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PASK and liver antioxidants: Comparison
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Please note this is a comparison between Version 3 by Vivi Li and Version 2 by Verónica Hurtado-Carneiro.

PAS kinase (PASK) is a serine/threonine kinase containing an N-terminal Per-Arnt-Sim (PAS) domain, able to detect redox state. It is a nutrient sensor and during fasting/feeding changes, PASK regulates the expression and activation of critical liver proteins involved in carbohydrate and lipid metabolism and mitochondrial biogenesis.

  • oxidative stress
  • metabolic sensors
  • nutritional states
  • reactive oxygen species
  • antioxidant enzymes
  • obesity
  • diabetes
  • antioxidant defense
  • fasting
  • feeding

1. Introduction

The liver is a vital organ for adapting to nutritional changes (e.g., fasting/feeding states) by responding appropriately to achieve metabolic and energy homeostasis through its role in the storage and redistribution of carbohydrates, proteins, vitamins, and lipids.

2. Liver Metabolic Function and Detoxification

After food intake, the liver stores glucose as glycogen, facilitating glycemic control [1]. Furthermore, the excess carbohydrate in carbohydrate-rich diets is converted into fatty acids via de novo lipogenesis [2][3].

By contrast, the liver produces glucose under fasting conditions, first by glycogenolysis and subsequently through hepatic gluconeogenesis, as the main fuel source for other tissues and contributing to whole-body energy homeostasis [3][4]. The liver’s high metabolic rate means it is also an important source of reactive oxygen species (ROS).

The liver is also the main organ involved in the detoxification of substances harmful to the body. Many drugs, various endogenous molecules, and xenobiotics are lipophilic molecules that need to be metabolized to water-soluble compounds that facilitate their subsequent biliary or renal excretion. Hepatic elimination of most toxic substances involves cytochrome P450 enzymes (CYP) [5][6] system and UDP-glucuronosyltransferases [7].

2.1. ROS and Antioxidant Defense

ROS are produced by normal cellular metabolism. The main source of endogenous ROS in the liver, as well as in other organs, is oxidative phosphorylation in the mitochondrial electron transfer chain and nicotinamide adenine dinucleotide phosphate NADPH oxidase enzymes (NOX). Mitochondrial ROS generation will depend on the metabolic rate, although the presence of toxic compounds and their transformation by CYP can sometimes be another source of cytosolic ROS, associated with the consumption of NADPH by CYP [8] ROS is a physiological consequence not only of normal cell function but also of the presence of unpaired electrons in free radicals, which gives them high reactivity and can cause damage to other cellular components, such as proteins, lipids, and DNA. An excess of ROS could therefore trigger a state referred to as oxidative stress.

The most important ROS, which includes radical superoxide (O2−), non-radical hydrogenperoxide (H2O2), and hydroxyl radicals (•OH−, and the reactive nitrogen species (RNS) that derive from peroxynitrite (ONOO−), are the most relevant radical species present in living systems (Figure 1).

Fortunately, and in contrast, liver cells also have potent antioxidant enzymatic and nonenzymatic mechanisms to prevent ROS and repair any damage caused. The antioxidant enzymes include cytosolic and mitochondrial superoxide dismutase (SOD), which eliminates the superoxide ion by converting it into hydrogen peroxide and glutathione peroxidase (GPx), which are involved in detoxifying hydrogen and cellular peroxides for their conversion into oxygen and water, acting in tandem with peroxiredoxins (Prx), thioredoxins (Trx) and glutaredoxins (Grx), and peroxisomal catalase (CAT) (Figure 1). In addition, nonenzymatic molecules such as reduced glutathione (GSH) are present at high concentrations in the liver; vitamin A, vitamin C, vitamin E, bilirubin, ubiquinone, and uric acid remove ROS and restore reduced protein and lipid reserves. Ceruloplasmin and ferritin also help to eliminate the metals that promote oxidative reactions [9][10][11][12].

Figure 1. Production scheme of different types of ROS and the antioxidant enzymes involved in their elimination. The main sources of endogenous ROS are oxidative phosphorylation in the mitochondrial electron transfer chain and NOX enzymes. Cytosolic superoxide (O2−) is quickly converted into hydrogen peroxide (H2O2) by SOD. H2O2 oxidizes critical thiols within proteins to regulate vital biological processes, including metabolic adaptation, differentiation, and proliferation, or it can be detoxified in water (H2O) by Prx, GPx, and CAT. Moreover, H2O2 reacts with Fe2+ or Cu2+ to generate the hydroxyl radical (•OH) that causes irreversible oxidative damage to lipids, proteins, and DNA. The different colors indicate the subcellular location of the antioxidant enzymes. (Image created in biorender.com accessed on 19 October 2021).

