Characterization of essential domains in HSD17B13 for cellular localization and enzymatic activity

Abstract

Human genetic studies recently identified an association of SNPs in the 17-β hydroxysteroid dehydrogenase 13 (HSD17B13) gene with alcoholic and nonalcoholic fatty liver disease development. Mutant HSD17B13 variants devoid of enzymatic function have been demonstrated to be protective from cirrhosis and liver cancer, supporting the development of HSD17B13 as a promising therapeutic target. Previous studies have demonstrated that HSD17B13 is a lipid droplet (LD)-associated protein. However, the critical domains that drive LD targeting or determine the enzymatic activity have yet to be defined. Here we used mutagenesis to generate multiple truncated and point-mutated proteins and were able to demonstrate in vitro that the N-terminal hydrophobic domain, PAT-like domain, and a putative α-helix/β-sheet/α-helix domain in HSD17B13 are all critical for LD targeting. Similarly, we characterized the predicted catalytic, substrate-binding, and homodimer interaction sites and found them to be essential for the enzymatic activity of HSD17B13, in addition to our previous identification of amino acid P260 and cofactor binding site. In conclusion, we identified critical domains and amino acid sites that are essential for the LD localization and protein function of HSD17B13, which may facilitate understanding of its function and targeting of this protein to treat chronic liver diseases. Human genetic studies recently identified an association of SNPs in the 17-β hydroxysteroid dehydrogenase 13 (HSD17B13) gene with alcoholic and nonalcoholic fatty liver disease development. Mutant HSD17B13 variants devoid of enzymatic function have been demonstrated to be protective from cirrhosis and liver cancer, supporting the development of HSD17B13 as a promising therapeutic target. Previous studies have demonstrated that HSD17B13 is a lipid droplet (LD)-associated protein. However, the critical domains that drive LD targeting or determine the enzymatic activity have yet to be defined. Here we used mutagenesis to generate multiple truncated and point-mutated proteins and were able to demonstrate in vitro that the N-terminal hydrophobic domain, PAT-like domain, and a putative α-helix/β-sheet/α-helix domain in HSD17B13 are all critical for LD targeting. Similarly, we characterized the predicted catalytic, substrate-binding, and homodimer interaction sites and found them to be essential for the enzymatic activity of HSD17B13, in addition to our previous identification of amino acid P260 and cofactor binding site. In conclusion, we identified critical domains and amino acid sites that are essential for the LD localization and protein function of HSD17B13, which may facilitate understanding of its function and targeting of this protein to treat chronic liver diseases. Associated with the global epidemic of lifestyle-associated obesity and metabolic syndrome, NAFLD has become a major global health burden and one of the leading causes for end-stage liver disease, hepatocellular carcinoma, and liver transplants (1Younossi Z. Anstee Q.M. Marietti M. Hardy T. Henry L. Eslam M. George J. Bugianesi E. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.Nat. Rev. Gastroenterol. Hepatol. 2018; 15: 11-20Crossref PubMed Scopus (1530) Google Scholar, 2Pais R. Barritt A.St. Calmus Y. Scatton O. Runge T. Lebray P. Poynard T. Ratziu V. Conti F. NAFLD and liver transplantation: current burden and expected challenges.J. Hepatol. 2016; 65: 1245-1257Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). Limited treatment options are available, stimulating the search for novel molecular targets suitable for therapeutic pharmacological intervention (3Rotman Y. Sanyal A.J. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease.Gut. 2017; 66: 180-190Crossref PubMed Scopus (238) Google Scholar). One approach to the discovery of these novel targets, based on the known heritability of NAFLD, is the use of genetic studies (4Loomba R. Schork N. Chen C.H. Bettencourt R. Bhatt A. Ang B. Nguyen P. Hernandez C. Richards L. Salotti J. et al.Heritability of hepatic fibrosis and steatosis based on a prospective twin study.Gastroenterology. 2015; 149: 1784-1793Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 5Schwimmer J.B. Celedon M.A. Lavine J.E. Salem R. Campbell N. Schork N.J. Shiehmorteza M. Yokoo T. Chavez A. Middleton M.S. et al.Heritability of nonalcoholic fatty liver disease.Gastroenterology. 2009; 136: 1585-1592Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar, 6Browning J.D. Szczepaniak L.S. Dobbins R. Nuremberg P. Horton J.D. Cohen J.C. Grundy S.M. Hobbs H.H. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.Hepatology. 