Storage and Utilization of Glycogen by Mouse Liver during Adaptation to Nutritional Changes Are GLP-1 and PASK Dependent

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.

Mechanisms for Improving Hepatic Glucolipid Metabolism by Cinnamic Acid and Cinnamic Aldehyde: An Insight Provided by Multi-Omics

“…Some proteins showed a tendency to change, though few were significant. According to the DIA results, AC treatment significantly induced the protein level of GLUT2, which is reported to mediate the glucose transportation between liver and plasma ( 54 ), the depletion of which causes suppressed hepatic glucose uptake and hyperglycemia ( 55 , 56 ). However, the increased glucose uptake by upregulated GLUT2 protein may be partially blunted by the upregulation of PEPCK, a rate-limiting enzyme in the gluconeogenesis process ( 57 ).…”

Wild Boars (Sus scrofa, L. 1758) from Castile and Leon Region (Spain): A Histopathology Survey

“…Hydropic and vacuolar changes were the most common liver changes observed and were associated to glycogen storage, suggesting good nutrition of these wild boars [ 26 ]. However, stress, bacteria, virus, and toxic chemical substances (as persistent organic pollutants, mercury, cadmium, and lead) are among other possible causes of hydropic changes in multiple organs, including the liver [ 22 , 27 ].…”

Preventing Oxidative Stress in the Liver: An Opportunity for GLP-1 and/or PASK

“…Thus, PASK deficiency alters certain exendin-4/GLP-1 anorexigenic effects [ 73 ]. Likewise, PASK and exendin-4/GLP-1 may control glucose transport and glycogen storage, which are key processes for liver metabolism [ 132 ]. Exendin-4 treatment, therefore, blocks hepatic Pask expression under both fasting and feeding conditions [ 132 ].…”

“…Likewise, PASK and exendin-4/GLP-1 may control glucose transport and glycogen storage, which are key processes for liver metabolism [ 132 ]. Exendin-4 treatment, therefore, blocks hepatic Pask expression under both fasting and feeding conditions [ 132 ]. The PI3K-AKT pathway is over-activated in PASK-deficient mice [ 77 , 91 ], and exendin-4 treatment decreases AKT activation in a basal state, while no effect has been observed under fasted conditions [ 132 ].…”

“…Exendin-4 treatment, therefore, blocks hepatic Pask expression under both fasting and feeding conditions [ 132 ]. The PI3K-AKT pathway is over-activated in PASK-deficient mice [ 77 , 91 ], and exendin-4 treatment decreases AKT activation in a basal state, while no effect has been observed under fasted conditions [ 132 ]. This could regulate GSK3 phosphorylation and activity.…”