 

Alterations in ROS production and/or diminished defense mechanisms can cause serious problems that trigger liver failure [13][14] 

When the balance between ROS production and/or antioxidant mechanisms is modified, the onset of oxidative stress leads to cell damage and toxicity and, therefore, multiple pathologies, including hepatic fibrogenesis [15][16][17].

Prolonged fasting produces oxidative stress, increasing hepatic free radical levels and decreasing antioxidant defenses [18][19]. Nevertheless, intermittent fasting has also been linked to a reduction in oxidative stress [20][21][22][23][24].

2.2. Hepatic Oxidative Stress and Nutritional Status

Oxidative stress may depend on nutritional conditions. Hyperglycemia induces the hyperactivation of NADPH oxidases, increasing oxidative stress [25]. During fasting or calorie restriction, cells are adapted by a metabolic shift in their energy source from glycolysis to oxidative phosphorylation [26][27][28], which requires an increase in mitochondrial oxidative phosphorylation for producing adenosine triphosphate (ATP), and therefore involves elevated ROS production [29].

Many chronic liver diseases are known to be associated with elevated oxidative stress [30]. Thus, the hyperglycemic state that characterizes insulin resistance, diabetes, and obesity [31] could modify cellular redox homeostasis and trigger oxidative stress, mirroring the effect of prolonged fasting. Oxidative stress has been involved in the pathophysiology of several liver diseases. For example, free radicals contribute to the onset and progression of non-alcoholic steatohepatitis (NASH) [32][33], cirrhosis, and liver cancer [34][35]. Mitochondrial ROS promote the presence of other mutations and favor metastatic processes in cancer cells [36].

ROS also operate as signaling molecules in support of normal biological processes and physiological functions. For example, ROS are involved in growth factor signaling, autophagy, hypoxic signaling, immune responses, and stem-cell proliferation and differentiation [37][8][38][39].

3. Nutrient Sensors and Oxidative Stress

Nutrient sensors detect changes in nutritional status and suitably adapt an intermediary metabolism to maintain energy and oxidative homeostasis. The following are examples of these sensors: AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), PASK, and nicotinamide-dependent histone deacetylases (SIRTs) (Figure 2).

3.1. PASK

PASK/PASKIN is a serine/threonine kinase containing an N-terminal Per-Arnt-Sim (PAS) domain able to respond to several intracellular parameters, as light, oxygen, and redox state [40][41]. These PAS domains have a well-conserved three-dimensional structure that creates a hydrophobic pocket where small metabolites bind, initiating cellular signaling [42][43][44]. In mammals, PASK responds according to nutritional status by contributing to the regulation of glucose homeostasis, energy metabolism and oxidative stress [45][46][47][48]. PASK regulates glucagon and insulin secretion [49][50]. Its role in differentiation processes and epigenetic regulation has recently been described [51][52][53].

PASK-deficient mice record an elevated metabolic rate, which has also been confirmed in PASK knockdown myoblast [54] and neuroblastoma cells [55]. PASK is also a critical signaling regulator of AMPK and mTOR pathways in neuroblastoma N2A cells, the hypothalamus, and the liver [55][56]. Meanwhile, PASK deficiency is associated with a reduction in ROS/RNS levels. Nonetheless, the relationship between PASK and ROS production and oxidative stress is still poorly understood. PAS domains are reported to detect intracellular oxygen, redox state, and various metabolites [41]. Moreover, PASK deficiency is associated with the overexpression of hepatic antioxidant enzymes in basal state and fasting conditions [57] (Figure 2). In addition, PASK deficiency avoids a decrease in the expression of age-related antioxidant enzymes, maintaining ROS/RNS production at a level similar to that of young wild-type (WT) mice. Aged PASK-deficient mice therefore record an overall improvement in their antioxidant mechanism and metabolic phenotype (i.e., PASK deficiency blocks the development of glucose intolerance and insulin resistance in aged mice) [58].

 

Figure 2. Fasting modulates oxidative stress through nutrient sensors. Fasting initiates a signaling cascade that leads to the activation of antioxidant mechanisms to reduce oxidative stress. Several sirtuins, in particular SIRT1 and SIRT3, are activated by fasting and reduce oxidative stress by controlling antioxidant expression at the transcriptional or post-translational level. In turn, fasting activates AMPK, which prevents oxidative stress by decreasing fatty acid synthesis and increasing the level of NADPH. In parallel, mTOR is inhibited, and GCN2 kinase is activated by fasting, thereby facilitating the autophagy process and the elimination of oxidized proteins and damaged mitochondria. At the center of this scenario is PASK, which fasting keeps inactive, exerting an oxidative stress-reducing effect partly by increasing the antioxidant mechanism. This action could be prompted by the inter-regulation of PASK, AMPK, mTOR, and SIRTs through their activation/deactivation, preventing aging and associated diseases. (Image created in biorender.com accessed on 19 October 2021).