2004; 40: 1387-1395Crossref PubMed Scopus (2771) Google Scholar). Several genes related to the incidence of NAFLD and to its progressive form of NASH were identified using this approach, including PNPLA3 (7Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. Boerwinkle E. Cohen J.C. Hobbs H.H. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat. Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (1942) Google Scholar, 8Yuan X. Waterworth D. Perry J.R. Lim N. Song K. Chambers J.C. Zhang W. Vollenweider P. Stirnadel H. Johnson T. et al.Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.Am. J. Hum. Genet. 2008; 83: 520-528Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar, 9Sookoian S. Castano G.O. Burgueno A.L. Gianotti T.F. Rosselli M.S. Pirola C.J. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity.J. Lipid Res. 2009; 50: 2111-2116Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 10Rotman Y. Koh C. Zmuda J.M. Kleiner D.E. Liang T.J. NASH CRN The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease.Hepatology. 2010; 52: 894-903Crossref PubMed Scopus (344) Google Scholar, 11Speliotes E.K. Butler J.L. Palmer C.D. Voight B.F. GIANT Consortium MIGen Consortium NASH CRN Hirschhorn J.N. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but metabolic disease.Hepatology. 2010; 52: PubMed Scopus Google Scholar, L. A. E. R. P. V. E. E. et for the patatin-like liver fibrosis in with nonalcoholic fatty liver disease.Hepatology. 2010; PubMed Scopus Google Zhang H. Y. W. Y. Zhang J. A. et of variation a variant in influencing and Genet. PubMed Scopus Google Scholar, J. E. S. H.H. A. T.F. Hobbs H.H. Cohen J.C. association a variant that confers susceptibility to nonalcoholic fatty liver disease.Nat. Genet. PubMed Scopus Google Scholar, H. A. S. A. A. A. P. F. is a of liver influencing and hepatic lipid droplet PubMed Scopus Google S. F. E. M. A. M. J. T. M. et genome-wide association PNPLA3 and and as risk loci for Genet. 2015; PubMed Scopus Google and the recently HSD17B13 Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google Scholar, J.C. Zhang W. J. X. P. H. S. M. et association loci influencing of liver in Genet. PubMed Scopus Google Scholar, X. Y. C. P. Y. Kozlitina J. S. et HSD17B13 variant and from chronic liver J. 2018; PubMed Scopus Google Scholar). HSD17B13 hydroxysteroid dehydrogenase a therapeutic for the treatment of chronic liver disease with a for HSD17B13 is a hepatic lipid droplet (LD)-associated with X. Y. C. P. Y. Kozlitina J. S. et HSD17B13 variant and from chronic liver J. 2018; PubMed Scopus Google and Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google as enzymatic genetic variants in HSD17B13 were found to confer from in NASH Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google Scholar, X. Y. C. P. Y. Kozlitina J. S. et HSD17B13 variant and from chronic liver J. 2018; PubMed Scopus Google Scholar, C.J. M. D. M. J. C. Castano G.O. S. variant histologic in with nonalcoholic fatty liver Lipid Res. Full Text Full Text PDF PubMed Scopus Google alcoholic liver disease Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google Scholar, X. Y. C. P. Y. Kozlitina J. S. et HSD17B13 variant and from chronic liver J. 2018; PubMed Scopus Google and hepatocellular F. P. S. V. J. D. J. et variation in HSD17B13 the risk of cirrhosis and hepatocellular in PubMed Scopus Google Scholar, J. E. P. C. E. S. T. J. et dehydrogenase 13 variant from hepatocellular development in alcoholic liver disease.Hepatology. Google Scholar). and identified a that to the of novel variants and Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google Scholar, X. Y. C. P. Y. Kozlitina J. S. et HSD17B13 variant and from chronic liver J. 2018; PubMed Scopus Google Scholar, Y. Y. to the the HSD17B13 variant a of PubMed Scopus Google the nonsynonymous a to amino acid Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google and the to J. S. Hobbs H.H. Cohen J.C. HSD17B13 and chronic liver disease in and J. 2018; PubMed Scopus Google Scholar). protective variants generate protein that are or predicted to be devoid enzymatic the of understanding the enzymatic function of these that HSD17B13 activity be domain and as as or critical the of the enzymatic activity with gene using or activity using are to and in which function as of metabolic and lipid The and of lipid Rev. PubMed Scopus Google Scholar). which in lipid are in or to the which and T. the and function of the lipid PubMed Scopus Google Scholar). have identified of including a of proteins to be LD proteins The and of lipid Rev. PubMed Scopus Google Scholar). of LD targeting have been for proteins to the LD and hydrophobic The and of lipid Rev. PubMed Scopus Google Scholar, N. of protein localization to lipid 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). The protein the proteins and M.A. an of lipid droplet proteins that lipid 2009; PubMed Scopus Google that domains that are essential for LD targeting S. J. C.J. C. B. for