Hepatic NLRP3-Derived Hsp70 Binding to TLR4 Mediates MASLD to MASH Progression upon Inhibition of PP2A by Harmful Algal Bloom Toxin Microcystin, a Second Hit.
Hepatic NLRP3-Derived Hsp70 Binding to TLR4 Mediates MASLD to MASH Progression upon Inhibition of PP2A by Harmful Algal Bloom Toxin Microcystin, a Second Hit.
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DOI：
10.3390/ijms242216354
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发表时间：
2023-11-15
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
有害的藻华毒素微囊藻毒素与代谢功能障碍相关的脂肪性肝病（MASLD）进展和肝细胞癌有关，尽管其机制尚不清楚。使用已建立的MASLD小鼠模型，我们表明NLRP 3-Hsp 70-TLR 4轴部分驱动肝小叶的炎症，导致MASLD进展为代谢功能障碍相关的脂肪性肝炎（MASH）。结果显示，NLRP 3缺陷小鼠表现出MASH病理学降低，Hsp 70表达受阻，并与肝脏炎性体的关键蛋白组分NLRP 3共结合。Hsp 70在肝小叶中和在肝血管系统中细胞外释放，在肝脏中作为TLR 4的配体，主要在肝细胞中激活NF-κB途径，最终导致肝细胞死亡和坏死性凋亡，这是MASH进展的关键病理学。上述研究显示了对炎性小体触发的Hsp 70介导的炎症的新见解，其可能在MASLD病理学中具有更广泛的意义。MASLD到MASH的进展通常需要多次点击。进行性MASLD的介质之一是环境毒素。在这份研究报告中，我们首次展示了一种新的机制，即微囊藻毒素-LR，一种环境毒素，通过触发Hsp 70作为DAMP的释放来激活TLR 4诱导的肝脏炎症，从而将MASLD推进到MASH。
Harmful algal bloom toxin microcystin has been associated with metabolic dysfunction-associated steatotic liver disease (MASLD) progression and hepatocellular carcinoma, though the mechanisms remain unclear. Using an established mouse model of MASLD, we show that the NLRP3–Hsp70–TLR4 axis drives in part the inflammation of the liver lobule that results in the progression of MASLD to metabolic dysfunction-associated steatohepatitis (MASH). Results showed that mice deficient in NLRP3 exhibited decreased MASH pathology, blocked Hsp70 expression, and co-binding with NLRP3, a crucial protein component of the liver inflammasome. Hsp70, both in the liver lobule and extracellularly released in the liver vasculature, acted as a ligand to TLR4 in the liver, primarily in hepatocytes to activate the NF-κB pathway, ultimately leading to hepatic cell death and necroptosis, a crucial pathology of MASH progression. The above studies show a novel insight into an inflammasome-triggered Hsp70-mediated inflammation that may have broader implications in MASLD pathology. MASLD to MASH progression often requires multiple hits. One of the mediators of progressive MASLD is environmental toxins. In this research report, we show for the first time a novel mechanism where microcystin-LR, an environmental toxin, advances MASLD to MASH by triggering the release of Hsp70 as a DAMP to activate TLR4-induced inflammation in the liver.
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小鼠的早期微囊LR暴露于小鼠的炎性体激活会导致脂肪肝病和胰岛素抵抗的发展。
影响因子：
4.3
作者：
Al-Badrani M;Saha P;Mondal A;Seth RK;Sarkar S;Kimono D;Bose D;Porter DE;Scott GI;Brooks B;Raychoudhury S;Nagarkatti M;Nagarkatti P;Chatterjee S
通讯作者：
Chatterjee S
DOI：
10.31083/j.fbs1403019
发表时间：
2022-07-15
期刊：
Frontiers in bioscience (Scholar edition)
影响因子：
--
作者：
Cosemans, Gwenny;Merckx, Caroline;De Paepe, Boel
通讯作者：
De Paepe, Boel
影响因子：
12.7
作者：
Bouhy, Delphine;Juneja, Manisha;Timmerman, Vincent
通讯作者：
Timmerman, Vincent
影响因子：
25.7
作者：
Engelmann, Cornelius;Habtesion, Abeba;Jalan, Rajiv
通讯作者：
Jalan, Rajiv
影响因子：
2.8
作者：
Fawell, JK;Mitchell, RE;Hill, RE
通讯作者：
Hill, RE