peptides of unknown origin. Comparison of matching metaproteome and metagenome data revealed a positive correlation between protein and gene abundances. Notably, nearly all functional categories of detected protein groups were differentially abundant in the metaproteome compared to what would be expected from the metagenome, highlighting the need to perform metaproteomics when studying complex microbiome samples.

Journal article

Nuzzo A, Guedj K, Curac S, Hercend C, Bendavid C, Gault N, Tran-Dinh A, Ronot M, Nicoletti A, Bouhnik Y, Castier Y, Corcos O, Peoc'h Ket al., 2021, Accuracy of citrulline, I-FABP and d-lactate in the diagnosis of acute mesenteric ischemia, Scientific Reports, Vol: 11, Pages: 1-10, ISSN: 2045-2322

Early diagnosis of acute mesenteric ischemia (AMI) remains a clinical challenge, and no biomarker has been consistently validated. We aimed to assess the accuracy of three promising circulating biomarkers for diagnosing AMI—citrulline, intestinal fatty acid-binding protein (I-FABP), and D-lactate. A cross-sectional diagnostic study enrolled AMI patients admitted to the intestinal stroke center and controls with acute abdominal pain of another origin. We included 129 patients—50 AMI and 79 controls. Plasma citrulline concentrations were significantly lower in AMI patients compared to the controls [15.3 μmol/L (12.0–26.0) vs. 23.3 μmol/L (18.3–29.8), p = 0.001]. However, the area under the receiver operating curves (AUROC) for the diagnosis of AMI by Citrulline was low: 0.68 (95% confidence interval = 0.58–0.78). No statistical difference was found in plasma I-FABP and plasma D-lactate concentrations between the AMI and control groups, with an AUROC of 0.44, and 0.40, respectively. In this large cross-sectional study, citrulline, I-FABP, and D-lactate failed to differentiate patients with AMI from patients with acute abdominal pain of another origin. Further research should focus on the discovery of new biomarkers.

Journal article

Bermudez-Martin P, Becker JAJ, Caramello N, Fernandez SP, Costa-Campos R, Canaguier J, Barbosa S, Martinez-Gili L, Myridakis A, Dumas M-E, Bruneau A, Cherbuy C, Langella P, Callebert J, Launay J-M, Chabry J, Barik J, Le Merrer J, Glaichenhaus N, Davidovic Let al., 2021, The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota, Microbiome, Vol: 9, Pages: 1-23, ISSN: 2049-2618

BackgroundAutism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice.ResultsMice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice.ConclusionsThe microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD.

Journal article

Martinez-Gili L, Pechlivanis A, Begum S, Mells G, Holmes E, Jones Det al., 2021, Response failure to ursodeoxycholic acid treatment in primary biliary cholangitis is associated with a distinct stool and urine secondary bile acid profile, Publisher: ELSEVIER, Pages: S404-S405, ISSN: 0168-8278

Conference paper

Martinez-Gili L, Mullish BH, Correia G, Chekmeneva E, Homeffer-Van Der Sluis V, McClure EL, Marchesi J, Gerber G, Bry L, Allegretti JRet al., 2021, A DISTINCTIVE SIGNATURE OF FECAL BILE ACIDS AND OTHER NOVEL METABOLITES ACCOMPANYING RECURRENCE AFTER PRIMARY CLOSTRIDIOIDES DIFFICILE INFECTION, Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S368-S368, ISSN: 0016-5085

Conference paper

Martinez-Gili L, McDonald JAK, Liu Z, Kao D, Allegretti JR, Monaghan TM, Barker GF, Miguens Blanco J, Williams HRT, Holmes E, Thursz MR, Marchesi JR, Mullish BHet al., 2020, Understanding the mechanisms of efficacy of fecal microbiota transplant in treating recurrent Clostridioides difficile infection and beyond: the contribution of gut microbial derived metabolites, Gut Microbes, Vol: 12, ISSN: 1949-0976

Fecal microbiota transplant (FMT) is a highly-effective therapy for recurrent Clostridioides difficile infection (rCDI), and shows promise for certain non-CDI indications. However, at present, its mechanisms of efficacy have remained poorly understood. Recent studies by our laboratory have noted the particular key importance of restoration of gut microbe-metabolite interactions in the ability of FMT to treat rCDI, including the impact of FMT upon short chain fatty acid (SCFAs) and bile acid metabolism. This includes a significant impact of these metabolites upon the life cycle of C. difficile directly, along with potential postulated additional benefits, including effects upon host immune response. In this Addendum, we first present an overview of these recent advancements in this field, and then describe additional novel data from our laboratory on the impact of FMT for rCDI upon several gut microbial-derived metabolites which had not previously been implicated as being of relevance.

