Apobec1 complementation factor overexpression promotes hepatic steatosis, fibrosis, and hepatocellular cancer
Valerie Blanc, … , Lewis R. Roberts, Nicholas O. Davidson
Valerie Blanc, … , Lewis R. Roberts, Nicholas O. Davidson
Published September 17, 2020
Citation Information: J Clin Invest. 2021;131(1):e138699. https://doi.org/10.1172/JCI138699.
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Research Article Hepatology Metabolism Article has an altmetric score of 51

Apobec1 complementation factor overexpression promotes hepatic steatosis, fibrosis, and hepatocellular cancer

Abstract

The RNA-binding protein Apobec1 complementation factor (A1CF) regulates posttranscriptional ApoB mRNA editing, but the range of RNA targets and the long-term effect of altered A1CF expression on liver function are unknown. Here we studied hepatocyte-specific A1cf-transgenic (A1cf+/Tg), A1cf+/Tg Apobec1–/–, and A1cf–/– mice fed chow or high-fat/high-fructose diets using RNA-Seq, RNA CLIP-Seq, and tissue microarrays from human hepatocellular cancer (HCC). A1cf+/Tg mice exhibited increased hepatic proliferation and steatosis, with increased lipogenic gene expression (Mogat1, Mogat2, Cidea, Cd36) associated with shifts in polysomal RNA distribution. Aged A1cf+/Tg mice developed spontaneous fibrosis, dysplasia, and HCC, and this development was accelerated on a high-fat/high-fructose diet and was independent of Apobec1. RNA-Seq revealed increased expression of mRNAs involved in oxidative stress (Gstm3, Gpx3, Cbr3), inflammatory response (Il19, Cxcl14, Tnfα, Ly6c), extracellular matrix organization (Mmp2, Col1a1, Col4a1), and proliferation (Kif20a, Mcm2, Mcm4, Mcm6), and a subset of mRNAs (including Sox4, Sox9, Cdh1) were identified in RNA CLIP-Seq. Increased A1CF expression in human HCC correlated with advanced fibrosis and with reduced survival in a subset with nonalcoholic fatty liver disease. In conclusion, we show that hepatic A1CF overexpression selectively alters polysomal distribution and mRNA expression, promoting lipogenic, proliferative, and inflammatory pathways leading to HCC.

Authors

Valerie Blanc, Jesse D. Riordan, Saeed Soleymanjahi, Joseph H. Nadeau, ILKe Nalbantoglu, Yan Xie, Elizabeth A. Molitor, Blair B. Madison, Elizabeth M. Brunt, Jason C. Mills, Deborah C. Rubin, Irene O. Ng, Yeonjung Ha, Lewis R. Roberts, Nicholas O. Davidson

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Figure 5

Hepatic overexpression of A1CF promotes fibrosis and spontaneous tumorigenesis.

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Hepatic overexpression of A1CF promotes fibrosis and spontaneous tumorig...
(A) Representative images of Sirius red–stained A1cf+/Tg and WT livers. Scale bars: 50 μm. Quantitation of Sirius red–stained area expressed as percentage total area (mean ± SEM). Significance was determined using unpaired Student’s t test, **P < 0.01 (n = 6). Bottom panel: qPCR evaluation of fibrogenic genes in livers of chow-fed 12-month-old A1cf+/Tg mice. Data are mean ± SEM (n = 6 per genotype). Unpaired t test was used to determine significance between 12-month-old groups, *P < 0.05. (B) Gross images of liver from A1cf+/Tg and A1cf+/Tg Apobec1–/– mice at 12 months of age fed a low-fat chow diet. (C) Representative images of H&E-stained liver sections from A1cf+/Tg and A1cf+/Tg Apobec1–/– mice. The dashed curved lines delineate tumor margin. Scale bars: 100 μm (left) and 50 μm (right). Macroscopic quantitation and size of nodules showing total number (top) and maximum size (bottom) of tumors.