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Hepatic Notch Signaling Correlates With Insulin Resistance and Nonalcoholic Fatty Liver Disease

Hepatic Notch signaling is inappropriately activated in obese/insulin-resistant mouse models. Genetic or pharmacologic inhibition of hepatic Notch signaling in obese mice simultaneously improves glucose tolerance and reduces hepatic triglyceride content. As such, we predicted that Notch signaling in...

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Autores principales: Valenti, Luca, Mendoza, Rosa M., Rametta, Raffaela, Maggioni, Marco, Kitajewski, Chris, Shawber, Carrie J., Pajvani, Utpal B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837035/
https://www.ncbi.nlm.nih.gov/pubmed/23990360
http://dx.doi.org/10.2337/db13-0769
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author Valenti, Luca
Mendoza, Rosa M.
Rametta, Raffaela
Maggioni, Marco
Kitajewski, Chris
Shawber, Carrie J.
Pajvani, Utpal B.
author_facet Valenti, Luca
Mendoza, Rosa M.
Rametta, Raffaela
Maggioni, Marco
Kitajewski, Chris
Shawber, Carrie J.
Pajvani, Utpal B.
author_sort Valenti, Luca
collection PubMed
description Hepatic Notch signaling is inappropriately activated in obese/insulin-resistant mouse models. Genetic or pharmacologic inhibition of hepatic Notch signaling in obese mice simultaneously improves glucose tolerance and reduces hepatic triglyceride content. As such, we predicted that Notch signaling in human liver would be positively associated with insulin resistance and hepatic steatosis. Here, we systematically survey Notch signaling in liver biopsy specimens, and show active Notch signaling in lean and obese adults, with expression of multiple Notch receptors and ligands. In morbidly obese patients undergoing bariatric surgery, we show that Notch activation positively correlates with glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase (PCK1) expression, key regulators of hepatic glucose output. We used immunofluorescence to identify active Notch signaling in hepatocytes and show highest activity in hyperglycemia, which we confirmed is a direct effect of hyperglycemia and insulin resistance. In a validation cohort of leaner individuals undergoing percutaneous liver biopsy for suspected nonalcoholic fatty liver disease (NAFLD), Notch activity showed independent positive association with insulin resistance and hepatic steatosis. Notably, Notch activity showed stronger correlation with the NAFLD activity score and alanine aminotransferase levels than with steatosis alone, suggesting that Notch activity is associated with nonalcoholic steatohepatitis. In summary, this study establishes that Notch signaling is activated in and may represent a therapeutic target for patients with obesity-related liver disease.
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spelling pubmed-38370352014-12-01 Hepatic Notch Signaling Correlates With Insulin Resistance and Nonalcoholic Fatty Liver Disease Valenti, Luca Mendoza, Rosa M. Rametta, Raffaela Maggioni, Marco Kitajewski, Chris Shawber, Carrie J. Pajvani, Utpal B. Diabetes Original Research Hepatic Notch signaling is inappropriately activated in obese/insulin-resistant mouse models. Genetic or pharmacologic inhibition of hepatic Notch signaling in obese mice simultaneously improves glucose tolerance and reduces hepatic triglyceride content. As such, we predicted that Notch signaling in human liver would be positively associated with insulin resistance and hepatic steatosis. Here, we systematically survey Notch signaling in liver biopsy specimens, and show active Notch signaling in lean and obese adults, with expression of multiple Notch receptors and ligands. In morbidly obese patients undergoing bariatric surgery, we show that Notch activation positively correlates with glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase (PCK1) expression, key regulators of hepatic glucose output. We used immunofluorescence to identify active Notch signaling in hepatocytes and show highest activity in hyperglycemia, which we confirmed is a direct effect of hyperglycemia and insulin resistance. In a validation cohort of leaner individuals undergoing percutaneous liver biopsy for suspected nonalcoholic fatty liver disease (NAFLD), Notch activity showed independent positive association with insulin resistance and hepatic steatosis. Notably, Notch activity showed stronger correlation with the NAFLD activity score and alanine aminotransferase levels than with steatosis alone, suggesting that Notch activity is associated with nonalcoholic steatohepatitis. In summary, this study establishes that Notch signaling is activated in and may represent a therapeutic target for patients with obesity-related liver disease. American Diabetes Association 2013-12 2013-11-16 /pmc/articles/PMC3837035/ /pubmed/23990360 http://dx.doi.org/10.2337/db13-0769 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Original Research
Valenti, Luca
Mendoza, Rosa M.
Rametta, Raffaela
Maggioni, Marco
Kitajewski, Chris
Shawber, Carrie J.
Pajvani, Utpal B.
Hepatic Notch Signaling Correlates With Insulin Resistance and Nonalcoholic Fatty Liver Disease
title Hepatic Notch Signaling Correlates With Insulin Resistance and Nonalcoholic Fatty Liver Disease
title_full Hepatic Notch Signaling Correlates With Insulin Resistance and Nonalcoholic Fatty Liver Disease
title_fullStr Hepatic Notch Signaling Correlates With Insulin Resistance and Nonalcoholic Fatty Liver Disease
title_full_unstemmed Hepatic Notch Signaling Correlates With Insulin Resistance and Nonalcoholic Fatty Liver Disease
title_short Hepatic Notch Signaling Correlates With Insulin Resistance and Nonalcoholic Fatty Liver Disease
title_sort hepatic notch signaling correlates with insulin resistance and nonalcoholic fatty liver disease
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837035/
https://www.ncbi.nlm.nih.gov/pubmed/23990360
http://dx.doi.org/10.2337/db13-0769
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