Journal article

Farràs M, Martinez-Gili L, Portune K, Arranz S, Frost G, Tondo M, Blanco-Vaca Fet al., 2020, Modulation of the gut microbiota by olive oil phenolic compounds: implications for lipid metabolism, immune system, and obesity, Nutrients, Vol: 12, Pages: 1-28, ISSN: 2072-6643

There is extensive information of the beneficial effects of virgin olive oil (VOO), especially on cardiovascular diseases. Some VOO healthy properties have been attributed to their phenolic-compounds (PCs). The aim of this review is to present updated data on the effects of olive oil (OO) PCs on the gut microbiota, lipid metabolism, immune system, and obesity, as well as on the crosstalk among them. We summarize experiments and clinical trials which assessed the specific effects of the olive oil phenolic-compounds (OOPCs) without the synergy with OO-fats. Several studies have demonstrated that OOPC consumption increases Bacteroidetes and/or reduces the Firmicutes/Bacteroidetes ratio, which have both been related to atheroprotection. OOPCs also increase certain beneficial bacteria and gut-bacteria diversity which can be therapeutic for lipid-immune disorders and obesity. Furthermore, some of the mechanisms implicated in the crosstalk between OOPCs and these disorders include antimicrobial-activity, cholesterol microbial metabolism, and metabolites produced by bacteria. Specifically, OOPCs modulate short-chain fatty-acids produced by gut-microbiota, which can affect cholesterol metabolism and the immune system, and may play a role in weight gain through promoting satiety. Since data in humans are scarce, there is a necessity for more clinical trials designed to assess the specific role of the OOPCs in this crosstalk.

Journal article

Martinez-Gili L, McDonald JA, Liu Z, Kao DH, Allegretti JR, Barker GF, Blanco JM, Holmes E, Thursz MR, Marchesi J, Mullish BHet al., 2020, 644 identification of novel changes in microbially-derived metabolites after fecal microbiota transplant for recurrent clostridioides difficile infection, Publisher: Elsevier BV, Pages: S-138-S-139, ISSN: 0016-5085

Conference paper

Abdul Rahim MBH, Chilloux J, Martinez-Gili L, Neves AL, Myridakis A, Gooderham N, Dumas M-Eet al., 2019, Diet-induced metabolic changes of the human gut microbiome: importance of short-chain fatty acids, methylamines and indoles, Acta Diabetologica, Vol: 56, Pages: 493-500, ISSN: 0940-5429

The human gut is a home for more than 100 trillion bacteria, far more than all other microbial populations resident on the body's surface. The human gut microbiome is considered as a microbial organ symbiotically operating within the host. It is a collection of different cell lineages that are capable of communicating with each other and the host and has an ability to undergo self-replication for its repair and maintenance. As the gut microbiota is involved in many host processes including growth and development, an imbalance in its ecological composition may lead to disease and dysfunction in the human. Gut microbial degradation of nutrients produces bioactive metabolites that bind target receptors, activating signalling cascades, and modulating host metabolism. This review covers current findings on the nutritional and pharmacological roles of selective gut microbial metabolites, short-chain fatty acids, methylamines and indoles, as well as discussing nutritional interventions to modulate the microbiome.

