MicroRNA-21 is associated with fibrosis in a rat model of nonalcoholic steatohepatitis and serves as a plasma biomarker for fibrotic liver disease.
Evidence indicates that hepatic fibrosis is the initial lesion of cirrhosis or hepatocellular carcinoma in diseases such as nonalcoholic steatohepatitis (NASH). To induce NASH, we fed rats a choline-deficient and iron-supplemented L-amino acid-defined (CDAA) diet. Histopathological examination revealed that fibrosis appeared from week 4 and progressed to bridging fibrosis from week 12. Using qRT-PCR assays, we detected increased expression of miR-21, Mmp-9, and Timp-1 in liver that peaked during week 4, when fibrosis was first detected. The expression pattern of miR-21 in plasma paralleled that in liver. Fibrosis tended to be resolved within 12 weeks of a recovery period after 12 weeks of feeding, and the expression of miR-21, Timp-1, and Mmp-9 decreased in liver. Comprehensive analyses of miRNA and mRNA expression in the liver using samples acquired at week 4 detected 16 miRNAs and 11 mRNAs that are mutually-interacting fibrosis-related factors. We therefore conclude that miR-21 was closely associated with fibrosis in a rat model of NASH and has potential as a plasma biomarker for hepatic fibrosis.
Drug Discovery Science & Management, Astellas Pharma Europe B.V., 2300 AH Leiden, The Netherlands; Drug Safety Research Labs, Astellas Pharma Inc., Ibaraki 305-8585, Japan. Electronic address: ayano.takeuchi@astellas.com.
Ayano
A
Takeuchi-Yorimoto
Drug Safety Research Labs, Astellas Pharma Inc., Ibaraki 305-8585, Japan.
Yu
Y
Yamaura
Drug Safety Research Labs, Astellas Pharma Inc., Ibaraki 305-8585, Japan.
Masayuki
M
Kanki
Drug Safety Research Labs, Astellas Pharma Inc., Ibaraki 305-8585, Japan.
Tetsuya
T
Ide
Drug Safety Research Division, Astellas Research Technologies Co., Ltd., Ibaraki 305-8585, Japan.
Ayumi
A
Nakata
Drug Safety Research Labs, Astellas Pharma Inc., Ibaraki 305-8585, Japan; Non-clinical Research, Santen Pharmaceutical Co., Ltd., Nara 630-0101, Japan.
Takahisa
T
Noto
Drug Safety Research Labs, Astellas Pharma Inc., Ibaraki 305-8585, Japan.
Masahiro
M
Matsumoto
D000818:Animals; D015415:Biomarkers / Q000097:blood; D002794:Choline / Q000627:therapeutic use; D002796:Choline Deficiency / Q000150:complications / Q000178:diet therapy / Q000209:etiology / Q000503:physiopathology; D004032:Diet / Q000009:adverse effects; D019587:Dietary Supplements / Q000506:poisoning; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D019190:Iron Overload / Q000150:complications / Q000209:etiology / Q000503:physiopathology; D019266:Iron, Dietary / Q000506:poisoning; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000209:etiology* / Q000517:prevention & control; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000097:blood / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D013047:Specific Pathogen-Free Organisms; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
D015415:Biomarkers; D019266:Iron, Dietary; D035683:MicroRNAs; D012333:RNA, Messenger; C576839:TIMP1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; C546082:mirn21 microRNA, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D002794:Choline
CDAA; Fibrosis; MiR-21; NASH