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Liver-selective γ-secretase inhibition ameliorates diet-induced hepatic steatosis, dyslipidemia and atherosclerosis
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Hepatocyte-specific Nicastrin KO mice (L-Ncst) had a plasma lipid profile similar to that observed in GSI-treated mice.
“These mice had a plasma lipid profile similar to that observed in GSI-treated mice, suggesting a specific and important role of hepatic γ-secretase in lipid metabolism [115].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [115]
The Results sections report that WTD-fed L-Ncst mice had lower plasma cholesterol and LDL-C, and that liver-selective Ncst ASO treatment produced consistent reductions. But the paper distinguishes Ncst ASO from GSI treatment; its discussion of earlier GSI-treated mice reports lower triglyceride-rich lipoproteins, not the same cholesterol profile. The comparison is supported for ASO-treated mice, but not established for GSI-treated mice as stated. (LLM, conf=0.82)
Experimental — accuracy not yet measuredLiver-selective γ-secretase inhibition ameliorated diet-induced dyslipidaemia in mice.
“Liver-selective γ-secretase inhibition ameliorated diet-induced dyslipidaemia in mice [55]”
From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [55]
Targeting the γ-secretase cleavage of the LDLR could provide an alternative therapeutic approach to treat hypercholesterolemia.
“indicating that targeting the γ-secretase cleavage of the LDLR could provide an alternative therapeutic approach to treat hypercholesterolemia.”
From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [55]
Specific inhibition of hepatic γ-secretase counters diet-induced hepatic steatosis, dyslipidemia, and atherosclerosis in mice.
“Furthermore, specific inhibition of hepatic γ-secretase counters diet-induced hepatic steatosis, dyslipidemia, and atherosclerosis in mice [115].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [115]
Hepatic γ-secretase plays a specific and important role in lipid metabolism.
“These mice had a plasma lipid profile similar to that observed in GSI-treated mice, suggesting a specific and important role of hepatic γ-secretase in lipid metabolism [115].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [115]
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Cites
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Impact of Lipids on Cardiovascular Health
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ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors
Gordts, P. L. S. M., Nock, R., Son, N.-H., Ramms, B., Lew, I., Gonzales, J. C., Thacker, B. E., Basu, D., Lee, R. G., Mullick, A. E., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci86610 · Cited by 274 · cited 1×
“We recently identified that GSI treatment in mice lowered plasma triglyceride-rich lipoproteins (TRLs) by increasing hepatocyte LDL-receptor (LDLR) stability [23], consistent with a role of LDLR in TRL clearance, but LDLR is well documented to regulate LDL-C uptake [24,25] and thus propensity to atherosclerosis [26].”
BackgroundTHOMPSON, A., & DANESH, J. (2006) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2006.01644.x · Cited by 252 · cited 4×
“With numerous studies that confirm the hypothesis that reduced LDL-C reduces CVD risk, LDL-C lowering with statins and other agents are mainstay medications for patients with dyslipidemia.”
MethodInfluentialHepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis
Zhu, C., Kim, K., Wang, X., Bartolome, A., Salomao, M., Dongiovanni, P., Meroni, M., Graham, M. J., Yates, K. P., Diehl, A. M., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aat0344 · Cited by 250
Self-citationγ-secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor
Kim, K., Goldberg, I. J., Graham, M. J., Sundaram, M., Bertaggia, E., Lee, S. X., Qiang, L., Haeusler, R. A., Metzger, D., Chambon, P., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.02.010 · Cited by 26
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Sorted by citations
The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms
Ndoj, K., Meurs, A., Papaioannou, D., Bjune, K., & Zelcer, N. (2025) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2024.119082 · Cited by 17
Aldworth, H., & Hooper, N. M. (2024) · Biochemical Society Transactions · doi:10.1042/bst20230918 · Cited by 11
Metadata
- Authors
- Kim, K., Yu, J., Kang, J. K., Morrow, J. P., & Pajvani, U. B.
- ORCID
- Morrow, John P.
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2020-07
- Volume
- 527
- Issue
- 4
- Pages
- 979-984
- ISSN
- 0006-291X
- PMC
- PMC7308114
- Cited by
- 11
- References
- 6
- Language
- en
- Funders
- American Heart Association
- National Research Foundation of Korea
- Inha University
- Columbia University
- National Institutes of Health
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