Journal article

Leboucher A, Pisani DF, Martinez-Gili L, Chilloux J, Bermudez-Martin P, Van Dijck A, Ganief T, Macek B, Becker JAJ, Le Merrer J, Kooy RF, Amri E-Z, Khandjian EW, Dumas M-E, Davidovic Let al., 2019, The translational regulator FMRP controls lipid and glucose metabolism in mice and humans, Molecular Metabolism, Vol: 21, Pages: 22-35, ISSN: 2212-8778

ObjectivesThe Fragile X Mental Retardation Protein (FMRP) is a widely expressed RNA-binding protein involved in translation regulation. Since the absence of FMRP leads to Fragile X Syndrome (FXS) and autism, FMRP has been extensively studied in brain. The functions of FMRP in peripheral organs and on metabolic homeostasis remain elusive; therefore, we sought to investigate the systemic consequences of its absence.MethodsUsing metabolomics, in vivo metabolic phenotyping of the Fmr1-KO FXS mouse model and in vitro approaches, we show that the absence of FMRP induced a metabolic shift towards enhanced glucose tolerance and insulin sensitivity, reduced adiposity, and increased β-adrenergic-driven lipolysis and lipid utilization.ResultsCombining proteomics and cellular assays, we highlight that FMRP loss increased hepatic protein synthesis and impacted pathways notably linked to lipid metabolism. Mapping metabolomic and proteomic phenotypes onto a signaling and metabolic network, we predicted that the coordinated metabolic response to FMRP loss was mediated by dysregulation in the abundances of specific hepatic proteins. We experimentally validated these predictions, demonstrating that the translational regulator FMRP associates with a subset of mRNAs involved in lipid metabolism. Finally, we highlight that FXS patients mirror metabolic variations observed in Fmr1-KO mice with reduced circulating glucose and insulin and increased free fatty acids.ConclusionsLoss of FMRP results in a widespread coordinated systemic response that notably involves upregulation of protein translation in the liver, increased utilization of lipids, and significant changes in metabolic homeostasis. Our study unravels metabolic phenotypes in FXS and further supports the importance of translational regulation in the homeostatic control of systemic metabolism.

Journal article

Hoyles L, Fernández-Real JM, Federici M, Serino M, Abbott J, Charpentier J, Heymes C, Latorre Luque J, Anthony E, Barton RH, Chilloux J, Myridakis A, Martinez-Gili L, Moreno-Navarrete JM, Rayah F, Azalbert V, Blasco-Baque V, Puig J, Xifra G, Ricart W, Tomlinson C, Woodbridge M, Cardellini M, Davato F, Cardolini I, Porzio O, Gentilieschi P, Lopez F, Foufelle F, Butcher SA, Holmes E, Nicholson JK, Postic C, Burcelin R, Dumas MEet al., 2018, Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women, Nature Medicine, Vol: 24, Pages: 1-17, ISSN: 1078-8956

Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies.

Journal article

Baulies A, Montero J, Matías N, Insausti N, Terrones O, Basañez G, Vallejo C, Conde de La Rosa L, Martinez L, Robles D, Morales A, Abian J, Carrascal M, Machida K, Kumar DBU, Tsukamoto H, Kaplowitz N, Garcia-Ruiz C, Fernández-Checa JCet al., 2017, The 2-oxoglutarate carrier promotes liver cancer by sustaining mitochondrial GSH despite cholesterol loading., Redox Biology, Vol: 14, Pages: 164-177, ISSN: 2213-2317

Cancer cells exhibit mitochondrial cholesterol (mt-cholesterol) accumulation, which contributes to cell death resistance by antagonizing mitochondrial outer membrane (MOM) permeabilization. Hepatocellular mt-cholesterol loading, however, promotes steatohepatitis, an advanced stage of chronic liver disease that precedes hepatocellular carcinoma (HCC), by depleting mitochondrial GSH (mGSH) due to a cholesterol-mediated impairment in mGSH transport. Whether and how HCC cells overcome the restriction of mGSH transport imposed by mt-cholesterol loading to support mGSH uptake remains unknown. Although the transport of mGSH is not fully understood, SLC25A10 (dicarboxylate carrier, DIC) and SLC25A11 (2-oxoglutarate carrier, OGC) have been involved in mGSH transport, and therefore we examined their expression and role in HCC. Unexpectedly, HCC cells and liver explants from patients with HCC exhibit divergent expression of these mitochondrial carriers, with selective OGC upregulation, which contributes to mGSH maintenance. OGC but not DIC downregulation by siRNA depleted mGSH levels and sensitized HCC cells to hypoxia-induced ROS generation and cell death as well as impaired cell growth in three-dimensional multicellular HCC spheroids, effects that were reversible upon mGSH replenishment by GSH ethyl ester, a membrane permeable GSH precursor. We also show that OGC regulates mitochondrial respiration and glycolysis. Moreover, OGC silencing promoted hypoxia-induced cardiolipin peroxidation, which reversed the inhibition of cholesterol on the permeabilization of MOM-like liposomes induced by Bax or Bak. Genetic OGC knockdown reduced the ability of tumor-initiating stem-like cells to induce liver cancer. These findings underscore the selective overexpression of OGC as an adaptive mechanism of HCC to provide adequate mGSH levels in the face of mt-cholesterol loading and suggest that OGC may be a novel therapeutic target for HCC treatment.

