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- Title
Apobec1 complementation factor overexpression promotes hepatic steatosis, fibrosis, and hepatocellular cancer.
- Authors
Blanc, Valerie; Riordan, Jesse D.; Soleymanjahi, Saeed; Nadeau, Joseph H.; Nalbantoglu, ILKe; Yan Xie; Molitor, Elizabeth A.; Madison, Blair B.; Brunt, Elizabeth M.; Mills, Jason C.; Rubin, Deborah C.; Ng, Irene O.; Yeonjung Ha; Roberts, Lewis R.; Davidson, Nicholas O.; Xie, Yan; Ha, Yeonjung
- 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.
- Subjects
LIVER cancer; FATTY liver; FATTY degeneration; FIBROSIS; RNA-binding proteins; PROTEIN metabolism; PROTEINS; RESEARCH; LIVER tumors; ANIMAL experimentation; RESEARCH methodology; CIRRHOSIS of the liver; MEDICAL cooperation; EVALUATION research; COMPARATIVE studies; HEPATOCELLULAR carcinoma; MICE
- Publication
Journal of Clinical Investigation, 2021, Vol 131, Issue 1, p1
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI138699