Phosphorylation of 17β-hydroxysteroid dehydrogenase 13 at serine 33 attenuates nonalcoholic fatty liver disease in mice.
Phosphorylation of 17β-hydroxysteroid dehydrogenase 13 at serine 33 attenuates nonalcoholic fatty liver disease in mice.
复制标题
DOI：
10.1038/s41467-022-34299-1
复制
发表时间：
2022-11-02
影响因子：
16.6
通讯作者：
Guan, Youfei
中科院分区：
文献类型：
--
作者：
Su, Wen;Wu, Sijin;Yang, Yongliang;Guo, Yanlin;Zhang, Haibo;Su, Jie;Chen, Lei;Mao, Zhuo;Lan, Rongfeng;Cao, Rong;Wang, Chunjiong;Xu, Hu;Zhang, Cong;Li, Sha;Gao, Min;Chen, Xiaocong;Zheng, Zhiyou;Wang, Bing;Liu, Yi'ao;Liu, Zuojun;Wang, Zimei;Liu, Baohua;Fan, Xinmin;Zhang, Xiaoyan;Guan, Youfei
17β-羟基类固醇脱氢酶-13是肝细胞特异性脂滴相关蛋白。一种常见的HSD 17 B13功能丧失变体（rs72613567：TA）可保护患者免受非酒精性脂肪肝疾病的侵害，其潜在机制尚不完全清楚。在本研究中，我们鉴定了17β-HSD 13的丝氨酸33作为进化上保守的PKA靶位点，其磷酸化通过促进其与脂滴上的ATGL的相互作用而促进脂解。Ser 33到Ala的靶向突变（S33 A）通过减少CGI-58介导的ATGL活化来减少培养的肝细胞中ATGL依赖性脂解。重要的是，携带HSD 17 B13 S33 A突变（HSD 17 B1333 A/A）的转基因敲入小鼠品系自发地发展出脂肪分解减少和炎症增加的肝脂肪变性。此外，Hsd 17 B1333 A/A小鼠对高脂饮食诱导的非酒精性脂肪性肝炎更敏感。最后，我们发现reprotrol，一种潜在的17β-HSD 13调节剂和FDA批准的药物，通过PKA介导的17β-HSD 13的Ser 33磷酸化提供对非酒精性脂肪性肝炎的保护。因此，靶向Ser 33磷酸化位点可能代表治疗NASH的潜在方法。17β-羟基类固醇脱氢酶-13（17β-HSD 13）是一种脂滴相关蛋白，其截短变体与慢性肝病风险降低相关。在这里，作者确定了17β-HSD 13中促进脂解的磷酸化位点，并报告说，具有磷酸化缺陷的17β-HSD 13突变体的基因敲入小鼠更容易患非酒精性脂肪性肝炎。
17β-hydroxysteroid dehydrogenase-13 is a hepatocyte-specific, lipid droplet-associated protein. A common loss-of-function variant of HSD17B13 (rs72613567: TA) protects patients against non-alcoholic fatty liver disease with underlying mechanism incompletely understood. In the present study, we identify the serine 33 of 17β-HSD13 as an evolutionally conserved PKA target site and its phosphorylation facilitates lipolysis by promoting its interaction with ATGL on lipid droplets. Targeted mutation of Ser33 to Ala (S33A) decreases ATGL-dependent lipolysis in cultured hepatocytes by reducing CGI-58-mediated ATGL activation. Importantly, a transgenic knock-in mouse strain carrying the HSD17B13 S33A mutation (HSD17B1333A/A) spontaneously develops hepatic steatosis with reduced lipolysis and increased inflammation. Moreover, Hsd17B1333A/A mice are more susceptible to high-fat diet-induced nonalcoholic steatohepatitis. Finally, we find reproterol, a potential 17β-HSD13 modulator and FDA-approved drug, confers a protection against nonalcoholic steatohepatitis via PKA-mediated Ser33 phosphorylation of 17β-HSD13. Therefore, targeting the Ser33 phosphorylation site could represent a potential approach to treat NASH. A truncating variant of 17β-hydroxysteroid dehydrogenase-13 (17β-HSD13), a lipid droplet -associated protein, associates with lower risk of chronic liver disease. Here the authors identify a phosphorylation site in 17β-HSD13 which promotes lipolysis, and report that a knock-in mouse with a 17β-HSD13 mutant defective for phosphorylation is more susceptible to nonalcoholic steatohepatitis.
登录
查看更多内容
细胞色素 P450 Omega-羟化酶 4a14 减轻胆汁淤积性肝纤维化
影响因子：
4
作者：
Li S;Wang C;Zhang X;Su W
通讯作者：
Su W
影响因子：
13.5
作者：
Ong, Kuok Teong;Mashek, Mara T.;Bu, So Young;Greenberg, Andrew S.;Mashek, Douglas G.
通讯作者：
Mashek, Douglas G.
影响因子：
6.5
作者：
Keenan SN;De Nardo W;Lou J;Schittenhelm RB;Montgomery MK;Granneman JG;Hinde E;Watt MJ
通讯作者：
Watt MJ
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
影响因子：
4.8
作者：
Granneman, James G.;Moore, Hsiao-Ping H.;Zhu, Zhengxian
通讯作者：
Zhu, Zhengxian