Neutral Ceramidase Mediates Nonalcoholic Steatohepatitis by Regulating Monounsaturated Fatty Acids and Gut IgA(+) B Cells.
Neutral Ceramidase Mediates Nonalcoholic Steatohepatitis by Regulating Monounsaturated Fatty Acids and Gut IgA(+) B Cells.
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中性神经酶通过调节单不饱和脂肪酸和肠道IgA（+）B细胞来介导非酒精性脂肪性肝炎。
DOI：
10.1002/hep.31628
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Deng Z
中科院分区：
文献类型：
--
作者：
Gu X;Sun R;Chen L;Chu S;Doll MA;Li X;Feng W;Siskind L;McClain CJ;Deng Z
非酒精性脂肪性肝炎（NASH）与肥胖和肝硬化和癌症风险增加有关。中性神经酰胺酶（Neutral ceramidase，NcDase）在小肠刷状缘高度表达，在消化膳食鞘脂（神经酰胺）以调节鞘氨醇和游离脂肪酸（free fatty acids，FFA）平衡中起关键作用。肥胖相关的NcDase改变是否有助于NASH的表现仍未解决。在此，我们揭示了NASH小鼠模型中中性神经酰胺酶缺乏可预防肝脏炎症和纤维化，但不能预防脂肪变性。在不同的饮食条件下，NcDase−/−小鼠表现出SCD 1表达减少，单不饱和脂肪酸（MUFA）组成减少。我们进一步发现，中性神经酰胺酶是肠B细胞的功能调节剂，并影响对肠道细菌的分泌型伊加应答的丰度和质量。对肠道微生物群组成的分析发现，NcDase−/−小鼠中的梭菌定植增加。来自NcDase−/−小鼠的肠道微生物群在无菌小鼠中的定殖导致相对于野生型（WT）同窝小鼠的肠道微生物群，肝脏中SCD 1表达和MUFA水平的降低更大，这与伊加结合细菌的交替相关，包括瘤胃球菌科的增加和脱硫弧菌的减少。从机制上讲，NcDase是控制SCD 1表达和MUFA介导的Wnt/β-catenin激活的关键环节。非常重要的是，我们的实验进一步证明了Wnt 3a刺激可以增强肝细胞中中性神经酰胺酶的活性。因此，NcDase-SCD 1-Wnt反馈环通过调节肠道伊加+免疫细胞促进饮食诱导的脂肪性肝炎和纤维化。
Nonalcoholic steatohepatitis (NASH) is associated with obesity and an increased risk for liver cirrhosis and cancer. Neutral ceramidase (NcDase), highly expressed in the intestinal brush border of the small intestine, plays a critical role in digesting dietary sphingolipids (ceramide) to regulate the balance of sphingosine and free fatty acids (FFAs). It remains unresolved whether obesity-associated alteration of NcDase contributes to the manifestation of NASH. Here we revealed that neutral ceramidase deficiency in murine models of NASH prevents hepatic inflammation and fibrosis, but not steatosis. NcDase−/− mice display reduced SCD1 expression with a compositional decrease of monounsaturated fatty acids (MUFAs) under the different dietary conditions. We further found that neutral ceramidase is a functional regulator of intestinal B cells and influences the abundance and quality of the secretory IgA response toward commensal bacteria. Analysis of composition of the gut microbiota found that Clostridiales colonization was increased in NcDase−/− mice. The colonization of germ-free mice with gut microbiota from NcDase−/− mice resulted in a greater decrease in the expression of SCD1 and the level of MUFAs in the liver relative to gut microbiota from wild-type (WT) littermates, which are associated with the alternation of IgA bound bacteria including increase of Ruminococcaceae and reduction of Desulfovibrio. Mechanistically, NcDase is a crucial link that controls the expression of SCD1 and MUFAs‐mediated activation of the Wnt/β-catenin. Very importantly, our experiments further demonstrated that Wnt3a stimulation can enhance the activity of neutral ceramidase in hepatocytes. Thus, the NcDase-SCD1-Wnt feedback loop promotes the diet-induced steatohepatitis and fibrosis through the regulation of intestinal IgA+ immune cells.
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影响因子：
30.3
作者：
Kubinak JL;Petersen C;Stephens WZ;Soto R;Bake E;O'Connell RM;Round JL
通讯作者：
Round JL
影响因子：
16.6
作者：
Kindt A;Liebisch G;Clavel T;Haller D;Hörmannsperger G;Yoon H;Kolmeder D;Sigruener A;Krautbauer S;Seeliger C;Ganzha A;Schweizer S;Morisset R;Strowig T;Daniel H;Helm D;Küster B;Krumsiek J;Ecker J
通讯作者：
Ecker J
影响因子：
56.9
作者：
Petersen, Charisse;Bell, Rickesha;Round, June L.
通讯作者：
Round, June L.
影响因子：
8.8
作者：
Rios-Esteves J;Resh MD
通讯作者：
Resh MD
影响因子：
32.4
作者：
Chu, Van Trung;Beller, Alexander;Berek, Claudia
通讯作者：
Berek, Claudia