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PREVENTION OF LIPID DROPLET ACCUMULATION BY DGAT1 INHIBITION AMELIORATES SEPSIS-INDUCED LIVER INJURY AND INFLAMMATION
Produção científica do Laboratório de Doenças Parasitárias.
Produção científica do Laboratório de Imunofarmacologia.
Authors' contributions: Lívia Teixeira and Patrícia T. Bozza conceptualised the study.
Lívia Teixeira, Filipe Santos Pereira Dutra, Patrícia Alves Reis, and Patrícia T. Bozza were responsible for the design and conducted the main experiments.
Contributing to the in vivo treatment, CLP surgeries and in vivo data collection: Lívia Teixeira, Filipe Santos Pereira Dutra, Patrícia Alves Reis, Tamires da Cunha Fernandes, Tathiany Igreja da Silva and Cassiano Felippe Gonçalves de Albuquerque.
Ex vivo analysis: Ellen Kiarely de Souza, Luciana de Souza Moreira, Hugo Espinheira da Silva, Maísa Mota Antunes, Eugenio Damaceno Hottz, Clarissa Menezes Maya Monteiro.
Performing respirometry analysis and data processing: Ana Cristina Souza Bombaça.
Performing lipidomic analysis and data processing: Lívia Teixeira, Ester de Andrade Barreto, and Marcos Yukio Yoshinaga.
Rubem Figueiredo Sadok Menna Barreto, Gustavo Batista de Menezes, RFAB, Sayuri Miyamoto, RCNM and Patrícia T. Bozza contributed to the study design and data analysis and critically revised the article.
The manuscript was drafted by Lívia Teixeira, Filipe Santos Pereira Dutra, and Patrícia T. Bozza and edited by all authors.
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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.
Publisher
Elsevier
Citation
TEIXEIRA, Lívia et al. Prevention of lipid droplet accumulation by DGAT1 inhibition ameliorates sepsis-induced liver injury and inflammation. JHEP Reports, v. 6, n. 2, p. 1-12, Feb. 2024.DOI
10.1016/j.jhepr.2023.100984ISSN
2589-5559Notes
Produção científica do Laboratório de Biologia Celular.Produção científica do Laboratório de Doenças Parasitárias.
Produção científica do Laboratório de Imunofarmacologia.
Authors' contributions: Lívia Teixeira and Patrícia T. Bozza conceptualised the study.
Lívia Teixeira, Filipe Santos Pereira Dutra, Patrícia Alves Reis, and Patrícia T. Bozza were responsible for the design and conducted the main experiments.
Contributing to the in vivo treatment, CLP surgeries and in vivo data collection: Lívia Teixeira, Filipe Santos Pereira Dutra, Patrícia Alves Reis, Tamires da Cunha Fernandes, Tathiany Igreja da Silva and Cassiano Felippe Gonçalves de Albuquerque.
Ex vivo analysis: Ellen Kiarely de Souza, Luciana de Souza Moreira, Hugo Espinheira da Silva, Maísa Mota Antunes, Eugenio Damaceno Hottz, Clarissa Menezes Maya Monteiro.
Performing respirometry analysis and data processing: Ana Cristina Souza Bombaça.
Performing lipidomic analysis and data processing: Lívia Teixeira, Ester de Andrade Barreto, and Marcos Yukio Yoshinaga.
Rubem Figueiredo Sadok Menna Barreto, Gustavo Batista de Menezes, RFAB, Sayuri Miyamoto, RCNM and Patrícia T. Bozza contributed to the study design and data analysis and critically revised the article.
The manuscript was drafted by Lívia Teixeira, Filipe Santos Pereira Dutra, and Patrícia T. Bozza and edited by all authors.
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