Journal article

Torres S, Matías N, Baulies A, Nuñez S, Alarcon-Vila C, Martinez L, Nuño N, Fernandez A, Caballeria J, Levade T, Gonzalez-Franquesa A, Garcia-Rovés P, Balboa E, Zanlungo S, Fabrías G, Casas J, Enrich C, Garcia-Ruiz C, Fernández-Checa JCet al., 2016, Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease, Redox Biology, Vol: 11, Pages: 60-72, ISSN: 2213-2317

Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature of NPC disease is the intracellular accumulation of cholesterol and gangliosides, predominantly in endolysosomes, mitochondrial cholesterol accumulation has also been reported. As accumulation of cholesterol in mitochondria is known to impair the transport of GSH into mitochondria, resulting in mitochondrial GSH (mGSH) depletion, we investigated the impact of mGSH recovery in NPC disease. We show that GSH ethyl ester (GSH-EE), but not N-acetylcysteine (NAC), restored the mGSH pool in liver and brain of Npc1(-/-) mice and in fibroblasts from NPC patients, while both GSH-EE and NAC increased total GSH levels. GSH-EE but not NAC increased the median survival and maximal life span of Npc1(-/-) mice. Moreover, intraperitoneal therapy with GSH-EE protected against oxidative stress and oxidant-induced cell death, restored calbindin levels in cerebellar Purkinje cells and reversed locomotor impairment in Npc1(-/-) mice. High-resolution respirometry analyses revealed that GSH-EE improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1(-/-) mice. Lipidomic analyses showed that GSH-EE treatment had not effect in the profile of most sphingolipids in liver and brain, except for some particular species in brain of Npc1(-/-) mice. These findings indicate that the specific replenishment of mGSH may be a potential promising therapy for NPC disease, worth exploring alone or in combination with other options.

Journal article

Martinez-Gili L, Garcia-Ruiz C, Fernandez-Checa C, 2016, Fatty Liver Disease: A Crosstalk Between Lipid Species, European Medical Journal: Hepatology, Vol: 4, Pages: 76-83

The role of different lipid species such as free fatty acids and sphingolipids in non-alcoholic fatty liver disease (NAFLD) has been extensively studied during the last decade. In addition, free cholesterol accumulation in hepatocytes plays a crucial role in the transition from steatosis to steatohepatitis. However, the contribution of these lipids to NAFLD pathology is often evaluated individually. This review attempts to enclose the main metabolic and signalling connections between lipotoxic lipid species, and how their homeostasis is disrupted in NAFLD.

Journal article

Baulies A, Ribas V, Núñez S, Torres S, Alarcón-Vila C, Martínez L, Suda J, Ybanez MD, Kaplowitz N, García-Ruiz C, Fernández-Checa JCet al., 2015, Lysosomal cholesterol accumulation sensitizes to acetaminophen hepatotoxicity by impairing mitophagy., Scientific Reports, Vol: 5, ISSN: 2045-2322

