Abstract
Glucagon-like peptide 1 (GLP-1) and PAS kinase (PASK) control glucose and energy homeostasis according to nutritional status. Thus, both glucose availability and GLP-1 lead to hepatic glycogen synthesis or degradation. We used a murine model to discover whether PASK mediates the effect of exendin-4 (GLP-1 analogue) in the adaptation of hepatic glycogen metabolism to nutritional status. The results indicate that both exendin-4 and fasting block the Pask expression, and PASK deficiency disrupts the physiological levels of blood GLP1 and the expression of hepatic GLP1 receptors after fasting. Under a non-fasted state, exendin-4 treatment blocks AKT activation, whereby Glucokinase and Sterol Regulatory Element-Binding Protein-1c (Srebp1c) expressions were inhibited. Furthermore, the expression of certain lipogenic genes was impaired, while increasing Glucose Transporter 2 (GLUT2) and Glycogen Synthase (GYS). Moreover, exendin-4 treatment under fasted conditions avoided Glucose 6-Phosphatase (G6pase) expression, while maintaining high GYS and its activation state. These results lead to an abnormal glycogen accumulation in the liver under fasting, both in PASK-deficient mice and in exendin-4 treated wild-type mice. In short, exendin-4 and PASK both regulate glucose transport and glycogen storage, and some of the exendin-4 effects could therefore be due to the blocking of the Pask expression.
Highlights
The liver plays a central role in metabolic homeostasis, considering its function in the storage and redistribution of carbohydrates, proteins and lipids
Our data show that the effects of exendin-4 on the liver’s adjustment to fasting/feeding could be conditioned by PAS kinase (PASK) activity, and PASK inactivation could be enhancing those effects
In a non-fasted state, exendin-4 blocks hepatic AKT activation, Lxrα Sterol Regulatory Element-Binding Protein-1c (Srebp1c) and both gene expression and GCK activity, so the expression of L-pk and the lipogenic genes is impaired after a three-hour treatment, while Glucose Transporter 2 (GLUT2) and Glycogen Synthase (GYS) are increased
Summary
The liver plays a central role in metabolic homeostasis, considering its function in the storage and redistribution of carbohydrates, proteins and lipids. It is an especially vital organ in the adjustment to nutritional changes under both feeding and fasting conditions. The liver is one of the main organs involved in glycogen synthesis and degradation [1]. During feeding periods when the uptake of glucose occurs, liver stores it as glycogen, helping to control glycemia. Glycogen synthesis and degradation processes are highly regulated by enzymes coordinated with hormonal control that adjust glycogen metabolism to the entire body’s glucose availability and demand [4] The liver produces glucose under fasting conditions, first by glycogenolysis and through hepatic gluconeogenesis, as the main fuel source for other tissues [2,3].
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