4. PASK deficiency reduces hepatic oxidative stress

PASK-deficient mice are protected against obesity and the insulin resistance induced by an HFD [54][59][60]. PASK regulates energy metabolism and glucose homeostasis, especially when adapting to fasting and feeding. Hepatic PASK expression is altered by an HFD [60]. Additionally, PASK deficiency improves the deleterious effects of an HFD such as the overexpression of hepatic genes that occurs in HFD-fed mice. In addition, PASK deficiency restores glucose tolerance and insulin sensitivity in mice under an HFD, maintaining body weight and serum lipid parameters within the physiological range [60].

High levels of ROS are associated with insulin resistance, type 2 diabetes, and obesity . The role of PASK in hepatic oxidative stress has been investigated under basal and fasting conditions in order to observe the liver’s adaptive response.

The adaptation to energy requirements under prolonged fasting depends on mitochondrial biogenesis. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) promotes cellular adjustment to conditions requiring energy input, enhancing mitochondrial mass [61][62][63]. PGC1α and SIRT1 are co-activators of several transcription factors and nuclear receptors, such as nuclear respiratory factors (NRFs), peroxisome proliferator-activated receptors (PPARs), and estrogen-related receptors (ERRs).

The expression of coactivator Ppargc1a transcription factors such as Pparg and FoxO3a, and activators such as deacetylase Sirt1, are overexpressed under basal conditions in PASK-deficient mice. Furthermore, the SIRT1 sub-cellular location is mainly nuclear in PASK-deficient mice [57]. Previous data have shown that an increase in nuclear SIRT1 activity, without changes in protein levels, positively correlates with an increased expression of genes regulated by PGC1α [64]. In contrast, the downregulation of PGC1α in obesity has been related to mitochondrial damage and decreased mass [65].

NRF2 (Nuclear factor erythroid 2-related factor 2) is considered the major regulator of the cellular redox balance[66][67][68]. NRF2 is usually degraded by the proteasome in the absence of oxidative stress. Nevertheless, NRF2 is translocated into the nucleus when there is an increase in such stress, inducing the expression of several genes coding to Glutamate-cysteine ligase (GCLm) and Heme oxygenase (HO1) [69][70]. NRF2 activation could be regulated positively by phosphorylation [71][72]. PASK deficiency, therefore, promotes extracellular signal-regulated kinases 1/2 (ERK1/2) over-activation [57], and likewise, the PI3K-AKT pathway is over-activated [57]. In turn, PASK deficiency increases the expression of proteins and mRNAs coding to NRF2, GCLm and HO1 under fasting conditions. These results are consistent with the data reporting that AKT activation decreases glycogen synthase kinase-3 beta GSK3β activity and increases NRF2 nuclear translocation [73], which promotes NRF1 expression and activates mitochondrial biogenesis and antioxidant cellular defenses [74].

Both AMPK activation and elevated SIRT1 under fasting conditions are reported to stimulate FoxO3a nuclear translocation and transcriptional activity [75][76]. Interestingly, PASK deficiency increases the expression of FoxO3a under both basal and fasting conditions, as well as the nuclear location of SIRT1 and AMPK activation [57].

PGC1α induces the expression of antioxidant enzymes such as SOD and GPx [77][78][79]. Accordingly, PASK-deficient mice overexpress the hepatic antioxidant enzymes GPx and MnSod in the basal state, and also increase their expression in response to fasting (MnSod, Cu/ZnSod GPx, Gclm and Ho1), while slightly increasing the Cat gene. PASK deficiency is therefore associated with both a reduction in ROS/RNS and slightly higher MnSOD activity under basal conditions [57][58].

All these effects of PASK deficiency are interesting for states that promote an increase in oxidative stress, such as aging, diabetes, and obesity. Here we have described new evidence in this field, whereby PASK blocking is a powerful promotor of antioxidant mechanisms for preventing oxidative stress in the liver.

This entry is adapted from 10.3390/antiox10122028

        ;                                  10.3389/fendo.2020.594053

                      ;                    10.1038/s41598-018-32192-w

 

 

                                        

 

 

 

                                         

 

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