The role of lysosomes in acetaminophen (APAP) hepatotoxicity is poorly understood. Here, we investigated the impact of genetic and drug-induced lysosomal cholesterol (LC) accumulation in APAP hepatotoxicity. Acid sphingomyelinase (ASMase)(-/-) mice exhibit LC accumulation and higher mortality after APAP overdose compared to ASMase(+/+) littermates. ASMase(-/-) hepatocytes display lower threshold for APAP-induced cell death and defective fusion of mitochondria-containing autophagosomes with lysosomes, which decreased mitochondrial quality control. LC accumulation in ASMase(+/+) hepatocytes caused by U18666A reproduces the susceptibility of ASMase(-/-) hepatocytes to APAP and the impairment in the formation of mitochondria-containing autolysosomes. LC extraction by 25-hydroxycholesterol increased APAP-mediated mitophagy and protected ASMase(-/-) mice and hepatocytes against APAP hepatotoxicity, effects that were reversed by chloroquine to disrupt autophagy. The regulation of LC by U18666A or 25-hydroxycholesterol did not affect total cellular sphingomyelin content or its lysosomal distribution. Of relevance, amitriptyline-induced ASMase inhibition in human hepatocytes caused LC accumulation, impaired mitophagy and increased susceptibility to APAP. Similar results were observed upon glucocerebrosidase inhibition by conduritol β-epoxide, a cellular model of Gaucher disease. These findings indicate that LC accumulation determines susceptibility to APAP hepatotoxicity by modulating mitophagy, and imply that genetic or drug-mediated ASMase disruption sensitizes to APAP-induced liver injury.

Journal article

Martinez Gili L, Torres S, Baulies A, Alarcón-Vila C, Elena M, Fabriàs G, Casas J, Caballeria J, Fernandez-Checa JC, García-Ruiz Cet al., 2015, Myristic acid potentiates palmitic acid-induced lipotoxicity and steatohepatitis associated with lipodystrophy by sustaning de novo ceramide synthesis., Oncotarget, Vol: 6, Pages: 41479-41496, ISSN: 1949-2553

Palmitic acid (PA) induces hepatocyte apoptosis and fuels de novo ceramide synthesis in the endoplasmic reticulum (ER). Myristic acid (MA), a free fatty acid highly abundant in copra/palmist oils, is a predictor of nonalcoholic steatohepatitis (NASH) and stimulates ceramide synthesis. Here we investigated the synergism between MA and PA in ceramide synthesis, ER stress, lipotoxicity and NASH. Unlike PA, MA is not lipotoxic but potentiated PA-mediated lipoapoptosis, ER stress, caspase-3 activation and cytochrome c release in primary mouse hepatocytes (PMH). Moreover, MA kinetically sustained PA-induced total ceramide content by stimulating dehydroceramide desaturase and switched the ceramide profile from decreased to increased ceramide 14:0/ceramide16:0, without changing medium and long-chain ceramide species. PMH were more sensitive to equimolar ceramide14:0/ceramide16:0 exposure, which mimics the outcome of PA plus MA treatment on ceramide homeostasis, than to either ceramide alone. Treatment with myriocin to inhibit ceramide synthesis and tauroursodeoxycholic acid to prevent ER stress ameliorated PA plus MA induced apoptosis, similar to the protection afforded by the antioxidant BHA, the pan-caspase inhibitor z-VAD-Fmk and JNK inhibition. Moreover, ruthenium red protected PMH against PA and MA-induced cell death. Recapitulating in vitro findings, mice fed a diet enriched in PA plus MA exhibited lipodystrophy, hepatosplenomegaly, increased liver ceramide content and cholesterol levels, ER stress, liver damage, inflammation and fibrosis compared to mice fed diets enriched in PA or MA alone. The deleterious effects of PA plus MA-enriched diet were largely prevented by in vivo myriocin treatment. These findings indicate a causal link between ceramide synthesis and ER stress in lipotoxicity, and imply that the consumption of diets enriched in MA and PA can cause NASH associated with lipodystrophy.

