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dc.contributor.authorEnguita, Mónica
dc.contributor.authorRazquin, Nerea
dc.contributor.authorPamplona Gras, Reinald
dc.contributor.authorQuiroga, Jorge
dc.contributor.authorPrieto, Jesús
dc.contributor.authorFortes, Puri
dc.description.abstractLiver cirrhosis results from chronic hepatic damage and is characterized by derangement of the organ architecture with increased liver fibrogenesis and defective hepatocellular function. It frequently evolves into progressive hepatic insufficiency associated with high mortality unless liver transplantation is performed. We have hypothesized that the deficiency of critical nutrients such as essential omega-3 fatty acids might play a role in the progression of liver cirrhosis. Here we evaluated by LC-MS/MS the liver content of omega-3 docosahexaenoic fatty acid (DHA) in cirrhotic patients and investigated the effect of DHA in a murine model of liver injury and in the response of hepatic stellate cells (HSCs) (the main producers of collagen in the liver) to pro-fibrogenic stimuli. We found that cirrhotic livers exhibit a marked depletion of DHA and that this alteration correlates with the progression of the disease. Administration of DHA exerts potent anti-fibrogenic effects in an acute model of liver damage. Studies with HSCs show that DHA inhibits fibrogenesis more intensely than other omega-3 fatty acids. Data from expression arrays revealed that DHA blocks TGFβ and NF-κB pathways. Mechanistically, DHA decreases late, but not early, SMAD3 nuclear accumulation and inhibits p65/RelA-S536 phosphorylation, which is required for HSC survival. Notably, DHA increases ADRP expression, leading to the formation of typical quiescence-associated perinuclear lipid droplets. In conclusion, a marked depletion of DHA is present in the liver of patients with advanced cirrhosis. DHA displays anti-fibrogenic activities on HSCs targeting NF-κB and TGFβ pathways and inducing ADPR expression and quiescence in these cells.ca_ES
dc.description.sponsorshipThis study was supported by European FEDER funding and grants from the Ministry of Economy (SAF2015-70971-R), Gobierno de Navarra 0011-1365-2016-000308, Fundación Echevano, Fundación Unicaja, and Fondo de Investigación Sanitaria (PI16/02081), financed by the Instituto de Salud Carlos III.ca_ES
dc.publisherNature Researchca_ES
dc.relation.isformatofReproducció del document publicat a
dc.relation.ispartofCell Death & Disease, 2019, vol. 10, núm. 14, p. 1-13ca_ES
dc.rightscc-by (c) Mónica Enguita et al., 2019ca_ES
dc.titleThe cirrhotic liver is depleted of docosahexaenoic acid (DHA), a key modulator of NF-κB and TGFβ pathways in hepatic stellate cellsca_ES

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cc-by (c) Mónica Enguita et al., 2019
Except where otherwise noted, this item's license is described as cc-by (c) Mónica Enguita et al., 2019