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https://www.arca.fiocruz.br/handle/icict/63031
PREVENTION OF LIPID DROPLET ACCUMULATION BY DGAT1 INHIBITION AMELIORATES SEPSIS-INDUCED LIVER INJURY AND INFLAMMATION
Author
Teixeira, Lívia
Pereira-Dutra, Filipe S.
Reis, Patrícia A.
Cunha-Fernandes, Tamires
Yoshinaga, Marcos Y.
Souza-Moreira, Luciana
Souza, Ellen K.
Barreto, Ester A.
Silva, Thiago P.
Espinheira-Silva, Hugo
Igreja, Tathiany
Antunes, Maísa M.
Bombaça, Ana Cristina S.
Gonçalves-de-Albuquerque, Cassiano F.
Menezes, Gustavo B.
Hottz, Eugênio D.
Menna-Barreto, Rubem F. S.
Maya-Monteiro, Clarissa M.
Bozza, Fernando A.
Miyamoto, Sayuri
Melo, Rossana C. N.
Bozza, Patrícia T.
Pereira-Dutra, Filipe S.
Reis, Patrícia A.
Cunha-Fernandes, Tamires
Yoshinaga, Marcos Y.
Souza-Moreira, Luciana
Souza, Ellen K.
Barreto, Ester A.
Silva, Thiago P.
Espinheira-Silva, Hugo
Igreja, Tathiany
Antunes, Maísa M.
Bombaça, Ana Cristina S.
Gonçalves-de-Albuquerque, Cassiano F.
Menezes, Gustavo B.
Hottz, Eugênio D.
Menna-Barreto, Rubem F. S.
Maya-Monteiro, Clarissa M.
Bozza, Fernando A.
Miyamoto, Sayuri
Melo, Rossana C. N.
Bozza, Patrícia T.
Affilliation
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / Oswaldo Cruz Foundation. Center for Research. Innovation and Surveillance in COVID-19 and Heath Emergencies. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / State University of Rio de Janeiro. Roberto Alcântara Gomes Biology Institute. Biochemistry Department. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / Oswaldo Cruz Foundation. Center for Research. Innovation and Surveillance in COVID-19 and Heath Emergencies. Rio de Janeiro, RJ, Brazil.
University of São Paulo. Department of Biochemistry. Laboratory of Modified Lipids. São Paulo, SP, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil.
Federal University of Juiz de Fora. Institute of Biological Sciences. Department of Biology. Laboratory of Cellular Biology. Juiz de Fora, MG, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / Oswaldo Cruz Foundation. Center for Research. Innovation and Surveillance in COVID-19 and Heath Emergencies. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil.
Federal University of Minas Gerais. Institute of Biological Sciences. Department of Morphology. Center for Gastrointestinal Biology. Belo Horizonte, MG, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Cellular Biology. Rio de Janeiro, RJ, Brazil / Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Parasitic Disease. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / Federal University of the State of Rio de Janeiro. Department of Physiology. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil.
Federal University of Minas Gerais. Institute of Biological Sciences. Department of Morphology. Center for Gastrointestinal Biology. Belo Horizonte, MG, Brazil.
Federal University of Juiz de Fora. Department of Biochemistry. Laboratory of Immunothrombosis. Juiz de Fora, MG, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Cellular Biology. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / Oswaldo Cruz Foundation. Center for Research. Innovation and Surveillance in COVID-19 and Heath Emergencies. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Center for Research. Innovation and Surveillance in COVID-19 and Heath Emergencies. Rio de Janeiro, RJ, Brazil / Oswaldo Cruz Foundation. Evandro Chagas National Institute of Infectious Diseases. Intensive Care Medicine Laboratory. Rio de Janeiro, RJ, Brazil / D'Or Institute Research and Education. Rio de Janeiro, RJ, Brazil.
University of São Paulo. Department of Biochemistry. Laboratory of Modified Lipids. São Paulo, SP, Brazil.
Federal University of Juiz de Fora. Institute of Biological Sciences. Department of Biology. Laboratory of Cellular Biology. Juiz de Fora, MG, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / Oswaldo Cruz Foundation. Center for Research. Innovation and Surveillance in COVID-19 and Heath Emergencies. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / Oswaldo Cruz Foundation. Center for Research. Innovation and Surveillance in COVID-19 and Heath Emergencies. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / State University of Rio de Janeiro. Roberto Alcântara Gomes Biology Institute. Biochemistry Department. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / Oswaldo Cruz Foundation. Center for Research. Innovation and Surveillance in COVID-19 and Heath Emergencies. Rio de Janeiro, RJ, Brazil.
