• 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • Herein we explore the role of PON and CCL


    Herein, we explore the role of PON1 and CCL2 in liver disease and how oxidative stress and inflammation modulate hepatic intracellular signaling molecules and the adaptive metabolic response to fat-induced liver injury. Specifically, we investigated the alterations produced by the diet in mice triple deficient in the genes of low density lipoprotein receptor, PON1 and CCL2 (CPLKO mice), using as control groups wild type (WT) mice and mice double deficient in the low density lipoprotein receptor and PON1 (PLKO). These last animals have previously been used as a model of hyperlipidemia, hepatic steatosis and metabolic syndrome [[8], [9], [10]].
    Discussion The mechanisms establishing metabolic reprogramming in hepatocytes remains poorly understood. Overnutrition is causal in the altered expression of genes relevant for metabolism, oxidative stress and inflammation inducing epigenetic mechanisms responsible for the remarkable capacity of hepatocytes to switch their phenotypic status [9,[19], [20], [21]]. Hence, prevention of obesity and dietary restraint is a crucial first step in protecting the liver [22]. Reversibility of epigenetic mechanisms provides an interface between the host and environment. Here, we provide evidence indicating that oxidative stress probably interferes in the course of DNA and protein methylation through methionine metabolism and glutathione oxidation. The course of action may be substantially reversed, avoiding inflammation, which may provide a converging point between PON1 and CCL2 and are key mechanisms to explain the usefulness of epigenetic intervention through nutrition and drugs such as metformin and aspirin [23]. Our analysis of the coupled oxidation-inflammation system reveals in vivo a pivotal role in liver disease and potential alternative strategies capable of delaying NAFLD development. Deprivation of PON1, an important component of antioxidant defenses, results in increased production of lipid peroxides, which correlated with fat accumulation and variations in the distribution of liver macrophages. Examination of Z-Guggulsterone metabolism in the livers of pon1-deficient mice suggested mitochondrial damage and decoupling from glycolysis, confirming that mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver [24]. Mitochondrial damage can cause an imbalance between ROS production and removal, resulting in net ROS production. Potentially, overexpression of antioxidant defenses might improve lifespan and healthspan in mice [25]. The increase in glutathione peroxidase and glutathione reductase expression in PLKO mice can be interpreted as a mechanism of hepatocytes to defend against oxidative stress. Consequently, the GSH/GSSG ratio in these mice was extremely low in PLKO mice. This effect was also accompanied by a relative deficiency in methyl donors resembling the pro-oxidant, pro-inflammatory disturbances observed in mice fed methionine-choline deficient mice. Interestingly, most defects were completely reversed by the concomitant ccl2 deficiency, most likely mediated by amelioration in macrophage functionality [26,27]. Although the liver has several types of immune cells such as natural killer cells, natural killer T cells, neutrophils, γδT cells, dendritic cells and lymphocytes T and B, macrophages represent one third of hepatic non-parenchymal cells and are considered the first response to liver injury, playing a major role in repair and regeneration processes [28]. Energy metabolism in the livers of CPLKO mice was also partially restored when compared with PLKO mice and suggested an important role of lactate and β-hydroxybutyrate as primary CAC substrates and in controlling the release of pro-inflammatory cytokines [29,30]. In addition, the restoration of branched chain amino acid metabolism observed in CPLKO mice might also contribute to the alleviation of liver steatosis and liver injury [31]. The AMPK signaling pathway coordinates autophagy and metabolism [32]. The heterotrimeric (αβγ) complex AMPK is a key player in maintaining cellular energy balance, and in these genetically modified mice, activation through phosphorylation at T172 of its catalytic subunit is significantly inhibited. Oxidative stress and energy stress may also differentially regulate AMPK activity through oxidation at several cysteine residues, a mechanism apparently dependent on the source of ROS, abundance of nutrients and the antioxidant capacity of cells [33]. AMPK activity and mTORC1 activation were inversely related, and autophagy was inhibited in both PLKO and CPLKO mice precluding the conjugation of LC3-I to phosphatidylethanolamine (LC3-II), which induced a low LC3-II/LC3-I ratio [34]. Therefore, the livers of these mice were deprived of a crucial mechanism to cope with a variety of cellular stresses. However, when we examined LAMP2A as a proxy for chaperone-mediated autophagy (CMA), we found that pon1 deficiency altered this mechanism, which was completely reversed by the addition of ccl2 deficiency. Accumulating evidence highlights the importance of autophagy in the maintenance of liver homeostasis and the involvement in the pathogenesis of NAFLD affecting hepatocytes and other hepatic cell types [18,35,36]. Our results suggest a possible link between CMA and NAFLD progression. CMA participates in protein quality control by degrading oxidized and damaged proteins under stress conditions and contributes amino acids through the degradation of proteins. The role of CMA in cellular fate has already been established by modulating carbohydrate and lipid metabolism, transcriptional programs, immune responses and the cell cycle through selective degradation of key enzymes in these pathways [[37], [38], [39]]. Indeed, it has been reported that high lipid concentrations can stimulate LAMP2A degradation through the modification of the lysosome membranes [40].