17-Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated With Histological Features of Nonalcoholic Fatty Liver Disease.
17-Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated With Histological Features of Nonalcoholic Fatty Liver Disease.
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DOI：
10.1002/hep.30350
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发表时间：
2019-04
期刊：
影响因子：
--
通讯作者：
Rotman Y
中科院分区：
文献类型：
--
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
非酒精性脂肪肝（NAFLD）是慢性肝病的常见原因。单核苷酸多态性（SNP）rs6834314与一般人群中的血清肝酶相关，可能反映了肝脏脂肪或损伤。我们研究了rs6834314及其最近的基因，HSD17 B13（17-β羟类固醇脱氢酶13），以确定与NAFLD组织学特征的相关性，并表征HSD17 B13在NAFLD发病机制中的功能作用。rs6834314的次要等位基因与768例经活检证实患有NAFLD的成年高加索人和一般人群中的肝硬化的脂肪变性增加显著相关，但与炎症、气球样变、Mallory-Denk小体和肝酶水平降低显著相关。我们在HSD17B13基因中发现了两种可能的致病变异。rs72613567，一个与rs6834314高度连锁的剪接位点SNP（r2 = 0.94）产生了新的剪接变体，并显示出与NAFLD组织学相关的相似模式。其次要等位基因产生外显子6跳跃和G-核苷酸插入变体的同时表达。另一个SNP rs62305723（编码P260S突变）与气球样变和炎症的减少显著相关。在NAFLD患者中，HSD17 B13的肝脏表达高5.9倍（p = 0.003）。HSD17 B13靶向脂滴，需要保守的AA22 - 28序列和AA71 - 106区域。该蛋白具有视黄醇脱氢酶（RDH）活性，酶活性依赖于脂滴靶向和辅因子结合位点。外显子6缺失、G插入和新描述的天然存在的P260S突变都使酶活性丧失。总之，我们证明了HSD17B13变异体与NAFLD组织学特征的相关性，并将该酶鉴定为脂滴相关RDH。我们的数据表明，HSD17 B13通过其酶活性在NAFLD中发挥作用。
Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. A single nucleotide polymorphism (SNPs), rs6834314, was associated with serum liver enzymes in the general population, presumably reflecting liver fat or injury. We studied rs6834314 and its nearest gene, HSD17B13 (17-beta hydroxysteroid dehydrogenase 13) to identify associations with histological features of NAFLD, and to characterize the functional role of HSD17B13 in NAFLD pathogenesis. The minor allele of rs6834314 was significantly associated with increased steatosis, but decreased inflammation, ballooning, Mallory-Denk bodies, and liver enzyme levels in 768 adult Caucasians with biopsy-proven NAFLD, and with cirrhosis in the general population. We found two plausible causative variants in the HSD17B13 gene. rs72613567, a splice-site SNP in high linkage with rs6834314 (r2=0.94) generates novel splice variants and shows a similar pattern of association with NAFLD histology. Its minor allele generates simultaneous expression of exon 6-skipping and G-nucleotide insertion variants. Another SNP, rs62305723 (encoding a P260S mutation) is significantly associated with decreased ballooning and inflammation. Hepatic expression of HSD17B13 is 5.9-fold higher (p=0.003) in patients with NAFLD. HSD17B13 is targeted to lipid droplets, requiring the conserved AA22–28 sequence and AA71–106 region. The protein has a retinol dehydrogenase (RDH) activity, with enzymatic activity dependent on lipid droplet targeting and co-factor binding site. The exon 6-deletion, G-insertion, and newly-described naturally-occurring P260S mutation, all confer loss of enzymatic activity. In conclusion, we demonstrate the association of variants in HSD17B13 with specific features of NAFLD histology, and identify the enzyme as a lipid droplet-associated RDH. Our data suggest that HSD17B13 plays a role in NAFLD through its enzymatic activity.
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影响因子：
3.9
作者：
Horiguchi, Yuka;Araki, Makoto;Motojima, Kiyoto
通讯作者：
Motojima, Kiyoto
影响因子：
30.8
作者：
Holmen OL;Zhang H;Fan Y;Hovelson DH;Schmidt EM;Zhou W;Guo Y;Zhang J;Langhammer A;Løchen ML;Ganesh SK;Vatten L;Skorpen F;Dalen H;Zhang J;Pennathur S;Chen J;Platou C;Mathiesen EB;Wilsgaard T;Njølstad I;Boehnke M;Chen YE;Abecasis GR;Hveem K;Willer CJ
通讯作者：
Willer CJ
DOI：
10.1073/pnas.1323785111
发表时间：
2014-06-17
影响因子：
11.1
作者：
Mahdessian, Hovsep;Taxiarchis, Apostolos;van't Hooft, Ferdinand
通讯作者：
van't Hooft, Ferdinand
影响因子：
2.9
作者：
Duax, WL;Pletnev, V;Weeks, CM
通讯作者：
Weeks, CM
影响因子：
2.9
作者：
Belyaeva, OV;Korkina, OV;Kedishvili, NY
通讯作者：
Kedishvili, NY