Abstract
The Wnt/β-catenin pathway plays a pivotal role in liver structural and metabolic homeostasis. Wnt activity is tightly regulated by the acyltransferase Porcupine through the addition of palmitoleate. Interestingly palmitoleate can be endogenously produced by the stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme transcriptionally regulated by insulin. This study aimed to determine whether nutritional conditions, and insulin, regulate Wnt pathway activity in liver. An adenoviral TRE-Luciferase reporter was used as a readout of Wnt/β-catenin pathway activity, in vivo in mouse liver and in vitro in primary hepatocytes. Refeeding enhanced TRE-Luciferase activity and expression of Wnt target genes in mice liver, revealing a nutritional regulation of the Wnt/β-catenin pathway. This effect was inhibited in liver specific insulin receptor KO (iLIRKO) mice and upon wortmannin or rapamycin treatment. Overexpression or inhibition of SCD1 expression regulated Wnt/β-catenin activity in primary hepatocytes. Similarly, palmitoleate added exogenously or produced by SCD1-mediated desaturation of palmitate, induced Wnt signaling activity. Interestingly, this effect was abolished in the absence of Porcupine, suggesting that both SCD1 and Porcupine are key mediators of insulin-induced Wnt/β-catenin activity in hepatocytes. Altogether, our findings suggest that insulin and lipogenesis act as potential novel physiological inducers of hepatic Wnt/β-catenin pathway.
Highlights
Liver plays a central role in the control of energy homeostasis as it contributes to the maintenance of glycemia upon varying nutritional conditions through the regulation of glucose and lipid metabolism[1,2]
We revealed a novel mechanism for the regulation of the Wnt/β-catenin pathway in hepatocytes, involving insulin signaling and lipid metabolism
Insulin stimulates de novo lipogenesis through PI3K/mTORC1 signaling, leading to the expression of the fatty acid desaturase stearoyl-CoA-desaturase 1 (SCD1) which acts as a supplier of palmitoleate and the acyltransferase Porcupine to activate the Wnt signaling pathway
Summary
Liver plays a central role in the control of energy homeostasis as it contributes to the maintenance of glycemia upon varying nutritional conditions through the regulation of glucose and lipid metabolism[1,2]. Hepatic glucose production ensures a constant plasma glucose concentration and energy supply to peripheral tissues, whereas in the post-prandial period increased plasma insulin concentration favors liver glucose uptake restoring glycogen contents and stimulating lipid synthesis through de novo lipogenesis and fatty acid esterification[2]. These opposite metabolic functions are finely regulated by hormonal, nutrient and molecular gradients existing along the liver acini[3,4]. Our findings unravel the insulin-dependent de novo lipogenesis as a novel physiological inducer of the hepatic Wnt/β-catenin pathway
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