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  • Previous studies suggest that the heterogeneous


    Previous studies suggest that the heterogeneous histological grades found in human biopsies were proportional to oxidative flux [24]. Our findings suggest that PON1 and CCL2 are key molecules modulating hepatic oxidative stress and inflammation that appear to be associated with increased oxidative metabolism, likely altering anabolic pathways. Both molecules are circulating in the blood at easily measurable concentrations and may represent possible predictive and diagnostic biomarkers of liver disease, but future research requires standardization of reagents and methods to overcome difficulties in interpretation [7]. Data may also suggest and/or potentiate novel therapeutic targets, which is important because there is no specific pharmacotherapy approved for NAFLD. For instance, it is plausible that increased PON1 activity may have beneficial effects in humans. Molecular mechanisms involved in the regulation of hepatic PON1 gene expression have not been explored, but several compounds may increase gene transcription, including probucol, several statins, vitamins and polyphenols (e.g., quercetin, naringenin, catechins, punicalagins, silymarin, and resveratrol) [41]. Similarly, polyphenol-rich foods may modulate plasma CCL2 in humans [42], and several anti-CCL2 Angeli’s Salt and antagonists of its functional receptor (CCR2) are currently under investigation. Preclinical and clinical data on the dual CCR2/CCR5 inhibitor cenicriviroc are advanced in the path to approval (phase 3 trial) to specifically manage NASH and liver fibrosis [43,44]. Finally, our data also suggest that combination therapies are more likely to benefit patients with NAFLD than a single therapy and that drugs that may target AMPK activity and/or autophagy might be useful.
    Materials and methods
    Declarations of interest
    Author contributions
    Transparency document
    Acknowledgment The authors thank Dr. Diana Shih, from the Division of Cardiology of the University of California in Los Angeles, for the generous gift of a breeding pair of PON1-deficient mice. This study was funded by grant PI15/00285 from the (Madrid, Spain), co-funded by the (FEDER), and by grant 60/U/2016 from the (Barcelona, Spain). We also acknowledge the support provided by the (Grant 2016FI_B 00352) and the (Grant URVPFRB21545). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
    Introduction Observational clinical studies demonstrate that hypovitaminosis D is very common in the obese population and low vitamin D levels are associated with obesity-associated metabolic disorders such as type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) [[1], [2], [3]]. With regard to the strongly increasing prevalence of these diseases, vitamin D supplementation is currently considered as a potential therapeutic option [[4], [5], [6]]. However, there is partially conflicting evidence regarding the therapeutic effects of vitamin D from interventional human studies. While some clinical trials found improvement of metabolic parameters and/or amelioration of NAFLD (e.g. measured by liver fat content or certain serum markers of liver damage) by vitamin D treatment [[7], [8], [9], [10]], other studies could not confirm these positive effects [[11], [12], [13]]. Thus, the precise mechanistic contributions of vitamin D to metabolic disorders including NAFLD and its putative therapeutic relevance in humans have so far remained unclear. On the biochemical level, activated vitamin D (1,25-dihydroxyvitamin D) binds to the nuclear receptor superfamily member, vitamin D receptor (VDR, NR1I1), which serves as a ligand-activated transcription factor controlling a large number of genes in various tissues [14]. Currently available preclinical studies in rodents are, however, partially controversial with regard to the metabolic effects of vitamin D [[15], [16], [17], [18], [19], [20], [21], [22], [23]], and indicate so far not fully understood cell type- and context-specific effects of VDR signaling [[24], [25], [26], [27], [28]]. Thus, more experimental data on the tissue-specific effects of vitamin D and the underlying modes of action are required to translate the currently available knowledge from observational and interventional clinical studies into future treatment strategies.