Notch signaling pathways modulate various cellular processes, including cell proliferation, differentiation, adhesion, and communication. Recent studies have demonstrated that Notch1 signaling also regulates hepatic
glucose production and
lipid synthesis. However, the effect of Notch1 signaling on hepatic
lipid oxidation has not yet been directly investigated. To define the function of Notch1 signaling in hepatic lipid metabolism, wild type mice and Notch1 deficient antisense transgenic (
NAS) mice were fed a high-fat diet. High-fat diet -fed
NAS mice exhibited a marked reduction in hepatic
triacylglycerol accumulation compared with wild type obese mice. The improved
fatty liver was associated with an increased expression of hepatic genes involved in
fatty acid oxidation. However, lipogenic genes were not differentially expressed in the
NAS liver, suggesting lipolytic-specific regulatory effects by Notch1 signaling. Expression of
fatty acid oxidative genes and the rate of
fatty acid oxidation were also increased by inhibition of Notch1 signaling in HepG2 cells. In addition, similar regulatory effects on
lipid accumulation were observed in adipocytes. Taken together, these data show that inhibition of Notch1 signaling can regulate the expression of
fatty acid oxidation genes and may provide therapeutic strategies in
obesity-induced hepatic steatosis.