ABSTRACT
Metabolic dysfunction in the liver is the cause of numerous pathologies, which are associated with an altered redox state. PASK (PAS Domain Kinase) is a nutrient and bioenergetic sensor. We contend that PASK could act as an oxidative stress sensor in liver and/or control the metabolic balance, playing a role in the mitochondrial homeostasis. Using PASK-deficient mice, we observed that PASK deficiency promotes antioxidant response mechanisms: a lower production of ROS/RNS under non-fasting conditions, overexpression of genes coding to ROS-detoxifying enzymes and mitochondrial fusion proteins (MnSod Gpx, Mfn1 and Opa1), coactivator Ppargc1a, transcription factors (Pparg and FoxO3a) and deacetylase Sirt1. Also, under fasting conditions, PASK deficiency induced the overexpression of Ppargc1a, Ppara, Pparg, FoxO3a and Nrf2 leading to the overexpression of genes coding to antioxidant enzymes such as MnSOD, Cu/ZnSOD, GPx, HO1 and GCLm. Additionally, inducing PINK1 involved in cell survival and mitophagy. These changes kept ROS steady levels and improved the regenerative state. We suggest a new role for PASK as a controller of oxidative stress and mitochondrial dynamics in the liver. In fact, antioxidant response is PASK dependent. PASK-targeting could therefore be a good way of reducing the oxidative stress in order to prevent or treat liver diseases.
Subject(s)
Liver/metabolism , Protein Serine-Threonine Kinases/deficiency , Protein Serine-Threonine Kinases/metabolism , Animals , Antioxidants/metabolism , Glucose/metabolism , Homeostasis/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondria/metabolism , Mitochondrial Dynamics/physiology , Mitochondrial Proteins/metabolism , Oxidation-Reduction , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Sirtuin 1/metabolism , Superoxide Dismutase/metabolism , Transcription Factors/metabolismABSTRACT
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.