lipid droplet association and proteins in and Full Text Full Text PDF PubMed Scopus Google Scholar, Y. T. M. K. T. of to lipid is the putative hydrophobic Res. PubMed Scopus Google Scholar). HSD17B13 is an protein Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google Scholar, X. Y. C. P. Y. Kozlitina J. S. et HSD17B13 variant and from chronic liver J. 2018; PubMed Scopus Google Scholar, Y. M. K. dehydrogenase 13 is a lipid Res. 2008; PubMed Scopus Google Scholar, W. Y. X. W. L. X. S. C. H. J. et as a protein in nonalcoholic fatty liver PubMed Scopus Google and we identified a PAT-like domain its that is essential for its targeting to and enzymatic function Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google Scholar). However, domains in HSD17B13 that are essential for to have yet been defined. to HSD17B13 have been M. Sanyal A.J. of NAFLD development and therapeutic 2018; PubMed Scopus Google Scholar). However, the and cofactor binding sites that we identified Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google sites or domains critical for its enzymatic activity and targeting are In the current we to critical domains and that are essential for LD targeting and the enzymatic activity of HSD17B13 multiple truncated and point-mutated may facilitate the of and to a understanding of the protein function that is essential for HSD17B13 to be a therapeutic in chronic liver of HSD17B13 using the A. A for in protein Google and E. A. J.C. identification and in the Google with and were in with were on a in with and were in a to and fatty were with fatty in to generate fatty acid were fatty acid for with a of and of Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google were using were in and using and were in for on and for The protein and the variant variant were from and The used to generate HSD17B13 with mutagenesis and were used as mutagenesis for the localization and for the enzymatic Mutant were The of the sites for based on a of sites to activity using the domain search and on with were in a and with or using the LD fatty were the to of fatty acid treatment were in for and with for and for the of HSD17B13 variant with the were with from and were in and in and in of with for used used to of a for and HSD17B13 were to demonstrate targeting of HSD17B13 and were used for and were used to and were activity using the dehydrogenase activity as Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google Scholar, N. of protein localization to lipid 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). were in with HSD17B13, HSD17B13 or or in with a to the and were for or were of and of and were with a and acid levels were protein and are to HSD17B13 used as a with multiple in the of the of were for protein and were with from or from with 3 of were with of of were with with for proteins were and with the were in to and to The were with a in for were with from in with an and for the of HSD17B13 and or HSD17B13 were using The HSD17B13 protein is to are the of protein and LD targeting with the of the PAT-like N-terminal or with the of a variant with Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google The of HSD17B13 is predicted to be a putative domain and to the protein to are to on the our in to the of the N-terminal that are critical for LD targeting. a the hydrophobic domain of HSD17B13 to in the of and that the hydrophobic domain is to drive protein LD targeting. the addition of the PAT-like domain to the hydrophobic domain a of HSD17B13 that to the of the hydrophobic domain is for HSD17B13 to we an HSD17B13 devoid of the hydrophobic as found that this hydrophobic HSD17B13 to has a of and we found to be in to our that the of HSD17B13, and are for LD of domains critical for LD targeting of were with HSD17B13 the variant or and with fatty to were with which used to determine localization were with and were with were The of HSD17B13 and The targeting to the The variant of HSD17B13 is a of a leading to the of the of HSD17B13 has been to are for a of HSD17B13, with on the of in HSD17B13 are predicted to form a α-helix/β-sheet/α-helix which is in variant we identified that variant is to the hydrophobic domain and PAT-like domain and has enzymatic function Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google we the of this in determine which of the α-helix/β-sheet/α-helix is essential for LD we proteins of and The of of the domains to LD localization that the is these is in the and with an protein is that the of the α-helix/β-sheet/α-helix to of in the its from the to or with the α-helix/β-sheet/α-helix to we that the N-terminal hydrophobic and PAT-like domains the of of HSD17B13 to the the α-helix/β-sheet/α-helix is for the of the protein from the to our we with HSD17B13 or proteins with critical domains that the domains are in to drive the LD targeting of HSD17B13 