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. © 2013 by the American Diabetes Association.
Hepatic notch signaling correlates with insulin resistance and nonalcoholic fatty liver disease / L. Valenti, R.M. Mendoza, R. Rametta, M. Maggioni, C. Kitajewski, C.J. Shawber, U.B. Pajvani. - In: DIABETES. - ISSN 0012-1797. - 62:12(2013 Aug 29), pp. 4052-4062.
|Titolo:||Hepatic notch signaling correlates with insulin resistance and nonalcoholic fatty liver disease|
|Parole Chiave:||Adult; Alanine Transaminase; Fatty Liver; Female; Glucose-6-Phosphatase; Hepatocytes; Humans; Hyperglycemia; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Liver; Male; Middle Aged; Obesity; Phosphoenolpyruvate Carboxykinase (GTP); Receptors, Notch; Signal Transduction; Internal Medicine; Endocrinology, Diabetes and Metabolism|
|Settore Scientifico Disciplinare:||Settore MED/09 - Medicina Interna|
|Data di pubblicazione:||29-ago-2013|
|Centro di ricerca:||Centro per lo studio e la cura delle malattie metaboliche del fegato|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.2337/db13-0769|
|Appare nelle tipologie:||01 - Articolo su periodico|