Circulating microRNA 122 in the methionine and choline-deficient mouse model of non-alcoholic steatohepatitis

John D. Clarke, Tatiana Sharapova, April D. Lake, Eric Blomme, Jonathan Maher, Nathan J Cherrington

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)726-732
Number of pages7
JournalJournal of Applied Toxicology
Volume34
Issue number6
DOIs
StatePublished - 2014

Fingerprint

Fatty Liver
Choline
MicroRNAs
Methionine
Liver
Nutrition
Diet
Liver Failure
Serum
Biomarkers
Clinical Chemistry
Wounds and Injuries
Transaminases
Liver Cirrhosis
Metabolism
Fatty Acids
Animal Models
Cholesterol
Animals
Monitoring

Keywords

  • Biomarker
  • Liver toxicity
  • Methionine- and choline-deficient diet
  • MicroRNA 122
  • Non-alcoholic fatty liver disease
  • Non-alcoholic steatohepatitis

ASJC Scopus subject areas

  • Toxicology
  • Medicine(all)

Cite this

Circulating microRNA 122 in the methionine and choline-deficient mouse model of non-alcoholic steatohepatitis. / Clarke, John D.; Sharapova, Tatiana; Lake, April D.; Blomme, Eric; Maher, Jonathan; Cherrington, Nathan J.

In: Journal of Applied Toxicology, Vol. 34, No. 6, 2014, p. 726-732.

Research output: Contribution to journalArticle

Clarke, John D. ; Sharapova, Tatiana ; Lake, April D. ; Blomme, Eric ; Maher, Jonathan ; Cherrington, Nathan J. / Circulating microRNA 122 in the methionine and choline-deficient mouse model of non-alcoholic steatohepatitis. In: Journal of Applied Toxicology. 2014 ; Vol. 34, No. 6. pp. 726-732.
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abstract = "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.",
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AB - 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.

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