HSD17B13 LD or we with or a of and found that HSD17B13 targets LD all in the have a of six the P. and function of PubMed Scopus Google Scholar). in the predicted of HSD17B13 using as a HSD17B13 is to chronic liver disease its enzymatic and are associated with from liver Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google Scholar, X. Y. C. P. Y. Kozlitina J. S. et HSD17B13 variant and from chronic liver J. 2018; PubMed Scopus Google Scholar). to the sites that are critical for its enzymatic have demonstrated the of the cofactor binding V. A. J. identification and cofactor in the PubMed Scopus Google for enzymatic activity Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google Scholar). In a we HSD17B13 with in the putative binding or homodimer interaction and The C. J. S. T. E. R. H. for and in Full Text Full Text PDF PubMed Scopus Google is predicted to be in to the cofactor A from to the predicted the activity of HSD17B13 and were we putative A of and that are critical for activity the of of these with protein or LD targeting in putative binding sites in HSD17B13 and the activity of the proteins A and or and the enzymatic activity of HSD17B13 but associated with protein levels A of but activity that sites are critical for the enzymatic activity of The and a major as a homodimer or as an with 3 to the levels of acid L. The is for of acid 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). the is that HSD17B13 for its we were able to of HSD17B13 in vitro with and and a putative homodimer interaction and found that the protein activity A of essential sites for HSD17B13 enzymatic activity is in and sites for enzymatic activity of for of droplet protein droplet protein cofactor protein protein protein in a domains and amino in essential for localization are in essential for enzymatic activity are with predicted The of genetic variants is in to Human genetic studies identified an association HSD17B13 and NASH Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google Scholar, X. Y. C. P. Y. Kozlitina J. S. et HSD17B13 variant and from chronic liver J. 2018; PubMed Scopus Google Scholar, C.J. M. D. M. J. C. Castano G.O. S. variant histologic in with nonalcoholic fatty liver Lipid Res. Full Text Full Text PDF PubMed Scopus Google alcoholic liver disease Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google Scholar, X. Y. C. P. Y. Kozlitina J. S. et HSD17B13 variant and from chronic liver J. 2018; PubMed Scopus Google and hepatocellular F. P. S. V. J. D. J. et variation in HSD17B13 the risk of cirrhosis and hepatocellular in PubMed Scopus Google Scholar, J. E. P. C. E. S. T. J. et dehydrogenase 13 variant from hepatocellular development in alcoholic liver disease.Hepatology. Google Scholar). protein of HSD17B13, genetic confer from the of fatty liver disease Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google Scholar, X. Y. C. P. Y. Kozlitina J. S. et HSD17B13 variant and from chronic liver J. 2018; PubMed Scopus Google the of the enzymatic activity of HSD17B13, this in Y. J. D. J. J. R. et from Scopus Google Scholar). to HSD17B13 and to HSD17B13 enzymatic activity are the critical for its enzymatic activity is for and to the protein In this we on based on our previous that targeting to is for enzymatic activity Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google and in based on to this approach, we identified critical domains hydrophobic domain, PAT-like domain, and a putative α-helix/β-sheet/α-helix for LD targeting and binding and homodimer interaction for the enzymatic activity of The N-terminal has been to be in HSD17B13 to Y. M. K. dehydrogenase 13 is a lipid Res. 2008; PubMed Scopus Google Scholar). Here we the to the N-terminal and as of domains with an N-terminal hydrophobic domain predicted to be a and an PAT-like domain with domains for LD targeting. HSD17B13 is related to the with or fatty as S. C. T. M. A. A. R. M. K. M. et as therapeutic protein and in PubMed Scopus Google and the of which have been to as C. of of 2015; PubMed Scopus Google Scholar). of the as and have been identified as proteins W. J.L. The dehydrogenase to lipid Full Text Full Text PDF PubMed Scopus Google Scholar, Y. M. K. and of the in dehydrogenase 2008; PubMed Scopus Google and a the of targeting hydrophobic domain is known to be for LD targeting of and W. J.L. The dehydrogenase to lipid Full Text Full Text PDF PubMed Scopus Google Scholar, Y. M. K. and of the in dehydrogenase 2008; PubMed Scopus Google Scholar). The has been in Y. M. K. and of the in dehydrogenase 2008; PubMed Scopus Google Scholar, M. A. localization and of PubMed Scopus Google but is in with the known of the proteins to to as of the HSD17B13 N-terminal domains in PAT-like domain protein the of the hydrophobic domain HSD17B13 from to leading to protein from to have been for N. T. protein has domains for targeting