Pulmonary succinate receptor 1 elevation in high-fat diet mice exacerbates lipopolysaccharides-induced acute lung injury via sensing succinate

作者全名：Liu, Ling; Tang, Wenjing; Wu, Siqi; Ma, Jingyue; Wei, Ke

作者地址：[Liu, Ling; Tang, Wenjing; Wu, Siqi; Ma, Jingyue; Wei, Ke] Chongqing Med Univ, Dept Anesthesiol, Affiliated Hosp 1, Chongqing 400016, Peoples R China

通信作者：Wei, K (通讯作者)，Chongqing Med Univ, Dept Anesthesiol, Affiliated Hosp 1, Chongqing 400016, Peoples R China.

来源：BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001223600400001

JCR分区：Q1

影响因子：4.2

年份：2024

卷号：1870

期号：5

开始页：　

结束页：　

文献类型：Article

关键词：Obesity; Acute lung injury; Succinate; Succinate receptor 1; Lipopolysaccharides

摘要：Background: Individuals with obesity have higher level of circulating succinate, which acts as a signaling factor that initiates inflammation. It is obscure whether succinate and succinate receptor 1 (SUCNR1) are involved in the process of obesity aggravating acute lung injury (ALI). Methods: The lung tissue and blood samples from patients with obesity who underwent lung wedgectomy or segmental resection were collected. Six-week-old male C57BL/6J mice were fed a high-fat diet for 12 weeks to induce obesity and lipopolysaccharides (LPS) were injected intratracheally (100 mu g, 1 mg/ml) for 24 h to establish an ALI model. The pulmonary SUCNR1 expression and succinate level were measured. Exogenous succinate was supplemented to assess whether succinate exacerbated the LPS-induced lung injury. We next examined the cellular localization of pulmonary SUCNR1. Furthermore, the role of the succinate-SUCNR1 pathway in LPS-induced inflammatory responses in MH-s macrophages and obese mice was investigated. Result: The pulmonary SUCNR1 expression and serum succinate level were significantly increased in patients with obesity and in HFD mice. Exogenous succinate supplementation significantly increased the severity of ALI and inflammatory response. SUCNR1 was mainly expressed on lung macrophages. In LPS-stimulated MH-s cells, knockdown of SUCNR1 expression significantly inhibited pro-inflammatory cytokines' expression, the increase of hypoxia-inducible factor-1 alpha (HIF-1 alpha) expression, inhibitory kappa B-alpha (I kappa B-alpha) phosphorylation, p65 phosphorylation and p65 translocation to nucleus. In obese mice, SUCNR1 inhibition significantly alleviated LPS-induced lung injury and decreased the HIF-1 alpha expression and I kappa B-alpha phosphorylation. Conclusion: The high expression of pulmonary SUCNR1 and serum succinate accumulation at least partly participate in the process of obesity aggravating LPS-induced lung injury.

基金机构：Chongqing Science & Technology Bureau [CSTC2019jscx-msxmX0214]; Chongqing Municipal Health Commission [2017HBRC001]

基金资助正文：This work was supported by grants from Chongqing Science & Technology Bureau (Project no. CSTC2019jscx-msxmX0214), Chongqing Municipal Health Commission (Project no. 2017HBRC001).