Department of Medicine and Surgery, Metabolic Diseases and Insulin Resistance Study Group (GEMMAIR) - AGAUR, Applied Medicine, Rovira i Virgili University (URV), Pere Virgili Health Research Institute (IISPV), Tarragona, Spain.
Joan XXIII University Hospital of Tarragona (HUJXXIII), Internal Medicine Service, Rovira i Virgili University (URV), Tarragona, Spain.
Obesity (Silver Spring). 2020 Aug;28(8):1487-1493. doi: 10.1002/oby.22873. Epub 2020 Jul 13.
This cohort study aimed to explore the relationship between the Notch signaling pathway and the degree of nonalcoholic fatty liver disease (NAFLD). Moreover, this study intended to investigate whether this pathway is related to hepatic lipid metabolism and Toll-like receptors (TLRs).
This study used real-time polymerase chain reaction analysis to evaluate the hepatic expression level of all genes studied (Notch receptors NOTCH1, NOTCH2, NOTCH3, and NOTCH4, transcription factors HES1 and HES5, and Hes-related repressor proteins HEY1 and HEY2) in hepatic tissue from two cohorts: women with severe obesity (n = 57) and normal liver structure (n = 20) or NAFLD (n = 37).
In women with severe obesity and NAFLD, this study found downregulation of hepatic HES5 expression. This expression correlated positively with the hepatic expression of HES1, HEY1, and NOTCH3. This study also found a positive correlation between HES5 expression and sterol regulatory element-binding protein 1c (SREBP1c) and between NOTCH3 and several genes related to hepatic lipid metabolism (encoding liver X nuclear receptor α variant 1, farnesoid X nuclear receptor, SREBP1c, acetyl-CoA carboxylase 1, fatty acid synthase, peroxisome proliferator-activated receptor α, carnitine palmitoyltransferase 1, carnitine O-octanoyltransferase, ATP-binding cassette subfamily A member 1, and ATP-binding cassette subfamily G member 1). Finally, this study found a positive correlation between NOTCH2 and TLR2, TLR4, and TLR9 and a positive relationship between NOTCH1 and TLR9.
Taken together, these findings suggest that hepatic expression of Notch proteins and ligands in relation to lipid metabolism pathways in the liver could have a role in NAFLD pathogenesis.
本队列研究旨在探讨 Notch 信号通路与非酒精性脂肪性肝病（NAFLD）严重程度的关系。此外，本研究还旨在探讨该通路是否与肝内脂质代谢和 Toll 样受体（TLRs）有关。
本研究使用实时聚合酶链反应分析评估了来自两个队列的肝组织中所有研究基因（Notch 受体 NOTCH1、NOTCH2、NOTCH3 和 NOTCH4、转录因子 HES1 和 HES5 以及 Hes 相关阻遏蛋白 HEY1 和 HEY2）的肝表达水平：重度肥胖女性（n=57），正常肝结构（n=20）或 NAFLD（n=37）。
在重度肥胖伴 NAFLD 的女性中，本研究发现肝 HES5 表达下调。这种表达与肝内 HES1、HEY1 和 NOTCH3 的表达呈正相关。本研究还发现 HES5 表达与固醇调节元件结合蛋白 1c（SREBP1c）之间呈正相关，NOTCH3 与肝内脂质代谢相关基因（编码肝 X 核受体α变体 1、法尼醇 X 核受体、SREBP1c、乙酰辅酶 A 羧化酶 1、脂肪酸合成酶、过氧化物酶体增殖物激活受体α、肉碱棕榈酰转移酶 1、肉碱 O-辛酰基转移酶、ATP 结合盒亚家族 A 成员 1 和 ATP 结合盒亚家族 G 成员 1）之间呈正相关。最后，本研究发现 NOTCH2 与 TLR2、TLR4 和 TLR9 呈正相关，NOTCH1 与 TLR9 呈正相关。
综上所述，这些发现表明 Notch 蛋白及其配体在肝脏中与脂质代谢途径的肝表达可能在 NAFLD 发病机制中起作用。
