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
Laboratory of Immunopharmacology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
Center for Research, Innovation and Surveillance in COVID-19 and Heath Emergencies, FIOCRUZ, Rio de Janeiro, Brazil.
JHEP Rep. 2023 Dec 11;6(2):100984. doi: 10.1016/j.jhepr.2023.100984. eCollection 2024 Feb.
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.
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.
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.
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.
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.
细胞和组织中脂滴（LD）的积累被认为是一种进化上保守的组织耐受机制，以防止过量脂质引起的脂毒性；然而，过量脂滴的存在与多种疾病有关。脓毒症会引发脂质代谢重编程以及细胞和组织（包括肝脏）中的脂滴积累。脓毒症引发的肝脏脂滴积累的功能和后果尚不清楚。
通过盲肠结扎和穿刺（CLP）在小鼠中诱导实验性脓毒症。使用功能、成像、脂质组学、蛋白质表达和免疫酶分析等多种方法，分析肝脏脂肪变性、肝损伤、肝脏氧化应激和炎症的标志物。为防止脂滴形成，给小鼠口服A922500（一种DGAT1的药理抑制剂）进行治疗。
我们发现肝脏脂滴过载与肝损伤和脓毒症严重程度相关。此外，CLP后24小时至48小时脂肪变性的进展与细胞因子表达增加、炎症细胞募集和氧化应激同时发生。对纯化脂滴的脂质组学分析表明，脓毒症导致脂滴中不饱和脂肪酸含量增加，主要是18:1和18:2。还观察到脂滴内脂质过氧化物含量增加。相反，通过抑制DGAT1酶来损害脂滴形成，可降低肝脏炎症和脂质过氧化标志物水平，并改善脓毒症诱导的肝损伤。
我们的结果表明，脓毒症引发脂质代谢改变，最终导致肝脏脂滴积累增加。脂滴增加与疾病严重程度和肝损伤相关。此外，抑制脂滴积累可减少炎症介质的产生和脂质过氧化，同时改善组织功能，表明脂滴参与了脓毒症引发的肝损伤的发病机制。
脓毒症是一种由宿主对感染的炎症和代谢反应失调引起的复杂的危及生命的综合征。脂滴可能通过放大脂质过氧化和炎症而导致脓毒症相关器官损伤，这一观察结果为在脓毒症中靶向脂滴和脂质代谢提供了治疗依据。
