FABP4 in Paneth cells regulates antimicrobial protein expression to reprogram gut microbiota.
FABP4 in Paneth cells regulates antimicrobial protein expression to reprogram gut microbiota.
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潘氏细胞中的 FABP4 调节抗菌蛋白表达以重新编程肠道微生物群。
DOI：
10.1080/19490976.2022.2139978
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发表时间：
2022-01
期刊：
影响因子：
12.2
通讯作者：
中科院分区：
文献类型：
--
作者：
抗菌蛋白具有广泛的杀菌活性，在塑造肠道微生物群组成方面发挥着重要作用，而肠道微生物群与代谢综合征等多种疾病相关。然而，对于肠道潘氏细胞中防御素表达的调控机制，人们尚未完全了解。在此，我们发现肠道上皮细胞和类器官的潘氏细胞中的脂肪酸结合蛋白4（FABP4）可下调防御素的表达。FABP4fl/flpvillinCreT小鼠对鼠伤寒沙门氏菌（S.T）感染具有高度抗性，且对病原体的杀菌能力增强。FABP4介导的防御素下调是通过K48泛素化后降解过氧化物酶体增殖物激活受体γ（PPARγ）实现的。我们还证实，高脂饮食（HFD）介导的防御素下调是通过诱导潘氏细胞中大量表达FABP4来实现的。FABP4fl/flpvillinCreT小鼠的厚壁菌门/拟杆菌门（F/B）比值低于对照小鼠，这与高脂饮食喂养小鼠的情况相反，表明潘氏细胞中的FABP4可对肠道微生物群进行重编程。有趣的是，FABP4介导的潘氏细胞中防御素下调不仅发生在小鼠身上，在人类中同样存在。更好地理解防御素的调控机制，尤其是高脂饮食介导的潘氏细胞中防御素下调，将为深入了解现代疾病的潜在因素提供思路。
缩写词：
FABP4：脂肪酸结合蛋白4
S.T：鼠伤寒沙门氏菌
HFD：高脂饮食
Defa：α - 防御素
HD5：人α - 防御素5
HD6：人α - 防御素6
F/B：厚壁菌门/拟杆菌门
SFB：分节丝状菌
AMPs：抗菌肽
PPARγ：过氧化物酶体增殖物激活受体γ
P - PPAR：磷酸化的PPAR
Dhx15：DEAD盒解旋酶15
EGF：表皮生长因子
ENR：头蛋白和R - 脊椎蛋白1
CFU：菌落形成单位
Lyz1：溶菌酶1
Saa1：血清淀粉样蛋白A 1
Pla2g2a：磷脂酶A2，IIA组
MMP - 7：基质金属蛋白酶
AU - PAGE：酸 - 尿素聚丙烯酰胺凝胶电泳
PA：棕榈酸
GPR40：G蛋白偶联受体
GF：无菌的
LP：固有层
KO：基因敲除
WT：野生型
Antimicrobial proteins possess a broad spectrum of bactericidal activity and play an important role in shaping the composition of gut microbiota, which is related to multiple diseases such as metabolic syndrome. However, it is incompletely known for the regulation of defensin expression in the gut Paneth cells. Here, we found that FABP4 in the Paneth cells of gut epithelial cells and organoids can downregulate the expression of defensins. FABP4fl/flpvillinCreT mice were highly resistance to Salmonella Typhimurium (S.T) infection and had increased bactericidal ability to pathogens. The FABP4-mediated downregulation of defensins is through degrading PPARγ after K48 ubiquitination. We also demonstrate that high-fat diet (HFD)-mediated downregulation of defensins is through inducing a robust FABP4 in Paneth cells. Firmicutes/Bacteroidetes (F/B) ratio in FABP4fl/flpvillinCreT mice is lower than control mice, which is opposite to that in mice fed HFD, indicating that FABP4 in the Paneth cells could reprogram gut microbiota. Interestingly, FABP4-mediated downregulation of defensins in Paneth cells not only happens in mice but also in human. A better understanding of the regulation of defensins, especially HFD-mediated downregulation of defensin in Paneth cells will provide insights into factor(s) underlying modern diseases. Abbreviations: FABP4: Fatty acid binding protein 4; S. T: Salmonella Typhimurium; HFD: High-fat diet; Defa: α-defensin; 930 HD5: Human α-defensin 5; HD6: Human α-defensin 6; F/B: Firmicutes/Bacteroidetes; SFB: Segmental filamentous bacteria; AMPs: Antimicrobial peptides; PPARγ: Peroxisome proliferator-activated receptor γ; P-PPAR: Phosphorylated PPAR; Dhx15: DEAD-box helicase 15; 935 EGF: Epidermal growth factor; ENR: Noggin and R-spondin 1; CFU: Colony forming unit; Lyz1: Lysozyme 1; Saa1: Serum amyoid A 1; Pla2g2a: Phospholipase A2, group IIA; MMP-7: Matrix metalloproteinase; AU-PAGE: Acid-urea polyacrylamide gel electrophoresis; PA: Palmitic 940 acid; GPR40: G-protein-coupled receptor; GF: Germ-free; EGF: Epidermal growth factor; LP: Lamina propria; KO: Knock out; WT: Wild-type.
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