The Vitamin D Receptor Regulates Glycerolipid and Phospholipid Metabolism in Human Hepatocytes

The vitamin D receptor (VDR) must be relevant to liver lipid metabolism because VDR deficient mice are protected from hepatosteatosis. Therefore, our objective was to define the role of VDR on the overall lipid metabolism in human hepatocytes. We developed an adenoviral vector for human VDR and performed transcriptomic and metabolomic analyses of cultured human hepatocytes upon VDR activation by vitamin D (VitD). Twenty percent of the VDR responsive genes were related to lipid metabolism, including MOGAT1, LPGAT1, AGPAT2, and DGAT1 (glycerolipid metabolism); CDS1, PCTP, and MAT1A (phospholipid metabolism); and FATP2, SLC6A12, and AQP3 (uptake of fatty acids, betaine, and glycerol, respectively). They were rapidly induced (4-6 h) upon VDR activation by 10 nM VitD or 100 µM lithocholic acid (LCA). Most of these genes were also upregulated by VDR/VitD in mouse livers in vivo. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) metabolomics demonstrated intracellular accumulation of triglycerides, with concomitant decreases in diglycerides and phosphatidates, at 8 and 24 h upon VDR activation. Significant alterations in phosphatidylcholines, increases in lyso-phosphatidylcholines and decreases in phosphatidylethanolamines and phosphatidylethanolamine plasmalogens were also observed. In conclusion, active VitD/VDR signaling in hepatocytes triggers an unanticipated coordinated gene response leading to triglyceride synthesis and to important perturbations in glycerolipids and phospholipids

SOC-V-11 New serum miRNA biomarkers to predict liver steatosis by valproic acid in paediatric epileptic patients

Depakine (Valproate, VPA) has been the first line, most-frequently prescribed, anti-epileptic drug in children for the past 50 years. Idiosyncratic hepatotoxicity (iDILI) by VPA has been demonstrated in several case reports, where microvesicular liver steatosis was the most frequent feature. Moreover, more than half of VPA-treated patients could have silent fatty liver as demonstrated by ultrasounds. Extensive experimental studies support that VPA has a high potential to induce steatosis in hepatocytes. However, there is an apparent lack of significant hepatic problems in the Neuropediatric Units, despite transaminitis is not uncommon. One of the reasons could be that iDILI and liver steatosis diagnosis lack specific biomarkers. Thus, it is likely that a relevant number of children under VPA treatment may have a significant, but sub-clinical, hepatosteatosis

The Synbiotic Combination of <i>Akkermansia muciniphila</i> and Quercetin Ameliorates Early Obesity and NAFLD through Gut Microbiota Reshaping and Bile Acid Metabolism Modulation

Gut microbiota plays a key role in obesity and non-alcoholic fatty liver disease (NAFLD), so synbiotics could be a therapeutic alternative. We aim to evaluate a nutritional intervention together with the administration of the bacteria Akkermansia muciniphila and the antioxidant quercetin in an in vivo model of early obesity and NAFLD. 21-day-old rats were fed with control or high-fat diet for six weeks. Then, all animals received control diet supplemented with/without quercetin and/or A. muciniphila for three weeks. Gut microbiota, NAFLD-related parameters, circulating bile acids (BAs) and liver gene expression were analyzed. The colonization with A. muciniphila was associated with less body fat, while synbiotic treatment caused a steatosis remission, linked to hepatic lipogenesis modulation. The synbiotic promoted higher abundance of Cyanobacteria and Oscillospira, and lower levels of Actinobacteria, Lactococcus, Lactobacillus and Roseburia. Moreover, it favored elevated unconjugated hydrophilic BAs plasma levels and enhanced hepatic expression of BA synthesis and transport genes. A. muciniphila correlated with circulating BAs and liver lipid and BA metabolism genes, suggesting a role of this bacterium in BA signaling. Beneficial effects of A. muciniphila and quercetin combination are driven by gut microbiota modulation, the shift in BAs and the gut-liver bile flow enhancement

Cluster-Partial Least Squares (c-PLS) regression analysis: application to miRNA and metabolomic data

&lt;p&gt;This study introduces a novel variable selection approach called&nbsp;cluster PLS (c-PLS) that aims to assess the joint impact of variable groups selected based on biological characteristics&nbsp;(such as miRNA-regulated metabolic pathway) on the predictive performance of a multivariate model. The usefulness of c-PLS is shown using a miRNomic datasets obtained from the analysis of 24 liver tissue biopsies collected in the frame of a clinical study of steatosis.&lt;/p&gt;&lt;p&gt;Results obtained show that c-PLS enables analyzing the effect of biologically relevant variable clusters, facilitating the identification of biological processes associated with the independent variable, and the prioritization of the biological factors influencing model performance, thereby improving the understanding of the biological factors driving model predictions. While the strategy is tested for the evaluation of PLS models, it could be extended to other linear and non-linear multivariate models.&lt;/p&gt;GQ acknowledges the grant PID2021-125573OB-I00 funded by MCIN/AEI/10.13039/501100011033 and by ERDF A way of making Europe, by the "European Union". JK acknowledges the financial support by the Instituto de Salud Carlos III [grant numbers PI20/00964 and CPII21/00003] (Co-funded by European Regional Development Fund "A way to make Europe"). RJ acknowledges grant PI20/00690 funded by Instituto de Salud Carlos III-FIS (Co-funded by European Regional Development Fund "A way to make Europe"). D.P.-G. acknowledges the financial support of the 2019 Ramón y Cajal (RYC) Contract Aids (RYC2019-026556-I) funded by MCIN/AEI/10.13039/501100011033 and FSE "El FSE invierte en tu futuro'' and the grant RPID2020-119326RA-I0 funded by MCIN/AEI/10.13039/501100011033. MMT acknowledges the grant RYC2021-031346-I, funded by MCIN/AEI/10.13039/501100011033 and by the European Union "NextGenerationEU''/PRTR