CD73 maintains hepatocyte metabolic integrity and mouse liver homeostasis in a sex-dependent manner
| Autor: | Marquet Minor, Kevin G. Greene, Dong Fu, Morgan A. Rouse, Natasha T. Snider, Karel P. Alcedo, Helen H. Willcockson, Gloria S. Jung |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine HFD high-fat diet Adenosine CD73-LKO liver-specific CD73 knockout Ecto-5’-Nucleotidase RC799-869 Mice chemistry.chemical_compound Liver disease NT5E PCR polymerase chain reaction 0302 clinical medicine AMP-activated protein kinase AMPK adenosine monophosphate–activated protein kinase Hepatic Zonation Homeostasis 5'-Nucleotidase Original Research Mice Knockout Sex Characteristics biology mTOR mechanistic target of rapamycin A2AR Gs-protein–coupled adenosine receptor 2A Gastroenterology K keratin Diseases of the digestive system. Gastroenterology Cell biology medicine.anatomical_structure Liver Hepatocyte Female 030211 gastroenterology & hepatology AMP-Activated Protein Kinase medicine.drug CoA coenzyme A GPI glycosylphosphatidylinositol Adenosine monophosphate medicine.medical_specialty ATP adenosine triphosphate PBS phosphate-buffered saline Serum albumin 03 medical and health sciences Internal medicine Extracellular medicine Animals TBST tris-buffered saline with 0.1% Tween 20 Inflammation Hepatology AMPK medicine.disease APCP adenosine 5'-(α β-methylene)diphosphate WT wild-type loxP locus of cross-over P1 Mice Inbred C57BL AMPase adenosine monophosphatase 030104 developmental biology Endocrinology chemistry AMP adenosine monophosphate Hepatocytes biology.protein NAFLD nonalcoholic fatty liver disease Steatosis HCC hepatocellular carcinoma CD73 ecto-5’-nucleotidase |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 1, Pp 141-157 (2021) Cellular and Molecular Gastroenterology and Hepatology |
| DOI: | 10.1101/2020.10.08.328930 |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
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