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MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis
Wei-Chih Tsai, … , Michael Hsiao, Ann-Ping Tsou
Wei-Chih Tsai, … , Michael Hsiao, Ann-Ping Tsou
Published July 23, 2012
Citation Information: J Clin Invest. 2012;122(8):2884-2897. https://doi.org/10.1172/JCI63455.
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Research Article

MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis

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Abstract

MicroRNA-122 (miR-122), which accounts for 70% of the liver’s total miRNAs, plays a pivotal role in the liver. However, its intrinsic physiological roles remain largely undetermined. We demonstrated that mice lacking the gene encoding miR-122a (Mir122a) are viable but develop temporally controlled steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). These mice exhibited a striking disparity in HCC incidence based on sex, with a male-to-female ratio of 3.9:1, which recapitulates the disease incidence in humans. Impaired expression of microsomal triglyceride transfer protein (MTTP) contributed to steatosis, which was reversed by in vivo restoration of Mttp expression. We found that hepatic fibrosis onset can be partially attributed to the action of a miR-122a target, the Klf6 transcript. In addition, Mir122a–/– livers exhibited disruptions in a range of pathways, many of which closely resemble the disruptions found in human HCC. Importantly, the reexpression of miR-122a reduced disease manifestation and tumor incidence in Mir122a–/– mice. This study demonstrates that mice with a targeted deletion of the Mir122a gene possess several key phenotypes of human liver diseases, which provides a rationale for the development of a unique therapy for the treatment of chronic liver disease and HCC.

Authors

Wei-Chih Tsai, Sheng-Da Hsu, Chu-Sui Hsu, Tsung-Ching Lai, Shu-Jen Chen, Roger Shen, Yi Huang, Hua-Chien Chen, Chien-Hsin Lee, Ting-Fen Tsai, Ming-Ta Hsu, Jaw-Ching Wu, Hsien-Da Huang, Ming-Shi Shiao, Michael Hsiao, Ann-Ping Tsou

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Figure 1

Pathophysiological features of Mir122a–/– mice.

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Pathophysiological features of Mir122a–/– mice.
 
(A) Total serum choles...
(A) Total serum cholesterol, fasting TG, ALP, and ALT levels were measured enzymatically on a DRI-CHEM 3500S autoanalyzer (Fujifilm). n = 20 mice per group. White bars, Mir122a+/+; gray bars, Mir122a–/–. (B) Mir122a–/– livers exhibited progressive accumulation of lipid (oil red O) and reduced glycogen storage (PAS). n = 6. (C) The progressive increase in the number of Kupffer cells (F4/80 antibody) and the activation of HSCs near the portal regions (Sirius red staining and anti-desmin antibody) in Mir122a–/– livers. Scale bars: 100 μm, 50 μm (insets), and 20 μm (insets, desmin). n = 6. (D) The number of Kupffer cells (anti-F4/80) per high-power field (×200). n = 10. (E) RT-qPCR results for 2 markers of fibrosis (Ctgf and Tgfb1). n = 8 per group. (F) Western blot analysis of desmin expression. The results shown are representative of 5 independent experiments. *P < 0.05, †P < 0.01, §P < 0.001.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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