title: Downregulation of microRNA-451 in non-alcoholic steatohepatitis inhibits fatty acid-induced proinflammatory cytokine production through the AMPK/AKT pathway.
abstract: Mechanisms associated with the progression of non-alcoholic fatty liver disease (NAFLD) remain unclear. We attempted to identify the pattern of altered gene expression at different time points in a high fat diet (HFD)-induced NAFLD mouse model. The early up-regulated genes are mainly involved in the innate immune responses, while the late up-regulated genes represent the inflammation processes. Although recent studies have shown that microRNAs play important roles in hepatic metabolic functions, the pivotal role of microRNAs in the progression of NAFLD is not fully understood. We investigated the functions of miR-451, which was identified as a target gene in the inflammatory process in NAFLD. miR-451 expression was significantly decreased in the palmitate (PA)-exposed HepG2 cells and in liver tissues of HFD-induced non-alcoholic steatohepatitis (NASH) mice. Its decreased expressions were also observed in liver specimens of NASH patients. In vitro analysis of the effect of miR-451 on proinflammatory cytokine provided evidence for negative regulation of PA-induced interleukin (IL)-8 and tumor necrosis factor-alpha (TNF-α) production. Furthermore, miR-451 over-expression inhibited translocation of the PA-induced NF-κB p65 subunit into the nucleus. Our result showed that Cab39 is a direct target of miRNA-451 in steatotic cells. Further study showed that AMPK activated through Cab39 inhibits NF-κB transactivation induced in steatotic HepG2 cells. miR-451 over-expression in steatotic cells significantly suppressed PA-induced inflammatory cytokine. These results provide new insights into the negative regulation of miR-451 in fatty acid-induced inflammation via the AMPK/AKT pathway and demonstrate potential therapeutic applications for miR-451 in preventing the progression from simple steatosis to severely advanced liver disease.
authors.affiliation: The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: wendyhur@catholic.ac.kr.
authors.forename: Wonhee
authors.initials: W
authors.lastname: Hur
authors.affiliation: The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: JoonHo@catholic.ac.kr.
authors.forename: Joon Ho
authors.initials: JH
authors.lastname: Lee
authors.affiliation: The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: never-i@nate.com.
authors.forename: Sung Woo
authors.initials: SW
authors.lastname: Kim
authors.affiliation: The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: kim.jh@catholic.ac.kr.
authors.forename: Jung-Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: baesh@catholic.ac.kr.
authors.forename: Si Hyun
authors.initials: SH
authors.lastname: Bae
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, Republic of Korea. Electronic address: hyung926@postech.ac.kr.
authors.forename: Minhyung
authors.initials: M
authors.lastname: Kim
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, Republic of Korea; Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, DGIST, Daegu, Republic of Korea. Electronic address: dhwang@dgist.ac.kr.
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.affiliation: Department of Internal Medicine, Soon Chun Hyang University Hospital Bucheon, Soon Chun Hyang University College of Medicine, Bucheon, Republic of Korea. Electronic address: liverkys@schmc.ac.kr.
authors.forename: Young Seok
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Food and Nutrition, Yonsei University, Republic of Korea. Electronic address: tspark@yonsei.ac.kr.
authors.forename: Taesun
authors.initials: T
authors.lastname: Park
authors.affiliation: Department of Bioscience and Biotechnology/Institute of Bioscience, Sejong University, Republic of Korea. Electronic address: umsj@sejong.ac.kr.
authors.forename: Soo-Jong
authors.initials: SJ
authors.lastname: Um
authors.affiliation: Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA. Electronic address: bj.song@nih.gov.
authors.forename: Byoung-Joon
authors.initials: BJ
authors.lastname: Song
authors.affiliation: The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: yoonsk@catholic.ac.kr.
authors.forename: Seung Kew
authors.initials: SK
authors.lastname: Yoon
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D059305:Diet, High-Fat / Q000009:adverse effects*; D015536:Down-Regulation; D015870:Gene Expression / Q000276:immunology; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D019308:Palmitic Acid / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D016207:Cytokines; D035683:MicroRNAs; C550758:Mirn451 microRNA, mouse; D019308:Palmitic Acid; D051057:Proto-Oncogene Proteins c-akt; D000263:Adenylate Kinase
keywords: Cab39/MO25; Inflammation; MicroRNA-451; MicroRNAs; Non-alcoholic fatty liver; Non-alcoholic steatohepatitis