Hepatocyte-Specific Ablation of PP2A Catalytic Subunit α Attenuates Liver Fibrosis Progression via TGF-β 1/Smad Signaling
Open accessAbstract
Protein phosphatase 2A (PP2A), a family of the major serine/threonine phosphatases in cells, regulates many aspects of physiological processes. However, isoform-specific substrates and the biological role of each specific member of the PP2A family remain largely unknown. In this study, we investigated whether PP2A catalytic subunit Cα (PP2Acα) is involved in chronic hepatic injury and fibrosis. A hepatocyte-specific PP2Acα ablation mice model was established to examine the effect of PP2Acα on carbon tetrachloride- (CCl4-) induced chronic hepatic injury and fibrosis. Our results showed that PP2Acα knockout mice were less susceptible to chronic CCl4-induced liver injury as evidenced by lower levels of serum alanine aminotransferase and aspartate aminotransferase, decreased hepatocyte proliferation, and increased rate of apoptotic removal of the injured hepatocytes. PP2Acα knockout mice also displayed a lesser extent of liver fibrosis as a significant decrease in the proportion of α-smooth muscle actin-expressing cells and collagen deposition was observed in their liver tissues. Furthermore, the levels of serum TGF-β1 and hepatocytic Smad phosphorylation were reduced in the PP2Acα knockout mice. These data suggest that hepatocyte-specific ablation of PP2Acα protects against CCl4-induced chronic hepatic injury and fibrogenesis and the protective effect is mediated at least partially through the impaired TGF-β1/Smad signaling.
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In hepatocyte-specific Ppp2ca knockout mice, Cα expression is severely decreased but not completely absent, resulting in a 30% reduction in PP2A activity.
“Although severely decreased, Cα expression was not completely absent in this model, resulting in a 30% reduction in PP2A activity.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [95]
Cα knockout livers have 50% fewer fibrotic lesions than wild-type, with decreased collagen deposition and reduced serum ALT and AST levels.
“Compared with WT mice, 50% less fibrotic lesions were found in Cα KO livers, accompanied by decreased collagen deposition, as well as reduced serum levels of Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST)”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [95]
Hepatocyte-specific knockout of Ppp2ca results in a metabolic phenotype and appears protective against chronic liver injury induced by repeated intraperitoneal CCl4 injections.
“In the liver, hepatocyte-specific KO of Ppp2ca expression did not only result in a metabolic phenotype (see Section 6), but also appeared protective against chronic liver injury, as induced upon repeated i.p. injections with CCl 4 [95].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [95]
The decrease in fibrosis in Cα knockout livers may be attributable to a decline in serum TGFβ.
“The decrease in fibrosis could possibly be attributed to a decline in serum levels of TGFβ, normally activated in response to injury.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [95]
In injured Cα knockout livers, phosphorylated Smad2 and Smad3 are almost completely absent.
“phosphorylated Smad2 and Smad3, downstream mediators of TGF-β, were almost completely absent in the injured KO livers [95].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [95]
Injured Cα knockout livers show fewer activated stellate cells and reduced hepatocyte proliferation, partially correlated with a slight increase in apoptotic hepatocytes.
“Histologically, injured Cα KO livers showed less activated stellate cells, and clearly reduced hepatocyte proliferation, which partially correlated with a slight increase in number of apoptotic hepatocytes.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [95]
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- Authors
- Lu, N., Liu, Y., Tang, A., Chen, L., Miao, D., & Yuan, X.
- Affiliations
- Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Nanjing Medical University (CN)
- Model Animal Research Center (CN)
- Corresponding author
- Yuan, Xiaoqin
- Venue
- BioMed Research International
- Publisher
- Wiley
- Published
- 2015
- Volume
- 2015
- Pages
- 1-10
- ISSN
- 1110-7243 (ISSN-L)
- 2314-6133
- 2314-6141
- PMC
- PMC4332469
- OpenAlex
- W1963647498
- Cited by
- 21
- References
- 41
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 2 · 2016: 2 · 2015: 3
- FWCI
- 1.38
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- BioMed Research International (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Natural Science Foundation of Jiangsu Province (BK2011133)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- protein phosphatase 2A, liver fibrosis, hepatocyte-specific knockout, carbon tetrachloride-induced liver injury, TGF-β1/Smad signaling, hepatocyte apoptosis, hepatocyte proliferation, alpha-smooth muscle actin, collagen deposition
- MeSH terms
- Animals, Carbon Tetrachloride, Cells, Cultured, Enzyme Activation, Liver Cirrhosis, Structure-Activity Relationship, Signal Transduction, Apoptosis, Mice, Knockout, Disease Progression, Hepatocytes, Cell Proliferation, Mice, Smad Proteins, Transforming Growth Factor beta1, Protein Phosphatase 2
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