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

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 2

Analysis of lipid metabolism.

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Analysis of lipid metabolism. (A) Serum levels of lipoproteins. C, contr...
(A) Serum levels of lipoproteins. C, control: normal human serum; KO, Mir122a–/– mice. (B) Western blot analysis of the serum apoproteins. (C) RT-qPCR analysis of the genes involved in lipid metabolism. n = 5. *P < 0.05, †P < 0.01, §P < 0.001. (D) Western blot analysis of hepatic proteins. This blot is representative of 3 independent experiments. Values represent the relative levels of protein expression between Mir122a–/– and WT. (E) 1H-NMR spectra of hepatic lipid contents. 1H-NMR spectra of lipid extracts from liver of WT and Mir122a–/– mice (Mir122a-KO). Identified peaks: 1: total cholesterol C-18, CH3; 2: total cholesterol C-26, CH3/C-27, CH3; 3: fatty acyl chain CH3(CH2)n; 4: total cholesterol C-21, CH3; 5: free cholesterol C-19, CH3; 6: esterified cholesterol C-19, CH3; 7: multiple cholesterol protons; 8: fatty acyl chain (CH2)n; 9: multiple cholesterol protons; 10: fatty acyl chain -CH2CH2CO; 11: multiple cholesterol protons; 12: fatty acyl chain -CH2CH=; 13: fatty acyl chain -CH2CO; 14: fatty acyl chain =CHCH2CH=; 15: sphingomyelin and choline N(CH3)3; 16: free cholesterol C-3, CH; 17: phosphatidylcholine N-CH2; 18: glycerophospholipid backbone C-3, CH2; 19: glycerol backbone C-1, CH2; 20: glycerol backbone C-3, CH2; 21: phosphatidylcholine PO-CH2; 22: esterified cholesterol C-3, CH; 23: glycerolphospholipid backbone C-2, CH; 24: fatty acyl chain -HC=CH-.