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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

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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 6

Increased expression of HCC markers in 12-month-old A1cf+/Tg mice.

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Increased expression of HCC markers in 12-month-old A1cf+/Tg mice.
(A) R...
(A) Representative images of HSP70 and p62 expression in HCC from 12-month-old A1cf+/Tg mice. Representative images of hepatic GPC3 in 12-month-old A1cf+/Tg and A1cf+/Tg Apobec1–/– mice. Arrowheads indicate clusters of GPC3-positive cells. (B) Representative H&E images of pathological features identified in 12-month-old A1cf+/Tg liver. Left panel: Arrow indicates focal inflammation. Arrowheads indicate apoptotic cells. Right panel: Arrowhead indicates mitotic body. (C) Immunohistochemical staining of 12-month-old A1cf+/Tg livers with β-catenin antibody. Expression of β-catenin in liver tissue from A1cf+/Tg and littermate controls evaluated by Western blot and compared with actin. Representative images of cyclin D1 in liver from 12-month-old A1cf+/Tg mice. All panels, scale bars: 50 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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