Comparative proteomic study reveals 17β-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by a massive accumulation of lipid droplets (LDs). The aim of this study was to determine the function of 17β-hydroxysteroid dehydrogenase-13 (17β-HSD13), one of our newly identified LD-associated proteins in human subjects with normal liver histology and simple steatosis, in NAFLD development. LDs were isolated from 21 human liver biopsies, including 9 cases with normal liver histology (group 1) and 12 cases with simple steatosis (group 2). A complete set of LD-associated proteins from three liver samples of group 1 or group 2 were determined by 2D LC-MS/MS. By comparing the LD-associated protein profiles between subjects with or without NAFLD, 54 up-regulated and 35 down-regulated LD-associated proteins were found in NAFLD patients. Among them, 17β-HSD13 represents a previously unidentified LD-associated protein with a significant up-regulation in NAFLD. Because the 17β-HSD family plays an important role in lipid metabolism, 17β-HSD13 was selected for validating the proteomic findings and exploring its role in the pathogenesis of NAFLD. Increased hepatic 17β-HSD13 and its LD surface location were confirmed in db/db (diabetic) and high-fat diet-fed mice. Adenovirus-mediated hepatic overexpression of human 17β-HSD13 induced a fatty liver phenotype in C57BL/6 mice, with a significant increase in mature sterol regulatory element-binding protein 1 and fatty acid synthase levels. The present study reports an extensive set of human liver LD proteins and an array of proteins differentially expressed in human NAFLD. We also identified 17β-HSD13 as a pathogenic protein in the development of NAFLD.

• Authors: Wen Su, Yang Wang, Xiao Jia, Wenhan Wu, Linghai Li, Xiaodong Tian, Sha Li, Chunjiong Wang, Huamin Xu, Jiaqi Cao, Qifei Han, Shimeng Xu, Yong Chen, Yanfeng Zhong, Xiaoyan Zhang, Pingsheng Liu, Jan-Åke Gustafsson, Youfei Guan
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 31 Pg. 11437-42 (Aug 05 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25028495 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipids
• Proteome
• 17-Hydroxysteroid Dehydrogenases
• 3 (or 17)-beta-hydroxysteroid dehydrogenase

Topics

• 17-Hydroxysteroid Dehydrogenases (metabolism)
• Animals
• Cells, Cultured
• Diet, High-Fat
• Fatty Liver (enzymology, pathology)
• Hepatocytes (enzymology, pathology)
• Humans
• Lipids (chemistry)
• Lipogenesis
• Liver (enzymology, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease
• Proteome (metabolism)
• Proteomics (methods)
• Reproducibility of Results
• Up-Regulation