Elovl6 promotes nonalcoholic steatohepatitis.

Abstract

UNLABELLED:

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.

• Authors: Takashi Matsuzaka, Ayaka Atsumi, Rie Matsumori, Tang Nie, Haruna Shinozaki, Noriko Suzuki-Kemuriyama, Motoko Kuba, Yoshimi Nakagawa, Kiyoaki Ishii, Masako Shimada, Kazuto Kobayashi, Shigeru Yatoh, Akimitsu Takahashi, Kazuhiro Takekoshi, Hirohito Sone, Naoya Yahagi, Hiroaki Suzuki, Soichiro Murata, Makoto Nakamuta, Nobuhiro Yamada, Hitoshi Shimano
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 56 Issue 6 Pg. 2199-208 (Dec 2012) ISSN: 1527-3350 [Electronic] United States
• PMID: 22753171 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Association for the Study of Liver Diseases.

Chemical References

• Blood Glucose
• Carrier Proteins
• ELOVL6 protein, human
• Elovl6 protein, mouse
• Fatty Acids
• Inflammasomes
• Insulin
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• RNA, Messenger
• Transcription Factors
• Triglycerides
• Palmitic Acid
• Cholesterol
• Acetyltransferases
• Fatty Acid Elongases

Topics

• Acetyltransferases (genetics, metabolism)
• Analysis of Variance
• Animals
• Blood Glucose (metabolism)
• Carrier Proteins (metabolism)
• Cholesterol (metabolism)
• Diet, Atherogenic
• Diet, High-Fat
• Disease Models, Animal
• Fatty Acid Elongases
• Fatty Acids (metabolism)
• Fatty Liver (enzymology, genetics, pathology)
• Gene Expression Profiling
• Hepatocytes (metabolism)
• Humans
• Inflammasomes (metabolism)
• Insulin (blood)
• Insulin Resistance
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• NLR Family, Pyrin Domain-Containing 3 Protein
• Non-alcoholic Fatty Liver Disease
• Oxidative Stress
• Palmitic Acid (metabolism)
• RNA, Messenger (metabolism)
• Severity of Illness Index
• Transcription Factors (genetics)
• Triglycerides (metabolism)