University of São Paulo. Department of Biochemistry. Laboratory of Modified Lipids. São Paulo, SP, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil.
Federal University of Juiz de Fora. Institute of Biological Sciences. Department of Biology. Laboratory of Cellular Biology. Juiz de Fora, MG, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / Oswaldo Cruz Foundation. Center for Research. Innovation and Surveillance in COVID-19 and Heath Emergencies. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil.
Federal University of Minas Gerais. Institute of Biological Sciences. Department of Morphology. Center for Gastrointestinal Biology. Belo Horizonte, MG, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Cellular Biology. Rio de Janeiro, RJ, Brazil / Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Parasitic Disease. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / Federal University of the State of Rio de Janeiro. Department of Physiology. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil.
Federal University of Minas Gerais. Institute of Biological Sciences. Department of Morphology. Center for Gastrointestinal Biology. Belo Horizonte, MG, Brazil.
Federal University of Juiz de Fora. Department of Biochemistry. Laboratory of Immunothrombosis. Juiz de Fora, MG, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Cellular Biology. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / Oswaldo Cruz Foundation. Center for Research. Innovation and Surveillance in COVID-19 and Heath Emergencies. Rio de Janeiro, RJ, Brazil.
Oswaldo Cruz Foundation. Center for Research. Innovation and Surveillance in COVID-19 and Heath Emergencies. Rio de Janeiro, RJ, Brazil / Oswaldo Cruz Foundation. Evandro Chagas National Institute of Infectious Diseases. Intensive Care Medicine Laboratory. Rio de Janeiro, RJ, Brazil / D'Or Institute Research and Education. Rio de Janeiro, RJ, Brazil.
University of São Paulo. Department of Biochemistry. Laboratory of Modified Lipids. São Paulo, SP, Brazil.
Federal University of Juiz de Fora. Institute of Biological Sciences. Department of Biology. Laboratory of Cellular Biology. Juiz de Fora, MG, Brazil.
Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / Oswaldo Cruz Foundation. Center for Research. Innovation and Surveillance in COVID-19 and Heath Emergencies. Rio de Janeiro, RJ, Brazil.
Abstract
Background & aims: Lipid droplet (LD) accumulation in cells and tissues is understood to be an evolutionarily conserved tissue tolerance mechanism to prevent lipotoxicity caused by excess lipids; however, the presence of excess LDs has been associated with numerous diseases. Sepsis triggers the reprogramming of lipid metabolism and LD accumulation in cells and tissues, including the liver. The functions and consequences of sepsis-triggered liver LD accumulation are not well known. Methods: Experimental sepsis was induced by CLP (caecal ligation and puncture) in mice. Markers of hepatic steatosis, liver injury, hepatic oxidative stress, and inflammation were analysed using a combination of functional, imaging, lipidomic, protein expression and immune-enzymatic assays. To prevent LD formation, mice were treated orally with A922500, a pharmacological inhibitor of DGAT1. Results: We identified that liver LD overload correlates with liver injury and sepsis severity. Moreover, the progression of steatosis from 24 h to 48 h post-CLP occurs in parallel with increased cytokine expression, inflammatory cell recruitment and oxidative stress. Lipidomic analysis of purified LDs demonstrated that sepsis leads LDs to harbour increased amounts of unsaturated fatty acids, mostly 18:1 and 18:2. An increased content of lipoperoxides within LDs was also observed. Conversely, the impairment of LD formation by inhibition of the DGAT1 enzyme reduces levels of hepatic inflammation and lipid peroxidation markers and ameliorates sepsis-induced liver injury. Conclusions: Our results indicate that sepsis triggers lipid metabolism alterations that culminate in increased liver LD accumulation. Increased LDs are associated with disease severity and liver injury. Moreover, inhibition of LD accumulation decreased the production of inflammatory mediators and lipid peroxidation while improving tissue function, suggesting that LDs contribute to the pathogenesis of liver injury triggered by sepsis. Impact and implications: Sepsis is a complex life-threatening syndrome caused by dysregulated inflammatory and metabolic host responses to infection. The observation that lipid droplets may contribute to sepsis-associated organ injury by amplifying lipid peroxidation and inflammation provides a rationale for therapeutically targeting lipid droplets and lipid metabolism in sepsis.
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