Liver-selective γ-secretase inhibition ameliorates diet-induced hepatic steatosis, dyslipidemia and atherosclerosis.
Biochem Biophys Res Commun
; 527(4): 979-984, 2020 07 05.
Article
em En
| MEDLINE
| ID: mdl-32439159
ABSTRACT
Hepatic γ-secretase regulates low-density lipoprotein receptor (LDLR) cleavage and degradation, affecting clearance of plasma triglyceride (TG)-rich lipoproteins (TRLs). In this study, we investigated whether γ-secretase inhibition modulates risk of Western (high-fat/sucrose and high-cholesterol)-type diet (WTD)-induced hepatic steatosis, dyslipidemia and atherosclerosis. We evaluated liver and plasma lipids in WTD-fed mice with hepatocyte-specific ablation of the non-redundant γ-secretase-targeting subunit Nicastrin (L-Ncst). In parallel, we investigated the effect of liver-selective Ncst antisense oligonucleotides (ASO) on lipid metabolism and atherosclerosis in wildtype (WT) and ApoE knockout (ApoE-/-) mice fed normal chow or WTD. WTD-fed L-Ncst and Ncst ASO-treated WT mice showed reduced total cholesterol and LDL-cholesterol (LDL-C), as well as reduced hepatic lipid content as compared to Cre- and control ASO-treated WT mice. Treatment of WTD-fed ApoE-/- mice with Ncst ASO markedly lowered total and LDL cholesterol, hepatic TG and attenuated atherosclerotic lesions in the aorta, as compared to control ASO-treated mice. L-Ncst and Ncst ASO similarly showed reduced plasma glucose as compared to control mice. In conclusion, inhibition of hepatic γ-secretase reduces plasma glucose, and attenuates WTD-induced dyslipidemia, hepatic fat accumulation and atherosclerosis, suggesting potential pleiotropic application for diet-induced metabolic dysfunction.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Glicoproteínas de Membrana
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Oligonucleotídeos Antissenso
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Aterosclerose
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Dislipidemias
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Secretases da Proteína Precursora do Amiloide
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Fígado Gorduroso
Tipo de estudo:
Etiology_studies
Limite:
Animals
Idioma:
En
Revista:
Biochem Biophys Res Commun
Ano de publicação:
2020
Tipo de documento:
Article