Department of Medicine, Columbia University, New York, NY, USA.
Department of Medicine, New York University, New York, NY, USA.
Cell Metab. 2018 Apr 3;27(4):816-827.e4. doi: 10.1016/j.cmet.2018.02.010. Epub 2018 Mar 22.
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.
过量的血浆甘油三酯 (TGs) 是肥胖引起的代谢综合征的一个关键组成部分。我们已经表明，γ-分泌酶抑制剂 (GSI) 通过抑制肝 Notch 信号转导来改善葡萄糖耐量，但在 GSI 治疗的以及肝细胞特异性 γ-分泌酶敲除 (L-Ncst) 小鼠中发现了额外的 Notch 非依赖性血浆富含甘油三酯的脂蛋白 (TRLs) 的减少，这表明对肝细胞 TRL 摄取有主要影响。事实上，我们发现 L-Ncst 肝细胞和 Ncst 缺陷肝癌细胞中 VLDL 和 LDL 颗粒摄取增加，部分原因是 γ-分泌酶介导的低密度脂蛋白受体 (LDLR) 裂解和降解减少。为了利用这一新发现，我们生成了一种肝选择性的 Nicastrin ASO，它再现了 L-Ncst 小鼠的葡萄糖和脂质改善，肝细胞 LDLR 水平增加。总之，这些结果确定了肝 γ-分泌酶在调节 LDLR 中的作用，并表明肝特异性 GSI 可能同时改善代谢综合征的多个方面。
