γ-Secretase Inhibition Lowers Plasma Triglyceride-Rich Lipoproteins by Stabilizing the LDL Receptor

Publication date: Available online 22 March 2018
Source:Cell Metabolism
Author(s): KyeongJin Kim, Ira J. Goldberg, Mark J. Graham, Meenakshi Sundaram, Enrico Bertaggia, Samuel X. Lee, Li Qiang, Rebecca A. Haeusler, Daniel Metzger, Pierre Chambon, Zemin Yao, Henry N. Ginsberg, Utpal B. Pajvani
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.

Graphical abstract

Teaser

Kim et al. discover that hepatic γ-secretase inhibition improves glucose homeostasis and simultaneously reduces plasma triglycerides and non-HDL cholesterol, in part through blocking LDLR cleavage and degradation


https://ift.tt/2IOnwvl