γ-Secretase Inhibition Lowers Plasma Triglyceride-Rich Lipoproteins by Stabilizing the LDL Receptor.
Fiche publication
Date publication
avril 2018
Journal
Cell metabolism
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHAMBON Pierre, Dr METZGER Daniel
Tous les auteurs :
Kim K, Goldberg IJ, Graham MJ, Sundaram M, Bertaggia E, Lee SX, Qiang L, Haeusler RA, Metzger D, Chambon P, Yao Z, Ginsberg HN, Pajvani UB
Lien Pubmed
Résumé
Excess plasma triglycerides (TGs) are a key component of obesity-induced metabolic syndrome. We have shown that γ-secretase inhibitor (GSI) treatment improves glucose tolerance due to inhibition of hepatic Notch signaling but found additional Notch-independent reduction of plasma TG-rich lipoproteins (TRLs) in GSI-treated, as well as hepatocyte-specific, γ-secretase knockout (L-Ncst) mice, which suggested a primary effect on hepatocyte TRL uptake. Indeed, we found increased VLDL and LDL particle uptake in L-Ncst hepatocytes and Ncst-deficient hepatoma cells, in part through reduced γ-secretase-mediated low-density lipoprotein receptor (LDLR) cleavage and degradation. To exploit this novel finding, we generated a liver-selective Nicastrin ASO, which recapitulated glucose and lipid improvements of L-Ncst mice, with increased levels of hepatocyte LDLR. Collectively, these results identify the role of hepatic γ-secretase to regulate LDLR and suggest that liver-specific GSIs may simultaneously improve multiple aspects of the metabolic syndrome.
Mots clés
ASO, GSI, LDL, LDLR, Nicastrin, VLDL, gamma-secretase, triglyceride
Référence
Cell Metab.. 2018 Apr 3;27(4):816-827.e4