TY - JOUR
T1 - 17-Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated With Histological Features of Nonalcoholic Fatty Liver Disease
AU - (for the Nonalcoholic Steatohepatitis Clinical Research Network)
AU - Ma, Yanling
AU - Belyaeva, Olga V.
AU - Brown, Philip M.
AU - Fujita, Koji
AU - Valles, Katherine
AU - Karki, Suman
AU - de Boer, Ynto S.
AU - Koh, Christopher
AU - Chen, Yanhua
AU - Du, Xiaomeng
AU - Handelman, Samuel K.
AU - Chen, Vincent
AU - Speliotes, Elizabeth K.
AU - Nestlerode, Cara
AU - Thomas, Emmanuel
AU - Kleiner, David E.
AU - Zmuda, Joseph M.
AU - Sanyal, Arun J.
AU - Kedishvili, Natalia Y.
AU - Liang, T. Jake
AU - Rotman, Yaron
N1 - Funding Information:
The authors thank Ms. Ronda K. Sapp for technical assistance; Christopher O?Donnell, M.D., and Caroline Fox, M.D., M.P.H., from the Framingham Heart Study for collaboration during study initiation; the University of Michigan Medical School Central Biorepository for providing biospecimen processing, storage, management, and distribution services in support of the research reported in this publication; and Haiqing Fu from National Cancer Institute, National Institutes of Health, for sharing of plasmid. The authors are grateful to the NASH CRN investigators, coordinators, and patients for allowing data access.
Funding Information:
Supported by the Intramural Research Programs of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute; the National Institutes of Health, National Institute of Alcohol Abuse and Alcoholism (AA012153, to N.Y.K.); the National Institutes of Health (R01 DK106621, R01 DK107904, to E.K.S., X.D., and Y.C.; R01 DK106621, to S.K.H.); the University of Michigan Department of Internal Medicine (E.K.S., X.D., Y.C., S.K.H., and V.C.). The Nonalcoholic Steatohepatitis Clinical Research Network is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U01DK061713). Additional support was received from the National Center for Advancing Translational Sciences (UL1TR000439, UL1TR000436, UL1TR000006, UL1TR000448, UL1TR000100, UL1TR000004, UL1TR000423, UL1TR000058). The Liver Tissue and Cell Distribution System, Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Minnesota Medical School was funded by National Institutes of Health contract HHSN276201200017C. Data for UK Biobank analyses were provided under approved protocol 18120. © 2018 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.30350 Potential conflict of interest: Dr. Sanyal consults for and received grants from Mallinckrodt, Novartis, and Conatus. He is employed by Sanyal Bio. He consults for Pfizer, Nitto Denko, Hemoshear, Novo-Nordisk, Terns, and Lilly. He received grants from Galectin, Mallinckrodt, Gilead, Bristol-Myers Squibb, Salix, Merck, and Sequana. He received royalties from Elsevier and Uptodate. He owns stock in Akarna, GenFit, Indalo, Dureet, and Tiziana.
Publisher Copyright:
© 2018 by the American Association for the Study of Liver Diseases.
PY - 2019/4
Y1 - 2019/4
N2 - Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. A single-nucleotide polymorphism (SNP), rs6834314, was associated with serum liver enzymes in the general population, presumably reflecting liver fat or injury. We studied rs6834314 and its nearest gene, 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13), 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 (r 2 = 0.94) generates 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 amino acid 22-28 sequence and amino acid 71-106 region. The protein has retinol dehydrogenase (RDH) activity, with enzymatic activity dependent on lipid droplet targeting and cofactor binding site. The exon 6 deletion, G insertion, and naturally occurring P260S mutation all confer loss of enzymatic activity. 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.
AB - Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. A single-nucleotide polymorphism (SNP), rs6834314, was associated with serum liver enzymes in the general population, presumably reflecting liver fat or injury. We studied rs6834314 and its nearest gene, 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13), 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 (r 2 = 0.94) generates 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 amino acid 22-28 sequence and amino acid 71-106 region. The protein has retinol dehydrogenase (RDH) activity, with enzymatic activity dependent on lipid droplet targeting and cofactor binding site. The exon 6 deletion, G insertion, and naturally occurring P260S mutation all confer loss of enzymatic activity. 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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U2 - 10.1002/hep.30350
DO - 10.1002/hep.30350
M3 - Article
C2 - 30415504
AN - SCOPUS:85062515617
VL - 69
SP - 1504
EP - 1519
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 4
ER -