Journal article

Ordonez R, Fernandez A, Prieto-Dominguez N, Martinez L, Garcia-Ruiz C, Fernandez-Checa JC, Mauriz JL, Gonzalez-Gallego Jet al., 2015, Ceramide metabolism regulates autophagy and apoptotic cell death induced by melatonin in liver cancer cells, JOURNAL OF PINEAL RESEARCH, Vol: 59, Pages: 178-189, ISSN: 0742-3098

Journal article

Barcena C, Stefanovic M, Tutusaus A, Martinez-Nieto GA, Martinez L, Garcia-Ruiz C, de Mingo A, Caballeria J, Fernandez-Checa JC, Mari M, Morales Aet al., 2015, Angiogenin Secretion From Hepatoma Cells Activates Hepatic Stellate Cells To Amplify A Self-Sustained Cycle Promoting Liver Cancer, SCIENTIFIC REPORTS, Vol: 5, ISSN: 2045-2322

Journal article

Fucho R, Martinez L, Baulies A, Torres S, Tarrats N, Fernandez A, Ribas V, Astudillo AM, Balsinde J, Garcia-Roves P, Elena M, Bergheim I, Lotersztajn S, Trautwein C, Appelqvist H, Paton AW, Paton JC, Czaja MJ, Kaplowitz N, Fernandez-Checa JC, Garcia-Ruiz Cet al., 2014, ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis, JOURNAL OF HEPATOLOGY, Vol: 61, Pages: 1126-1134, ISSN: 0168-8278

Journal article

Barbero-Camps E, Fernandez A, Baulies A, Martinez L, Fernandez-Checa JC, Colell Aet al., 2014, Endoplasmic Reticulum Stress Mediates Amyloid beta Neurotoxicity via Mitochondrial Cholesterol Trafficking, AMERICAN JOURNAL OF PATHOLOGY, Vol: 184, Pages: 2066-2081, ISSN: 0002-9440

Journal article

Sinha RA, Farah BL, Singh BK, Siddique MM, Li Y, Wu Y, Ilkayeva OR, Gooding J, Ching J, Zhou J, Martinez L, Xie S, Bay B-H, Summers SA, Newgard CB, Yen PMet al., 2014, Caffeine Stimulates Hepatic Lipid Metabolism by the Autophagy-Lysosomal Pathway in Mice, HEPATOLOGY, Vol: 59, Pages: 1366-1380, ISSN: 0270-9139

Journal article

Baulies A, Nunez S, Ribas V, Torres S, Martinez L, Kaplowitz N, Garcia-Ruiz C, Fernandez-Checa Jet al., 2014, Lysosomal Cholesterol Accumulation Sensitizes To Acetaminophen Hepatotoxicity By Impairing Mitophagy, 65th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases, Publisher: WILEY-BLACKWELL, Pages: 222A-223A, ISSN: 0270-9139

Conference paper

Baulies A, Martinez L, Tsukamoto H, Kaplowitz N, Garcia-Ruiz C, Fernandez-Checa Jet al., 2013, ASMase deficiency unmasks the dissociation between hyperhomocysteinemia and intrasgastric alcohol feeding-induced endoplasmic reticulum stress, 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases, Publisher: WILEY-BLACKWELL, Pages: 827A-827A, ISSN: 0270-9139

Conference paper

Fernandez A, Matias N, Fucho R, Ribas V, Von Montfort C, Nuno N, Baulies A, Martinez L, Tarrats N, Mari M, Colell A, Morales A, Dubuquoy L, Mathurin P, Bataller R, Caballeria J, Elena M, Balsinde J, Kaplowitz N, Garcia-Ruiz C, Fernandez-Checa JCet al., 2013, ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading, JOURNAL OF HEPATOLOGY, Vol: 59, Pages: 805-813, ISSN: 0168-8278

Journal article

Barbero-Camps E, Fernandez A, Martinez L, Fernandez-Checa JC, Colell Aet al., 2013, APP/PS1 mice overexpressing SREBP-2 exhibit combined A accumulation and tau pathology underlying Alzheimers disease, HUMAN MOLECULAR GENETICS, Vol: 22, Pages: 3460-3476, ISSN: 0964-6906

Journal article

Martinez L, Fucho R, Elena M, Fernandez-Checa J, Garcia-Ruiz Cet al., 2012, Myristic acid potentiates palmitic acid-induced ceramide generation and lipotoxicity, 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: WILEY-BLACKWELL, Pages: 875A-875A, ISSN: 0270-9139

Conference paper

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