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Series GSE214615 Query DataSets for GSE214615
Status Public on Mar 08, 2024
Title Hepatocyte CCAAT/enhancer-binding protein alpha restricts liver fibrosis by inhibiting secreted phosphoprotein 1 expression (II)
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Persistent NAFLD can progress to nonalcoholic steatohepatitis (NASH) with inflammation and fibrosis, which predisposes patients to cirrhosis and hepatocellular carcinoma. CCAAT/enhancer-binding protein alpha (CEBPA) is a transcription factor that modulates glycolipid homeostasis, cell differentiation and tumor progression. MTL-CEBPA, a first-in-human small activating RNA therapeutic, has been used to overexpress CEBPA and treat hepatocellular carcinoma by targeting myeloid cells in clinical trials. However, whether and how hepatocyte-specific CEBPA modulates NASH are unknown. Here we found that CEBPA expression was inhibited in the livers of high-fat, high-cholesterol, and high-fructose diet (HFCFD)-fed mice, NASH patients and palmitic/oleic acid-treated primary hepatocytes. Liver-specific Cebpa knockout mice (Cebpa-dLiv) and liver-specific tamoxifen-inducible ERT2-Cre mice (Cebpa-dLiv-ERT2) were then generated. Both Cebpa-dLiv and Cebpa-dLiv-ERT2 mice (treated with tamoxifen) developed enhanced NASH and fibrosis compared to control mice. Global transcriptome analyses demonstrated hepatic secreted phosphoprotein 1 (Spp1) encoding the fibrosis-promoting factor SPP1, was markedly induced by hepatocyte CEBPA knockout in HFCFD-fed mice. Consistently, hepatic SPP1 was upregulated by NASH and negatively correlated with CEBPA expression in humans. Hepatocyte loss of CEBPA enhanced hepatic SPP1 expression and serum SPP1 levels both at the early and late stage of NASH in mice. CEBPA-knockout primary hepatocytes released more SPP1 to the culture medium than wild-type mouse hepatocytes, resulting in enhanced fibrogenesis of hepatic stellate cells, a phenotype that was rescued by the Spp1 shRNA. Hepatocyte-directed AAV8-deliverey of Spp1 shRNA rescued the fibrosis in HFCFD-fed Cebpa-dLiv mice. Mechanistically, CEBPA overexpression reduced, while CEBPA knockout enhanced, SPP1 expression in primary hepatocytes in vitro. The Spp1 promoter had functional CEBPA response elements, while CEBPA modulated histone acetylation to restrict SPP1 expression in a novel feedback loop. Furthermore, overexpression of CEBPA in hepatocytes with AAV8-TBG-CEBPA, inhibited hepatic SPP1 expression and reduced fibrosis in HFCFD-fed wild-type mice. This study demonstrates a novel hepatocyte CEBPA-SPP1 axis involved in modulating NASH fibrosis that supports hepatocyte CEBPA as an anti-NASH target.
Overall design Examination of the gene profiles changed by hepatocyte CEBPA knockout or overexpression in primary hepatocytes
Contributor(s) Yan T, Sawaswong V, Gonzalez FJ
Citation(s) 38557493
Submission date Oct 02, 2022
Last update date Apr 17, 2024
Contact name Tingting Yan
Organization name National Institutes of Health
Lab Laboratory of Metabolism
Street address Building 37, Room 3106, Mail Stop 4255
City Bethesda
State/province Maryland
ZIP/Postal code 20892
Country USA
Platforms (1)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (12)
GSM6613102 PMH, WT1
GSM6613103 PMH, WT2
GSM6613104 PMH, WT3
This SubSeries is part of SuperSeries:
GSE214616 Hepatocyte CCAAT/enhancer-binding protein alpha restricts liver fibrosis by inhibiting secreted phosphoprotein 1 expression
BioProject PRJNA886403

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Supplementary file Size Download File type/resource
GSE214615_RAW.tar 22.1 Mb (http)(custom) TAR (of RESULTS)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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