骨髓PGC1β通过线粒体裂变/mtDNA/Nlrp3途径减轻高脂饮食引起的炎症。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2024-10-02 DOI:10.1016/j.bbadis.2024.167528

En Li , Jiajia Ji , Gaoyang Zong , Hao Liu , Yue Sun , Liangliang Wei , Zhihao Xia , Xiaoyu Yang , Dageng Huang , Yan Zhang

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引用次数: 0

摘要

过氧化物酶体增殖体激活受体γ辅助激活因子1β（PGC1β）在线粒体氧化磷酸化和替代性巨噬细胞激活过程中至关重要。为了确定 PGC1β 在肥胖诱导的炎症中的作用，我们用高脂饮食（HFD）喂养 Ppargc1b（PGC1β 编码基因）髓系条件性基因敲除小鼠（cKO），以研究其以下影响。我们发现，喂食高脂饮食的 cKO 小鼠脂肪增加较多，血清甘油三酯（TG）、低密度脂蛋白（LDL）、脂肪连接蛋白和瘦素增加。HFD喂养的cKO小鼠脂肪生成受刺激，而脂肪分解受阻。在喂食高密度脂蛋白的 cKO 小鼠肝脏中，糖元生成、脂肪生成和脂肪酸摄取受到刺激，而脂肪分解受到抑制。表明脂肪肝的血清丙氨酸转氨酶（ALT）水平也升高了。cKO 小鼠的炎症细胞因子（包括肿瘤坏死因子-α（TNF-α）、IL-1β 和 IL-6）升高，并伴有葡萄糖不耐受和胰岛素抵抗。以高密度脂蛋白饲料喂养的cKO小鼠能量消耗减少。进一步的证据表明，cKO 小鼠的巨噬细胞在体外容易重新极化为 M1 炎症型。除了线粒体生物生成和氧化呼吸外，PGC1β还能调节线粒体裂变和细胞膜线粒体DNA（mtDNA）释放，从而促进NLR家族含吡咯啉结构域3（Nlrp3）炎性体的启动和激活。线粒体裂变抑制剂可抑制PGC1β耗竭诱导的Nlrp3和IL-1β mRNA水平的升高。敲除 Nlrp3 可恢复 PGC1β 缺乏诱导的 IL-1β mRNA 表达。骨髓PGC1β调节脂肪细胞的脂肪生成和脂肪分解。PGC1β功能缺失和mtDNA丰度与肥胖和糖尿病相关。这些观察结果揭示了 PGC1β 对肥胖引起的全身炎症的保护作用。增强骨髓PGC1β的功能可能是干预肥胖及相关疾病的一种潜在策略。

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Myeloid PGC1β attenuates high-fat-diet induced inflammation via mitochondrial fission/mtDNA/Nlrp3 pathway

Peroxisome proliferator-activated receptor gamma coactivators 1β (PGC1β) is essential in mitochondrial oxidative phosphorylation and alternative macrophages activation. To determine the contribution of PGC1β in obesity induced inflammation, Ppargc1b (PGC1β coding gene) myeloid conditional knockout mice (cKO) were fed with high fat diet (HFD) to examine the following effects. We found that HFD-fed cKO mice gained more fat with increased serum triglyceride (TG), low density lipoprotein (LDL), adiponectin, and leptin. Adipogenesis was stimulated while lipolysis was retarded in HFD-fed cKO mice adipose. Gluconeogenesis, lipogenesis, and fatty acid uptake were provoked while lipolysis was inhibited in HFD-fed cKO liver. Serum alanine transaminase (ALT) level, indicating fatty liver, also increased. Inflammatory cytokine including tumor necrosis factor-α (TNF-α), IL-1β, and IL-6 was elevated in cKO mice, accompanied with glucose intolerant and insulin resistance. Energy expenditure was decreased in HFD-fed cKO mice. Further evidence showed that cKO macrophages were prone to repolarize into M1 inflammatory type in vitro. In addition to mitochondrial biogenesis and oxidative respiration, PGC1β also modulated mitochondrial fission and cytosolic mitochondrial DNA (mtDNA) release, contributing to NLR family pyrin domain containing 3 (Nlrp3) inflammasome priming and activation. Treatment of mitochondrial fission inhibitor abolished the increased mRNA levels of Nlrp3 and IL-1β induced by PGC1β depletion. Nlrp3 knockdown restored the induced IL-1β mRNA expression by PGC1β deficiency. Myeloid PGC1β regulated adipocyte adipogenesis and lipolysis. PGC1β loss-of-function and mtDNA abundance correlated with obesity and diabetes. These observations uncovered the protective role of PGC1β against obesity induced systemic inflammation. Enhancing myeloid PGC1β function may be a potential strategy for the intervention of obesity and related diseases.

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来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.