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  • Pifithrin-α (PFTα) Since i melatonin inhibits biliary damage

    2019-07-08

    Since: (i) melatonin inhibits biliary damage and liver fibrosis by downregulation of miR-200b; and (ii) downregulation of miR-200b (by Vivo Morpholino) in Mdr2−/− mice decreases the Pifithrin-α (PFTα) of selected clock genes, we propose that the modulation of the melatonin/MT1/miR-200b/circadian rhythm may be important top modulate biliary damage and liver fibrosis. In summary, we demonstrated that PINX or prolonged exposure to light exacerbates biliary damage and liver fibrosis in cholestatic rats by decreased biliary melatonin synthesis (Fig. 8). We propose that the dramatic reduction of melatonin secretion in cholangiocytes during BDL plus PINX or light exposure aggravates biliary damage and liver fibrosis by: (i) increasing biliary senescence through reduced biliary levels of SASPs (e.g., TGFβ-1) and ROS thereby activating of HSCs by a paracrine mechanism; and (ii) directly interacting with MT1 on HSCs. The following are the supplementary data related to this article.
    Transparency document
    Financial support This study was supported by (i) VA Merit Awards (1I01BX003031, HF; 4I01BX000574, GA; 1I01BX001724, FM) from the United States Department of Veteran's Affairs, Biomedical Laboratory Research and Development Service and NIH grants DK054811, DK076898, DK107310, DK110035, DK062975 to GA, SG, FM, DK108959, HF, and DK082435 to SD; (ii) the PSC Partners Grant Award 460933-00001 and Dr. Nicholas C. Hightower Centennial Chair of Gastroenterology from Baylor Scott & White Health (GA); and (iii) Development Service, by University of Rome “La Sapienza” to PO. This material is the result of work supported with resources and the use of facilities at the Central Texas Veterans Health Care System, Temple, Texas. The content is the responsibility of the author(s) alone and does not necessarily reflect the views or policies of the Department of Veterans Affairs or the United States Government.
    Conflict of interest
    Introduction The liver is vulnerable to inappropriate food ingestion, and ectopic fat accumulation induces non-alcoholic fatty liver disease (NAFLD). NAFLD has become the most common liver disease worldwide and encompasses a histological spectrum, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which may progress to cirrhosis and hepatocellular carcinoma [1,2]. NASH is multifactorial and may be progressive, but the mechanisms affecting its development are too complex to be fully established in humans. Recent analytical tools are now available to explore the adaptive metabolic response to liver injury by examining the combined relationships among metabolic abnormalities, oxidative stress and inflammation, including paraoxonase 1 (PON1) and chemokine (C-C motif) ligand 2 (CCL2), as key molecules to understand the role of antioxidant defenses and monocyte recruitment in the liver [[3], [4], [5], [6]]. PON1 may be found both in hepatocytes and in the circulation bound to lipoproteins and functions primarily as an effective molecule to modulate lipid peroxidation and the inflammatory response, likely influencing the production of CCL2 [7]. In this context, we have previously reported in experimental models that pon1 deficiency or ccl2 overexpression render mice prone to liver steatosis and metabolic alterations [[8], [9], [10]]. Excessive calorie intake is a major cause of liver injury and compromises the ability of hepatocytes to alter their metabolism (metabolic reprogramming) to trigger the adaptive response of intracellular sensors and signaling molecules necessary for liver homeostasis [[11], [12], [13]]. To be efficient, this adaptation requires substantial mitochondrial activity. However, oxidative stress and inflammation induce mitochondrial dysfunction and eventually cellular death, indicating that these processes and energy metabolism pathways may be interrelated and can interfere with reparative mechanisms [14]. Mechanistically, we hypothesize that the relationships among mitochondrial function and the roles of PON1 and CCL2 could be associated with at least two essential activities. The first involves the link between the citric acid cycle (CAC) and methionine and the consequent role in the maintenance of correct glutathione synthesis [15]. The second is associated with the regulation of autophagy-lysosomal function, an essential process for liver metabolic homeostasis that is highly dependent on AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling in energy metabolism [[16], [17], [18]].