Hepatocyte Notch Signaling Deregulation Related to Lipid Metabolism in Women with Obesity and Nonalcoholic Fatty Liver

Identifier:  imarina:7237759

Handle: https://hdl.handle.net/20.500.11797/imarina7237759

Authors:  Auguet, Teresa; Bertran, Laia; Binetti, Jessica; Aguilar, Carmen; Martinez, Salome; Guiu-Jurado, Esther; Sabench, Fatima; Adalid, Laia; Antonio Porras, Jose; Riesco, David; Del Castillo, Daniel; Richart, Cristobal

Abstract:
Objective This cohort study aimed to explore the relationship between the Notch signaling pathway and the degree of nonalcoholic fatty liver disease (NAFLD). Moreover, this study intended to investigate whether this pathway is related to hepatic lipid metabolism and Toll-like receptors (TLRs). Methods This study used real-time polymerase chain reaction analysis to evaluate the hepatic expression level of all genes studied (Notch receptorsNOTCH1,NOTCH2,NOTCH3, andNOTCH4, transcription factorsHES1andHES5, and Hes-related repressor proteinsHEY1andHEY2) in hepatic tissue from two cohorts: women with severe obesity (n = 57) and normal liver structure (n = 20) or NAFLD (n = 37). Results In women with severe obesity and NAFLD, this study found downregulation of hepaticHES5expression. This expression correlated positively with the hepatic expression ofHES1,HEY1, andNOTCH3. This study also found a positive correlation betweenHES5expression and sterol regulatory element-binding protein 1c (SREBP1c) and betweenNOTCH3and several genes related to hepatic lipid metabolism (encoding liver X nuclear receptor alpha variant 1, farnesoid X nuclear receptor,SREBP1c, acetyl-CoA carboxylase 1, fatty acid synthase, peroxisome proliferator-activated receptor alpha, carnitine palmitoyltransferase 1, carnitineO-octanoyltransferase, ATP-binding cassette subfamily A member 1, and ATP-binding cassette subfamily G member 1). Finally, this study found a positive correlation betweenNOTCH2andTLR2,TLR4, andTLR9and a positive relationship betweenNOTCH1andTLR9. Conclusions Taken together, these findings suggest that hepatic expression of Notch proteins and ligands in relation to lipid metabolism pathways in the liver could have a role in NAFLD pathogenesis.