Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability

Increased hepatic lipid content is an early correlate of insulin resistance, and can be caused by nutrient-induced mTor activation. The latter increases basal Akt activity, leading to a self-perpetuating lipogenic cycle. We have previously shown that the developmental Notch pathway has metabolic functions in adult liver. Acute or chronic inhibition of Notch dampens hepatic glucose production and increases Akt tone, and might therefore be predicted to increase hepatic lipid content. Surprisingly, we show that constitutive liver-specific ablation of Notch signaling, or its acute inhibition with a decoy Notch1 receptor, prevents hepatosteatosis by blocking mTorc1. Conversely, Notch gain-of-function causes fatty liver through constitutive activation of mTorc1, an effect reversible by rapamycin treatment. We demonstrate that Notch signaling increases mTorc1 complex stability, augmenting mTorc1 function and Srebp1c-mediated lipogenesis. The data identify Notch as a therapeutically actionable branch point of metabolic signaling, where hepatic Akt activation can be uncoupled from steatosis.