Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis.
Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis.
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DOI：
10.1073/pnas.2217543120
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发表时间：
2023-01-24
影响因子：
11.1
通讯作者：
Shulman, Gerald I.
中科院分区：
文献类型：
--
作者：
Luukkonen, Panu K.;Sakuma, Ikki;Gaspar, Rafael C.;Mooring, Meghan;Nasiri, Ali;Kahn, Mario;Zhang, Xian-Man;Zhang, Dongyan;Sammalkorpi, Henna;Penttilae, Anne K.;Orho-Melander, Marju;Arola, Johanna;Juuti, Anne;Zhang, Xuchen;Yimlamai, Dean;Yki-Jaervinen, Hannele;Petersen, Kitt Falk;Shulman, Gerald I.
关键词：
非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病，其预后取决于肝纤维化。羟基类固醇17-β脱氢酶13（HSD 17 B13）的功能丧失变体与肝纤维化减少有关，但其潜在机制仍不清楚。在这里，我们证明了对肝纤维化的保护所赋予的人类和Hsd 17 b13敲低小鼠的变异与减少嘧啶catalysts在二氢嘧啶脱氢酶的水平。两种常见的NAFLD小鼠模型的特征在于显著的肝嘧啶耗竭。此外，二氢嘧啶脱氢酶抑制剂对嘧啶催化剂的药理学抑制表现出对肝纤维化的保护作用。我们的数据表明嘧啶catenin作为NAFLD的治疗靶点。非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病，其预后取决于肝纤维化。羟基类固醇17-β脱氢酶13（HSD 17 B13，rs72613567-A）的一种常见变异与NAFLD中纤维化风险降低相关，但其潜在机制仍不清楚。我们研究了这种变体在人类肝脏中的作用，并通过使用最先进的代谢组学方法在小鼠中敲低Hsd 17 b13。我们证明，在人类中由HSD 17 B13 rs72613567-A变体和在小鼠中由Hsd 17 b13敲低赋予的对肝纤维化的保护与在二氢嘧啶脱氢酶水平上减少嘧啶催化剂有关。此外，我们表明，肝嘧啶消耗在两个不同的小鼠模型的NAFLD和抑制嘧啶catenocopies由gimeracil的HSD 17 B13诱导的保护肝纤维化。我们的数据表明嘧啶类药物可以作为治疗NAFLD肝纤维化的靶点。
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which the prognosis is determined by liver fibrosis. A loss-of-function variant in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) is associated with decreased liver fibrosis, but the underlying mechanisms remain unclear. Here, we demonstrate that protection against liver fibrosis conferred by the variant in humans and by Hsd17b13 knockdown in mice is associated with decreased pyrimidine catabolism at the level of dihydropyrimidine dehydrogenase. Two common mouse models of NAFLD are characterized by a marked hepatic pyrimidine depletion. Furthermore, pharmacological inhibition of pyrimidine catabolism by a dihydropyrimidine dehydrogenase inhibitor phenocopies the protection against liver fibrosis. Our data suggest pyrimidine catabolism as a therapeutic target in NAFLD. Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which prognosis is determined by liver fibrosis. A common variant in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13, rs72613567-A) is associated with a reduced risk of fibrosis in NAFLD, but the underlying mechanism(s) remains unclear. We investigated the effects of this variant in the human liver and in Hsd17b13 knockdown in mice by using a state-of-the-art metabolomics approach. We demonstrate that protection against liver fibrosis conferred by the HSD17B13 rs72613567-A variant in humans and by the Hsd17b13 knockdown in mice is associated with decreased pyrimidine catabolism at the level of dihydropyrimidine dehydrogenase. Furthermore, we show that hepatic pyrimidines are depleted in two distinct mouse models of NAFLD and that inhibition of pyrimidine catabolism by gimeracil phenocopies the HSD17B13-induced protection against liver fibrosis. Our data suggest pyrimidine catabolism as a therapeutic target against the development of liver fibrosis in NAFLD.
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影响因子：
25.7
作者：
Luukkonen PK;Qadri S;Ahlholm N;Porthan K;Männistö V;Sammalkorpi H;Penttilä AK;Hakkarainen A;Lehtimäki TE;Gaggini M;Gastaldelli A;Ala-Korpela M;Orho-Melander M;Arola J;Juuti A;Pihlajamäki J;Hodson L;Yki-Järvinen H
通讯作者：
Yki-Järvinen H
DOI：
10.1002/hep.30350
发表时间：
2019-04
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Ma Y;Belyaeva OV;Brown PM;Fujita K;Valles K;Karki S;de Boer YS;Koh C;Chen Y;Du X;Handelman SK;Chen V;Speliotes EK;Nestlerode C;Thomas E;Kleiner DE;Zmuda JM;Sanyal AJ;(for the Nonalcoholic Steatohepatitis Clinical Research Network);Kedishvili NY;Liang TJ;Rotman Y
通讯作者：
Rotman Y
DOI：
10.1016/j.bbagrm.2016.04.010
发表时间：
2016-09
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Cui JY;Klaassen CD
通讯作者：
Klaassen CD
影响因子：
65.1
作者：
Sanyal, Arun J.
通讯作者：
Sanyal, Arun J.
影响因子：
29
作者：
Ezagouri, Saar;Zwighaft, Ziv;Asher, Gad
通讯作者：
Asher, Gad