Publications
49 results found
Torres S, Matías N, Baulies A, et 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.
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.
Baulies A, Ribas V, Núñez S, et 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.
Martinez Gili L, Torres S, Baulies A, et 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.
Ordonez R, Fernandez A, Prieto-Dominguez N, et 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
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- Citations: 78
Ordonez R, Fernandez A, Martinez L, et al., 2015, MELATONIN-INDUCED APOPTOSIS OF HepG2 CELLS IS ENHANCED BY AUTOPHAGY SUPPRESSION, 50th International Liver Congress of the European-Association-for-the-Study-of-the-Liver, Publisher: ELSEVIER SCIENCE BV, Pages: S424-S424, ISSN: 0168-8278
Martinez L, Elena M, Fernandez-Checa JC, et al., 2015, A DIET ENRICHED IN PALMITIC AND MYRISTIC ACID CAUSES STEATOHEPATITIS BY INCREASING DE NOVO CERAMIDE SYNTHESIS AND ENDOPLASMIC RETICULUM STRESS, 50th International Liver Congress of the European-Association-for-the-Study-of-the-Liver, Publisher: ELSEVIER SCIENCE BV, Pages: S706-S706, ISSN: 0168-8278
Barcena C, Stefanovic M, Tutusaus A, et 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
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- Citations: 36
Fucho R, Martinez L, Baulies A, et 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
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- Citations: 77
Barbero-Camps E, Fernandez A, Baulies A, et al., 2014, Endoplasmic Reticulum Stress Mediates Amyloid β Neurotoxicity via Mitochondrial Cholesterol Trafficking, AMERICAN JOURNAL OF PATHOLOGY, Vol: 184, Pages: 2066-2081, ISSN: 0002-9440
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- Citations: 76
Sinha RA, Farah BL, Singh BK, et al., 2014, Caffeine Stimulates Hepatic Lipid Metabolism by the Autophagy-Lysosomal Pathway in Mice, HEPATOLOGY, Vol: 59, Pages: 1366-1380, ISSN: 0270-9139
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- Citations: 246
Baulies A, Nunez S, Ribas V, et al., 2014, ROLE OF ACID SPHINGOMYELINASE IN APAP-INDUCED LIVER INJURY, 49th Annual International Liver Congress of the European-Association-for-the-Study-of-the-Liver, Publisher: ELSEVIER SCIENCE BV, Pages: S179-S179, ISSN: 0168-8278
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- Citations: 1
Baulies A, Nunez S, Ribas V, et 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
Baulies A, Martinez L, Tsukamoto H, et 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
Fernandez A, Matias N, Fucho R, et 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
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- Citations: 77
Barbero-Camps E, Fernandez A, Martinez L, et 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
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- Citations: 82
Martinez L, Fucho R, Elena M, et 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
Llacuna L, Fernandez A, von Montfort C, et al., 2011, Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia-reperfusion injury, JOURNAL OF HEPATOLOGY, Vol: 54, Pages: 1002-1010, ISSN: 0168-8278
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- Citations: 50
Caballero F, Fernandez A, Matias N, et al., 2010, Specific Contribution of Methionine and Choline in Nutritional Nonalcoholic Steatohepatitis <i>IMPACT ON MITOCHONDRIAL S</i>-<i>ADENOSYL</i>-<i>L</i>-<i>METHIONINE AND GLUTATHIONE</i>, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 285, Pages: 18528-18536
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- Citations: 177
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