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. Author manuscript; available in PMC: 2016 May 1.
Published in final edited form as: Trends Endocrinol Metab. 2015 Mar 21;26(5):248–255. doi: 10.1016/j.tem.2015.02.006

Figure 1. Notch regulates gluconeogenesis and lipogenesis of hepatocytes.

Figure 1

Notch signaling regulates hepatic glucose production through synergy with FoxO1, which directly activates the transcription of G6pc and Pck1, the rate-limiting enzymes in hepatic glycogenolysis and gluconeogenesis, respectively. Transcriptionally active FoxO1 is phosphorylated by AKT and excluded from nucleus. In addition, Notch signaling promotes hepatic lipogenesis through an unknown factor that stabilizes mTORC1, which is normally activated by amino acids, as well as the insulin-PI3K-AKT pathway. mTORC1 in turn activates Srebp1c, a key factor that turns on transcription of Fasn, which encodes a rate limiting enzyme in lipogenesis. In obesity, high levels of glucose and free fatty acids (FFA) activate the AMPK-mTOC1-STAT3 pathway, which eventually upregulates Jag1 and activates Notch signaling in the neighbor hepatocyte. Dotted line indicates indirect effect. G6pc, glucose-6-phosphatase, catalytic subunit; Pck1, phosphoenolpyruvate carboxykinase; AMPK, AMP-activated protein kinase; mTORC1, mammalian target of rapamycin complex 1; STAT3, signal transducer and activator of transcription 3; Srebp1c, sterol regulatory element-binding protein 1c; FoxO1, forkhead box protein O1; TG, triglyceride; Fasn, fatty acid synthase; PI3K, phosphatidylinositol 3-kinase.