These authors contributed equally to this work.
Steatohepatitis/Metabolic Liver Disease
Article first published online: 4 DEC 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 6, pages 2199–2208, December 2012
How to Cite
Matsuzaka, T., Atsumi, A., Matsumori, R., Nie, T., Shinozaki, H., Suzuki-Kemuriyama, N., Kuba, M., Nakagawa, Y., Ishii, K., Shimada, M., Kobayashi, K., Yatoh, S., Takahashi, A., Takekoshi, K., Sone, H., Yahagi, N., Suzuki, H., Murata, S., Nakamuta, M., Yamada, N. and Shimano, H. (2012), Elovl6 promotes nonalcoholic steatohepatitis. Hepatology, 56: 2199–2208. doi: 10.1002/hep.25932
Potential conflict of interest: Nothing to report.
Supported by Grant-in-Aid for Scientific Research 21390275 (to H. S.), 22117502 (to H. S.), and 21689025 (to T. M.) from the Ministry of Science, Education, Culture, and Technology of Japan; the Kowa Life Science Foundation (T. M.); and Suzuken Memorial Foundation International (T. M.).
- Issue published online: 4 DEC 2012
- Article first published online: 4 DEC 2012
- Accepted manuscript online: 30 JUN 2012 02:02AM EST
- Manuscript Accepted: 11 JUN 2012
- Manuscript Received: 25 DEC 2011
- Grant-in-Aid for Scientific Research. Grant Numbers: 21390275, 22117502, 21689025
- Ministry of Science, Education, Culture, and Technology of Japan
- Kowa Life Science Foundation
- Suzuken Memorial Foundation International
Nonalcoholic steatohepatitis (NASH) is associated with obesity and type 2 diabetes, and an increased risk for liver cirrhosis and cancer. ELOVL family member 6, elongation of very long chain fatty acids (Elovl6), is a microsomal enzyme that regulates the elongation of C12-16 saturated and monounsaturated fatty acids (FAs). We have shown previously that Elovl6 is a major target for sterol regulatory element binding proteins in the liver and that it plays a critical role in the development of obesity-induced insulin resistance by modifying FA composition. To further investigate the role of Elovl6 in the development of NASH and its underlying mechanism, we used three independent mouse models with loss or gain of function of Elovl6, and human liver samples isolated from patients with NASH. Our results demonstrate that (1) Elovl6 is a critical modulator for atherogenic high-fat diet–induced inflammation, oxidative stress, and fibrosis in the liver; (2) Elovl6 expression is positively correlated with severity of hepatosteatosis and liver injury in NASH patients; and (3) deletion of Elovl6 reduces palmitate-induced activation of the NLR family pyrin domain-containing 3 inflammasome; this could be at least one of the underlying mechanisms by which Elovl6 modulates the progress of NASH. Conclusion: Hepatic long-chain fatty acid composition is a novel determinant in NASH development, and Elovl6 could be a potential therapeutic target for the prevention and treatment of NASH. (HEPATOLOGY 2012;56:2199–2208)