Hepatic Notch Signaling Correlates With Insulin Resistance and Nonalcoholic Fatty Liver Disease
Luca Valenti,Rosa M. Mendoza,Raffaela Rametta,Marco Maggioni,Chris Kitajewski,Carrie J. Shawber,Utpal B. Pajvani +6 more
TLDR
This study establishes that Notch signaling is activated in and may represent a therapeutic target for patients with obesity-related liver disease.Abstract:
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.read more
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References
More filters
Journal ArticleDOI
Design and validation of a histological scoring system for nonalcoholic fatty liver disease
David E. Kleiner,Elizabeth M. Brunt,Mark L. Van Natta,Cynthia Behling,Melissa J. Contos,Oscar W. Cummings,Linda D. Ferrell,Yao Chang Liu,Michael Torbenson,Aynur Unalp-Arida,Matthew M. Yeh,Arthur J. McCullough,Arun J. Sanyal +12 more
TL;DR: A strong scoring system and NAS for NAFLD and NASH with reasonable inter‐rater reproducibility that should be useful for studies of both adults and children with any degree ofNAFLD are presented.
Journal ArticleDOI
Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.
Steven E. Kahn,Steven M. Haffner,Heise Ma,William H. Herman,Rury R. Holman,Nigel P. Jones,Barbara G. Kravitz,John M. Lachin,O'Neill Mc,Bernard Zinman,Giancarlo Viberti +10 more
TL;DR: The potential risks and benefits, the profile of adverse events, and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes.
Journal ArticleDOI
Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis
Arun J. Sanyal,Naga Chalasani,Kris V. Kowdley,Arthur J. McCullough,Anna Mae Diehl,Nathan M. Bass,Brent A. Neuschwander-Tetri,Joel E. Lavine,James Tonascia,Aynur Unalp,Mark L. Van Natta,Jeanne M. Clark,Elizabeth M. Brunt,David E. Kleiner,Jay H. Hoofnagle,Patricia R. Robuck +15 more
TL;DR: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes, and significant benefits of pioglitazone were observed for some of the secondary outcomes.
Journal ArticleDOI
TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.
Leif W. Ellisen,Jeffrey Bird,Daniel C. West,A. Lee Soreng,Thomas C. Reynolds,Stephen D. Smith,Jeffrey Sklar +6 more
TL;DR: It is shown that the locus on chromosome 9 contains a gene highly homologous to the Drosophila gene Notch, which may be important for normal lymphocyte function and that alteration of TAN-1 may play a role in the pathogenesis of some T cell neoplasms.
Journal ArticleDOI
Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis.
TL;DR: The evidence that suggests NAFLD is a multisystem disease and the factors that might determine interindividual variation in the development and progression of its major hepatic and extrahepatic manifestations are reviewed.