Butyrate Protects against Diet-Induced NASH and Liver Fibrosis and Suppresses Specific Non-Canonical TGF-β Signaling Pathways in Human Hepatic Stellate Cells.
Butyrate Protects against Diet-Induced NASH and Liver Fibrosis and Suppresses Specific Non-Canonical TGF-β Signaling Pathways in Human Hepatic Stellate Cells.
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DOI：
10.3390/biomedicines9121954
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发表时间：
2021-12-20
期刊：
影响因子：
4.7
通讯作者：
Morrison MC
中科院分区：
文献类型：
--
作者：
Gart E;van Duyvenvoorde W;Toet K;Caspers MPM;Verschuren L;Nielsen MJ;Leeming DJ;Souto Lima E;Menke A;Hanemaaijer R;Keijer J;Salic K;Kleemann R;Morrison MC
在肥胖相关的非酒精性脂肪性肝炎(NASH)中，持续性的肝细胞损伤和炎症是纤维化的关键驱动因素，而纤维化是NASH相关死亡率的主要决定因素。短链脂肪酸丁酸酯在NASH中具有改善代谢和抗炎的作用。然而，它对NASH相关性肝纤维化的影响尚不清楚。用含2.5%(w/w)丁酸盐的肥胖饲料(HFD)喂养Ldlr-/-Leiden小鼠38周，并与HFD对照组比较，研究了丁酸盐的抗肝纤维化作用。在转化生长因子-β刺激的原代人肝星状细胞上，进一步研究了丁酸盐的抗肝纤维化机制。高脂饲料喂养的小鼠出现肥胖、胰岛素抵抗、血浆瘦素水平升高、脂肪组织炎症、肠道通透性、生物失调和NASH相关的纤维化。丁酸盐纠正高胰岛素血症，降低血浆瘦素水平，减轻脂肪组织炎症，而不影响肠道通透性或微生物区系组成。丁酸能降低血浆ALT和CK-18M30水平，减轻肝脏脂肪变性和炎症。丁酸盐抑制肝纤维化的发展，表现为肝脏胶原含量和天狼星红阳性面积的减少。在转化生长因子-β刺激的肝星状细胞中，丁酸盐呈剂量依赖性地减少胶原沉积，并降低前胶原α1和PAI1蛋白的表达。转录本分析、后续途径分析和上游调节因子分析显示，丁酸可使特定的非典型转化生长因子-β信号通路Rho样GTP酶和PI3K/AKT以及其他重要的促纤维化调节因子(如YAP/TAZ、MYC)失活，为其抗纤维化作用提供了潜在的理论基础。总而言之，丁酸盐可以预防肥胖、胰岛素抵抗相关的NASH和肝纤维化。这些抗纤维化作用至少部分归因于丁酸对肝星状细胞胶原生成的直接影响，包括抑制非典型的转化生长因子-β信号通路。
In obesity-associated non-alcoholic steatohepatitis (NASH), persistent hepatocellular damage and inflammation are key drivers of fibrosis, which is the main determinant of NASH-associated mortality. The short-chain fatty acid butyrate can exert metabolic improvements and anti-inflammatory activities in NASH. However, its effects on NASH-associated liver fibrosis remain unclear. Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic diet (HFD) containing 2.5% (w/w) butyrate for 38 weeks and compared with a HFD-control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). HFD-fed mice developed obesity, insulin resistance, increased plasma leptin levels, adipose tissue inflammation, gut permeability, dysbiosis, and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels, and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 levels and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways Rho-like GTPases and PI3K/AKT and other important pro-fibrotic regulators (e.g., YAP/TAZ, MYC) by butyrate, providing a potential rationale for its antifibrotic effects. In conclusion, butyrate protects against obesity development, insulin resistance-associated NASH, and liver fibrosis. These antifibrotic effects are at least partly attributable to a direct effect of butyrate on collagen production in hepatic stellate cells, involving inhibition of non-canonical TGF-β signaling pathways.
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影响因子：
5.5
作者：
Higgins CE;Tang J;Higgins SP;Gifford CC;Mian BM;Jones DM;Zhang W;Costello A;Conti DJ;Samarakoon R;Higgins PJ
通讯作者：
Higgins PJ
影响因子：
5.2
作者：
Mueller AM;Kleemann R;Gart E;van Duyvenvoorde W;Verschuren L;Caspers M;Menke A;Krömmelbein N;Salic K;Burmeister Y;Seilheimer B;Morrison MC
通讯作者：
Morrison MC
影响因子：
4.2
作者：
Leeming, Diana J.;Nielsen, Mette J.;Karsdal, Morten A.
通讯作者：
Karsdal, Morten A.
影响因子：
5.6
作者：
Ghosh, Asish K.;Vaughan, Douglas E.
通讯作者：
Vaughan, Douglas E.
影响因子：
3.6
作者：
Bouter K;Bakker GJ;Levin E;Hartstra AV;Kootte RS;Udayappan SD;Katiraei S;Bahler L;Gilijamse PW;Tremaroli V;Stahlman M;Holleman F;van Riel NAW;Verberne HJ;Romijn JA;Dallinga-Thie GM;Serlie MJ;Ackermans MT;Kemper EM;Willems van Dijk K;Backhed F;Groen AK;Nieuwdorp M
通讯作者：
Nieuwdorp M