Abstract
The liver controls metabolic homeostasis in response to fasting and refeeding periods. Glucokinase (GCK) adjusts hepatic glucose phosphorylation to blood glucose levels, acting as a glucose sensor. Our objective was to determine whether PAS kinase (PASK), a nutrient sensor, could be affecting the expression or activity of liver GCK and the response to fasting and refeeding states of key hepatic metabolic pathways. PASK-deficient mice have impaired insulin signaling (AKT overactivation). Furthermore, PASK deficiency modified the expression of several transcription factors involved in the adjustment to fasting and refeeding. Foxo1 decreased under fasting conditions, while Ppara and Pparg were overexpressed in PASK-deficient mice. However, PEPCK protein levels were similar or higher, while the expression of Cpt1a decreased in PASK-deficient mice. By contrast, Lxra and Chrebp were overexpressed after refeeding, while the expression of Acc and Fas decreased in PASK-deficient mice. Likewise, with a decreased expression of Gck and increased nuclear location of the complex GCK-GCKR, GCK activity decreased in PASK-deficient mice. Therefore, PASK regulated some of the genes and proteins responsible for glucose sensing, such as glucokinase, and for insulin signalling, affecting glucose and lipid metabolism and consequently certain critical hepatic functions.
Highlights
The liver plays a key role in metabolic homeostasis
Gck and Gckr expression was measured in the liver of wild type (WT) and Pask−/− mice under non-fasted, fasted
Prolonged fasting blocked the expression of Gck and Gckr in Pask−/− mice (Fig. 1B,C)
Summary
The liver plays a key role in metabolic homeostasis. It is the main site for the synthesis, metabolism, storage and redistribution of carbohydrates, proteins and lipids. Glucokinase (GCK, hexokinase type IV) is a critical enzyme controlling hepatic metabolism, regulating hepatic carbohydrate metabolism by acting as a glucose sensor It triggers shifts in metabolism or cell function in response to changes in glucose levels, as occurs after a meal. Hepatic GCK acts in tandem with insulin in crucial functions in the liver, such as the maintenance of blood glucose and lipid homeostasis[8], as well as glycogen synthesis and storage. Insulin resistance in the liver contributes greatly to the development of type 2 diabetes mellitus[16,17,18], and may promote lipid synthesis, producing hepatic steatosis and further systemic insulin resistance[19] This is due to lower hepatic insulin sensitivity that leads to postprandial hyperglycemia and increased hepatic glucose production, exacerbating hyperglycemia and chronic hyperinsulinemia in diabetics[20]
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