Mechanism of action and clinical application of 17β-hydroxysteroid dehydrogenase 13 in alcohol-related liver diseases
-
摘要: 17β-羟基类固醇脱氢酶13(HSD17B13)是一种新型肝细胞特异性脂滴相关蛋白,参与肝细胞脂质合成。最近的研究发现,HSD17B13基因的插入缺失变体与慢性肝脏疾病风险降低相关。然而HSD17B13具体的生物学功能和参与肝脏疾病的发病机制尚不明确。阐述了HSD17B13的生物学功能及其在酒精性肝病中的作用机制及临床应用研究进展。
-
关键词:
- 肝疾病,酒精性 /
- 17-羟甾类脱氢酶类 /
- 基因表达调控
Abstract: As a new hepatocyte-specific lipid droplet-related protein,17β-hydroxysteroid dehydrogenase 13( HSD17 B13) is involved in hepatocyte lipid synthesis. Recent studies have shown that an insertion-deletion variant of the HSD17 B13 gene is associated with a reduced risk of chronic liver diseases; however,the specific biological function of HSD17 B13 and its involvement in the pathogenesis of liver diseases remain unclear. This article elaborates on the biological function of HSD17 B13,its mechanism of action in alcohol-related liver,and the research advances in clinical application. -
[1] GAO B,BATALLER R. Alcoholic liver disease:Pathogenesis and new therapeutic targets[J]. Gastroenterology,2011,141(5):1572-1585. [2] WHO. Global Health Estimates 2015:Deaths by cause,age,sex,by country and by region,2000-2015[EB/OL].(2016)https://www. who. int/healthinfo/global_burden_disease/estimates_regional_2000_2015/en/. [3] STICKEL F,BUCH S,LAU K,et al. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians[J]. Hepatology,2011,53(1):86-95. [4] TIAN C,STOKOWSKI RP,KERSHENOBICH D,et al. Variant in PNPLA3 is associated with alcoholic liver disease[J]. Nat Genet,2010,42(1):21-23. [5] TRPO E,GUSTOT T,DEGRD,et al. Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease[J]. J Hepatol,2011,55(4):906-912. [6] BURZA MA,MOLINARO A,ATTILIA ML,et al. PNPLA3 I148M(rs738409)genetic variant and age at onset of at-risk alcohol consumption are independent risk factors for alcoholic cirrhosis[J]. Liver Int,2014,34(4):514-520. [7] BUCH S,STICKEL F,TRPO E,et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis[J]. Nat Genet,2015,47(12):1443-1448. [8] ZHANG Y,GUO T,YANG F,et al. Single-nucleotide rs738409polymorphisms in the PNPLA3 gene are strongly associated with alcoholic liver disease in Han Chinese males[J]. Hepatol Int,2018,12(5):429-437. [9] STICKEL F,BUCH S,NISCHALKE HD,et al. Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis[J]. Am J Gastroenterol,2018,113(10):1475-1483. [10] ABUL-HUSN NS,CHENG X,LI AH,et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease[J]. N Engl J Med,2018,378(12):1096-1106. [11] SU W,MAO Z,LIU Y,et al. Role of HSD17B13 in the liver physiology and pathophysiology[J]. Mol Cell Endocrinol,2019,489:119-125. [12] LIU S,HUANG C,LI D,et al. Molecular cloning and expression analysis of a new gene for short-chain dehydrogenase/reductase 9[J]. Acta Biochim Pol,2007,54(1):213-218. [13] ZHANG X,WANG Y,LIU P. Omic studies reveal the pathogenic lipid droplet proteins in non-alcoholic fatty liver disease[J]. Protein Cell,2017,8(1):4-13. [14] SU W,WANG Y,JIA X,et al. Comparative proteomic study reveals 17β-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease[J]. Proc Natl Acad Sci U S A,2014,111(31):11437-11442. [15] ADAM M,HEIKELH,SOBOLEWSKI C,et al. Hydroxysteroid(17β)dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice[J]. FASEB J,2018,32(6):3434-3447. [16] MA Y,BELYAEVA OV,BROWN PM,et