ArticleCell metabolism2018
γ-Secretase Inhibition Lowers Plasma Triglyceride-Rich Lipoproteins by Stabilizing the LDL Receptor.
Article in Cell metabolism, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 24 citations in OpenAlex.
- The γ-secretase complex: from discovery to a therapeutic target.RSC chemical biology · 2026Review
- Pathways and Molecular Mechanisms Governing LDL Receptor Regulation.Circulation research · 2025Review
- The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- Molecular Regulation and Therapeutic Targeting of VLDL Production in Cardiometabolic Disease.Cellular and molecular gastroenterology and hepatology · 2025Review
- Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation.Biochemical Society transactions · 2024Article
- Hepatocyte Kctd17 Inhibition Ameliorates Glucose Intolerance and Hepatic Steatosis Caused by Obesity-induced Chrebp Stabilization.Gastroenterology · 2023Article
- Antisense oligonucleotide is a promising intervention for liver diseases.Frontiers in pharmacology · 2022Review
- Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver.Nature communications · 2021Article
- Maladaptive regeneration - the reawakening of developmental pathways in NASH and fibrosis.Nature reviews. Gastroenterology & hepatology · 2021Review
- Liver-selective γ-secretase inhibition ameliorates diet-induced hepatic steatosis, dyslipidemia and atherosclerosis.Biochemical and biophysical research communications · 2020Article
- Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake.Scientific reports · 2019Article
- Notch signaling dynamically regulates adult β cell proliferation and maturity.The Journal of clinical investigation · 2019Article
- Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis.Science translational medicine · 2018Article
Corrections and comments
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Authors and funding
13 authors at 5 institutions in 3 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.