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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.
Pubmed ID: 29576536 RIS Download
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This monoclonal targets Presenilin 1 (D39D1) Rabbit mAb
View all literature mentionsThis monoclonal targets Nicastrin (D38F9) Rabbit mAb
View all literature mentionsThis polyclonal targets donkey anti-goat IgG-HRP
View all literature mentionsThis unknown targets IgG
View all literature mentionsThis unknown targets IgG
View all literature mentionsThis recombinant monoclonal targets Syndecan
View all literature mentionsThis polyclonal targets LDL Receptor antibody
View all literature mentionsThis polyclonal targets Apolipoprotein B
View all literature mentionsThis polyclonal targets Proprotein Convertase 9 / PCSK9
View all literature mentionsThis monoclonal targets Human Apolipoprotein B/ApoB MAb (Clone 369717)
View all literature mentionsThis polyclonal targets Human Apolipoprotein CIII
View all literature mentionsThis monoclonal targets α-tubulin
View all literature mentionsThis monoclonal targets beta-Actin
View all literature mentionsThis monoclonal targets DYKDDDDK Tag
View all literature mentionsThis monoclonal targets Presenilin 2 (D30G3) Rabbit mAb
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsMus musculus with name B6.Cg-Speer6-ps1Tg(Alb-cre)21Mgn/J from IMSR.
View all literature mentionsMus musculus with name B6;129-Ncstntm1Sud/J from IMSR.
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line McA-RH7777 is a Cancer cell line with a species of origin Rattus norvegicus
View all literature mentionsThe SciCrunch Infrastructure was developed as a cooperative data platform to be used by diverse communities in making data more FAIR.
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