Abstract
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.
Highlights
Glucose 6-phosphatase (G6p) expression in the liver[14]
A similar expression pattern was detected in the white adipose tissue of obese and diabetic mice (Fig. 1E), suggesting a positive correlation between the expression of Notch[1] and lipid accumulation and metabolic diseases
Lipid oxidation is controlled by various factors including PPARα and mitochondrial enzymes[24]
Summary
Glucose 6-phosphatase (G6p) expression in the liver[14]. Forced expression of NICD1 in the liver increases fatty acid synthase (Fas) expression and induces hepatosteatosis, whereas NICD1 increases intestinal lipid accumulation by inducing RPL29 and Abhd[1] expression[14,15]. Recent studies have shown that inhibition of Notch[1] signaling in the liver decreases mTorc[1] stability, resulting in decreased lipogenesis and protection from diet-induced fatty liver[13]. These results indicate that Notch[1] plays a significant role in glucose and lipid metabolism. Our data show that inhibition of Notch[1] signaling suppresses diet induced hepatic lipid accumulation, likely through increased fatty acid oxidation. These data further suggest the diverse but conserved biological actions of Notch[1] signaling in metabolism
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