to lipid Res. PubMed Scopus Google Y. M. K. and of the in dehydrogenase 2008; PubMed Scopus Google and studies W. J.L. The dehydrogenase to lipid Full Text Full Text PDF PubMed Scopus Google LD and targeting that may a in the and interaction of these M. E. A. M. F. A. T. C. M. et and domains proteins to lipid 2009; PubMed Scopus Google Scholar). the PAT-like domain in HSD17B13 is a for Y. J. K. Horton P. K. of targeting and 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). the of the may be from the to the be and the H. N. S. Y. T. T. M. M. M. T. et of the in and of protein PubMed Scopus Google Scholar). this has or is an of is In this we for the a the of HSD17B13 in the α-helix/β-sheet/α-helix domain of which is in the variant of The of this domain to the protein in the and to the domain is the of these domains is as the LD targeting of and One is that the of the α-helix/β-sheet/α-helix domain to protein of the of the proteins are in the and to a to targeting proteins for in the PubMed Scopus Google Scholar). is the protein Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google that the may be this domain may be for interaction for the protein. A is for interaction and targeting from the to for proteins The and of lipid Rev. PubMed Scopus Google and the α-helix/β-sheet/α-helix we may a The domain is in and is in in the protein is a the and the The of its the in this found to be in Chen Song Chen Chen Chen of in function and in 2017; PubMed Scopus Google the and localization to protein function with sites essential for its enzymatic The variants and associated with generate an to protein Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google Scholar, X. Y. C. P. Y. Kozlitina J. S. et HSD17B13 variant and from chronic liver J. 2018; PubMed Scopus Google Scholar, Y. Y. to the the HSD17B13 variant a of PubMed Scopus Google Scholar). variant we identified is the the nonsynonymous genetic variant Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google Scholar). from the predicted catalytic, or cofactor binding the is an essential for the enzymatic activity of HSD17B13 Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google and its to may to an function and protein and K. M.S. of a the is for the of PubMed Scopus Google Scholar). variant to confer chronic liver disease J. S. Hobbs H.H. Cohen J.C. HSD17B13 and chronic liver disease in and J. 2018; PubMed Scopus Google the critical of Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google and protein we this protein to be are essential for S. C. T. M. A. A. R. M. K. M. et as therapeutic protein and in PubMed Scopus Google and in cofactor binding the enzymatic activity of Y. K. of and association domains in dehydrogenase J. 2009; PubMed Scopus Google and HSD17B13 Y. K. K. S. Koh C. Chen Y. X. et hydroxysteroid dehydrogenase 13 is a hepatic dehydrogenase associated with histological of nonalcoholic fatty liver disease.Hepatology. PubMed Scopus Google Scholar). a the of a with a predicted of C. J. S. T. E. R. H. for and in Full Text Full Text PDF PubMed Scopus Google Scholar). this is the the H. B. M. S. R. J. D. PubMed Scopus Google Scholar). identified HSD17B13 and as the of that and enzymatic activity for the HSD17B13 and the are with studies in and in 3 C. J. S. T. E. R. H. for and in Full Text Full Text PDF PubMed Scopus Google Scholar, Y. K. of and association domains in dehydrogenase J. 2009; PubMed Scopus Google Scholar). the in HSD17B13 has to a of that in in A. V. S. for the of and in dehydrogenase variants from the of the 15: Google and in C. J. S. T. E. R. H. for and in Full Text Full Text PDF PubMed Scopus Google in the activity but in which the enzymatic activity Y. K. of and association domains in dehydrogenase J. 2009; PubMed Scopus Google Scholar). for have the predicted and found them to be essential for HSD17B13 The binding is the domain in the which a of C. M. N. X. M. J. E. Y. B. et the PubMed Scopus Google Scholar, D. P. of and dehydrogenase PubMed Scopus Google and the of to the activity of A. V. S. for the of and in dehydrogenase variants from the of the 15: Google Scholar). of the essential sites to protein and a to has been in the protective variants X. Y. C. P. Y. Kozlitina J. S. et HSD17B13 variant and from chronic liver J. 2018; PubMed Scopus Google Scholar). In conclusion, we identified and domains and sites that are essential for the LD targeting hydrophobic domain, PAT-like domain, and a putative α-helix/β-sheet/α-helix and enzymatic activity binding and homodimer interaction of HSD17B13, which facilitate the therapeutic targeting of this protein chronic liver diseases. are and are from the The for with the with amino acid 17-β hydroxysteroid dehydrogenase 13 lipid droplet patatin-like phospholipase domain-containing protein 3 dehydrogenase

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