Circulating microRNA 122 in the methionine and choline-deficient mouse model of non-alcoholic steatohepatitis.
Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) and is a major cause of liver cirrhosis and hepatic failure. The methionine choline-deficient diet (MCD) is a frequently used hepatotoxicity animal model of NASH that induces hepatic transaminase (ALT, AST) elevations and hepatobiliary histological changes similar to those observed in human NASH. Liver-specific microRNA-122 (miR-122) has been shown as a key regulator of cholesterol and fatty acid metabolism in adult liver, and has recently been proposed as a sensitive and specific circulating biomarker of hepatic injury. The purpose of this study was to assess miR-122 serum levels in mice receiving an MCD diet for 0, 3, 7, 14, 28 and 56 days and compare the performance vs. routine clinical chemistry when benchmarked against the histopathological liver findings. MiR-122 levels were quantified in serum using RT-qPCR. Both miR-122 and ALT/AST levels were significantly elevated in serum at all timepoints. MiR-122 levels increased on average by 40-fold after 3 days of initiating the MCD diet, whereas ALT and AST changes were 4.8- and 3.3-fold, respectively. In general, miR-122 levels remained elevated across all time points, whereas the ALT/AST increases were less robust but correlated with the progressive severity of NASH as assessed by histopathology. In conclusion, serum levels of miR-122 can potentially be used as a sensitive biomarker for the early detection of hepatotoxicity and can aid in monitoring the extent of NAFLD-associated liver injury in mouse efficacy models.
Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
John D
JD
Clarke
Tatiana
T
Sharapova
April D
AD
Lake
Eric
E
Blomme
Jonathan
J
Maher
Nathan J
NJ
Cherrington
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002796:Choline Deficiency / Q000150:complications*; D004195:Disease Models, Animal; D042241:Early Diagnosis; D005819:Genetic Markers; D008297:Male; D008715:Methionine; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000097:blood*; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D011237:Predictive Value of Tests; D012720:Severity of Illness Index; D013997:Time Factors
D015415:Biomarkers; D005819:Genetic Markers; D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; D008715:Methionine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
biomarker; liver toxicity; methionine- and choline-deficient diet; microRNA 122; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis