[PDF][PDF] γ-Secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor

KJ Kim, IJ Goldberg, MJ Graham, M Sundaram… - Cell metabolism, 2018 - cell.com
KJ Kim, IJ Goldberg, MJ Graham, M Sundaram, E Bertaggia, SX Lee, L Qiang, RA Haeusler
Cell metabolism, 2018cell.com
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 …
Summary
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.
cell.com