al. 17-beta hydroxysteroid dehydrogenase 13 is a hepatic retinol dehydrogenase associated with histological features of nonalcoholic fatty liver disease[J]. Hepatology,2019,69(4):1504-1519. [17] SEITZ HK,BATALLER R,CORTEZ-PINTO H,et al. Alcoholic liver disease[J]. Nat Rev Dis Primers,2018,4(1):16. [18] BARAONA E,LIEBER CS. Effects of ethanol on lipid metabolism[J]. J Lipid Res,1979,20(3):289-315. [19] JEON S,CARR R. Alcohol effects on hepatic lipid metabolism[J]. J Lipid Res,2020,61(4):470-479. [20] SU W,PENG J,LI S,et al. Liver X receptorαinduces 17β-hydroxysteroid dehydrogenase-13 expression through SREBP-1c[J]. Am J Physiol Endocrinol Metab,2017,312(4):e357-e367. [21] ANSARI RA,HUSAIN K,RIZVI SA. Role of transcription factors in steatohepatitis and hypertension after ethanol:The epicenter of metabolism[J]. Biomolecules,2016,6(3):29. [22] de AZEVEDO LA,MATTE U,da SILVEIRA TR,et al. Genetic variants underlying vitamin D metabolism and VDR-TGFβ-1-SMAD3 interaction may impact on HCV progression:A study based on dbGaP data from the HALT-C study[J]. J Hum Genet,2017,62(11):969-977. [23] STICKEL F,LUTZ P,BUCH S,et al. Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers[J]. Hepatology,2020,72(1):88-102. [24] GELLERT-KRISTENSEN H,NORDESTGAARD BG,TYBJAERGHANSEN A,et al. High risk of fatty liver disease amplifies the alanine transaminase-lowering effect of a HSD17B13 variant[J].Hepatology,2020,71(1):56-66. [25] YANG J,TRPO E,NAHON P,et al. A 17-beta-hydroxysteroid dehydrogenase 13 variant protects from hepatocellular carcinoma development in alcoholic liver disease[J]. Hepatology,2019,70(1):231-240. [26] XU G,YANG F,DING CL,et al. Small nucleolar RNA 113-1suppresses tumorigenesis in hepatocellular carcinoma[J].Mol Cancer,2014,13:216. [27] CHEN J,ZHUO JY,YANG F,et al. 17-beta-hydroxysteroid dehydrogenase 13 inhibits the progression and recurrence of hepatocellular carcinoma[J]. Hepatobiliary Pancreat Dis Int,2018,17(3):220-226. [28] ZENG CM,YAN ML,SHI YH,et al. Changes in the expression of 17-β-hydroxysteroid dehydrogenase 13 and mitofusin 2 in liver cancer tissue and a bioinformatics analysis[J].J Clin Hepatol,2019,35(12):2736-2740.(in Chinese)曾钗明,严茂林,石益海,等.17β羟基类固醇脱氢酶13和线粒体融合蛋白2在肝细胞癌组织中的表达变化及生物信息学分析[J].临床肝胆病杂志,2019,35(12):2736-2740. [29] WANG X,LIAO X,YANG C,et al. Identification of prognostic biomarkers for patients with hepatocellular carcinoma after hepatectomy[J]. Oncol Rep,2019,41(3):1586-1602. [30] XING X,HUANG Y,WANG S,et al. Comparative analysis of primary hepatocellular carcinoma with single and multiple lesions by i TRAQ-based quantitative proteomics[J]. J Proteomics,2015,128:262-271. [31] HORIGUCHI Y,ARAKI M,MOTOJIMA K. 17beta-hydroxysteroid dehydrogenase type 13 is a liver-specific lipid droplet-associated protein[J]. Biochem Biophys Res Commun,2008,370(2):235-238. [32] ROTROFF DM,PIJUT SS,MARVEL SW,et al. Genetic variants in HSD17B3,SMAD3,and IPO11 impact circulating lipids in response to fenofibrate in individuals with type 2 diabetes[J]. Clin Pharmacol Ther,2018,103(4):712-721. [33] YOUNOSSI Z,HENRY L. Contribution of alcoholic and nonalcoholic fatty liver disease to the burden of liver-related morbidity and mortality[J]. Gastroenterology,2016,150(8):1778-1785.
本文二维码
计量
- 文章访问数: 1010
- HTML全文浏览量: 33
- PDF下载量: 130
- 被引次数: 0