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Updated: Nov 19, 2025
Cell Type-specific Gene Expression Profiling in the Mouse Liver
Published on: September 17, 2019
CD73 Maintains Hepatocyte Metabolic Integrity and Mouse Liver Homeostasis in a Sex-Dependent Manner
Karel P Alcedo1, Morgan A Rouse1, Gloria S Jung1
1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Background & Aims:
Metabolic imbalance and inflammation are common features of chronic liver diseases. Molecular factors controlling these mechanisms represent potential therapeutic targets. CD73 is the major enzyme that dephosphorylates extracellular adenosine monophosphate (AMP) to form the anti-inflammatory adenosine. CD73 is expressed on pericentral hepatocytes, which are important for long-term liver homeostasis. We aimed to determine if CD73 has nonredundant hepatoprotective functions.
Methods:
Liver-specific CD73 knockout (CD73-LKO) mice were generated by targeting the Nt5e gene in hepatocytes. The CD73-LKO mice and hepatocytes were characterized using multiple approaches.
Results:
Deletion of hepatocyte Nt5e resulted in an approximately 70% reduction in total liver CD73 protein (P < .0001). Male and female CD73-LKO mice developed normally during the first 21 weeks without significant liver phenotypes. Between 21 and 42 weeks, the CD73-LKO mice developed spontaneous-onset liver disease, with significant severity in male mice. Middle-aged male CD73-LKO mice showed hepatocyte swelling and ballooning (P < .05), inflammation (P < .01), and variable steatosis. Female CD73-LKO mice had lower serum albumin levels (P < .05) and increased inflammatory genes (P < .01), but did not show the spectrum of histopathologic changes in male mice, potentially owing to compensatory induction of adenosine receptors. Serum analysis and proteomic profiling of hepatocytes from male CD73-LKO mice showed significant metabolic imbalance, with increased blood urea nitrogen (P < .0001) and impairments in major metabolic pathways, including oxidative phosphorylation and AMP-activated protein kinase (AMPK) signaling. There was significant hypophosphorylation of AMPK substrates in CD73-LKO livers (P < .0001), while in isolated hepatocytes treated with AMP, soluble CD73 induced AMPK activation (P < .001).
Conclusions:
Hepatocyte CD73 supports long-term metabolic liver homeostasis through AMPK in a sex-dependent manner. These findings have implications for human liver diseases marked by CD73 dysregulation.
Insights
Hepatocyte CD73 is vital for liver homeostasis, particularly in males, by regulating metabolism via AMPK. Its absence leads to liver disease, highlighting CD73's therapeutic potential in chronic liver conditions.
Area of Science:
- Hepatology
- Molecular Biology
- Biochemistry
Background:
- Chronic liver diseases often involve metabolic imbalance and inflammation.
- CD73, an enzyme dephosphorylating adenosine monophosphate (AMP) to adenosine, is expressed in hepatocytes and has anti-inflammatory properties.
- Understanding CD73's role is crucial for identifying therapeutic targets in liver disease.
Purpose of the Study:
- To investigate the nonredundant hepatoprotective functions of CD73.
- To determine if CD73 plays a role in maintaining long-term liver homeostasis.
- To explore the sex-dependent effects of CD73 deficiency in the liver.
Main Methods:
- Generation of liver-specific CD73 knockout (CD73-LKO) mice by targeting the Nt5e gene in hepatocytes.
- Characterization of CD73-LKO mice and isolated hepatocytes using various biochemical and histological approaches.
- Analysis of metabolic pathways, inflammation markers, and AMP-activated protein kinase (AMPK) signaling.
Main Results:
- Hepatocyte CD73 deficiency led to spontaneous liver disease, particularly severe in male mice, characterized by inflammation, steatosis, and hepatocyte ballooning.
- Male CD73-LKO mice exhibited significant metabolic imbalance, including impaired oxidative phosphorylation and AMPK signaling.
- Female CD73-LKO mice showed milder phenotypes, possibly due to compensatory adenosine receptor induction.
Conclusions:
- Hepatocyte CD73 is essential for maintaining long-term metabolic liver homeostasis in a sex-dependent manner, primarily through AMPK.
- CD73 deficiency results in liver disease, underscoring its protective role.
- These findings have significant implications for understanding and treating human liver diseases associated with CD73 dysregulation.
