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Combination Treatment with Hydroxytyrosol and Vitamin E Improves NAFLD-Related Fibrosis.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD)-related liver fibrosis results in the encapsulation of injured liver parenchyma by a collagenous scar mainly imputable to hepatic stellate cells' activation. Approved pharmacological treatments against NAFLD-related fibrosis are still lacking, but natural compounds such as hydroxytyrosol (HXT) and vitamin E (VitE), are emerging as promising therapeutic opportunities. In this study, the potential anti-fibrotic effect of HXT + VitE combination therapy was investigated in vitro and in vivo. In particular, tumor growth factor (TGF)-β-activated LX-2 cells as an in vitro model, and carbon tetrachloride plus a Western diet as a mice model were employed. The effect of HXT + VitE on fibrosis was also investigated in children with biopsy-proven NAFLD. Our results demonstrated that HXT + VitE caused a reduction of proliferation, migration, contractility, and expression of pro-fibrogenic genes in TGF-β-activated LX-2 cells. HXT + VitE treatment also antagonized TGF-β-dependent upregulation of pro-oxidant NOX2 by interfering with nuclear translocation/activation of SMAD2/3 transcription factors. The mouse model of NAFLD-related fibrosis treated with HXT + VitE showed a marked reduction of fibrosis pattern by histology and gene expression. Accordingly, in children with NAFLD, HXT + VitE treatment caused a decrease of circulating levels of PIIINP and NOX2 that was supported over time. Our study suggests that HXT + VitE supplementation may improve NAFLD-related fibrosis.

SUBMITTER: Panera N

PROVIDER: S-EPMC9505330 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Combination Treatment with Hydroxytyrosol and Vitamin E Improves NAFLD-Related Fibrosis.

Panera Nadia N Braghini Maria Rita MR Crudele Annalisa A Smeriglio Antonella A Bianchi Marzia M Condorelli Angelo Giuseppe AG Nobili Rebecca R Conti Libenzio Adrian LA De Stefanis Cristiano C Lioci Gessica G Gurrado Fabio F Comparcola Donatella D Mosca Antonella A Sartorelli Maria Rita MR Scoppola Vittorio V Svegliati-Baroni Gianluca G Trombetta Domenico D Alisi Anna A

Nutrients 20220914 18

Non-alcoholic fatty liver disease (NAFLD)-related liver fibrosis results in the encapsulation of injured liver parenchyma by a collagenous scar mainly imputable to hepatic stellate cells' activation. Approved pharmacological treatments against NAFLD-related fibrosis are still lacking, but natural compounds such as hydroxytyrosol (HXT) and vitamin E (VitE), are emerging as promising therapeutic opportunities. In this study, the potential anti-fibrotic effect of HXT + VitE combination therapy was ...[more]

PMID: 36145170

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Project description:Liver fibrosis is the excessive expression and accumulation of extracellular matrix proteins in the liver. Fibrotic scarring occurs as the consequence of chronic injury and inflammation. While the successful treatment of hepatitis B and C reduced the burden of liver disease related to viral hepatitis, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) are nowadays the leading causes of hepatic fibrosis worldwide. Although basic research activities have significantly advanced our understanding of the molecular disease pathogenesis, the present therapeutic options for fibrosis are still limited. In advanced disease stages, liver transplantation often remains the only curative treatment. This highlights the necessity of preventive strategies to avoid complications of fibrosis, particularly cirrhosis, portal hypertension and liver cancer. Lifestyle modifications (weight loss, exercise, healthy diet) are the basis for prevention and treatment of NAFLD-associated fibrosis. In the present review, we discuss recent advances in antifibrotic prevention and therapy. In particular, we review the current concepts for antifibrotic drug candidates in the treatment of NAFLD and NASH. While some compounds aim at reverting pathogenic liver metabolism, an alternative approach is to disconnect the injury (e.g., NAFLD) from inflammation and/or fibrosis. Investigational drugs typically target metabolic pathways, insulin resistance, hepatocyte death, inflammatory cell recruitment or activation, the gut-liver axis, matrix expression or matrix turnover. While several promising drug candidates failed in phase 2 or 3 clinical trials (including elafibranor, emricasan and selonsertib), promising results with the farnesoid X receptor agonist obeticholic acid, the pan-PPAR agonist lanifibranor and the chemokine receptor CCR2/CCR5 inhibitor cenicriviroc support the expectation of an effective pharmacological therapy for liver fibrosis in the near future. Tackling NAFLD-associated fibrosis from different directions by combinatorial drug treatment and effective lifestyle changes hold the greatest prospects.

Project description:IntroductionThe study aimed to explore the association of serum 25(OH)D3 and hepatic steatosis in non-alcoholic fatty liver disease (NAFLD) patients and to determine whether the effect of vitamin D (VD) is mediated by activation of the peroxisome proliferator-activated receptor α (PPARα) pathway.MethodsThe study contained a case-control study, in vivo and in vitro experiments. A case-control study was conducted to compare serum parameters between NAFLD patients and controls and to evaluate the association of 25(OH)D3 and NAFLD. In vivo study, male Wistar rats were randomly divided into control and model groups, fed a standard chow diet and a high-fat diet (HFD), respectively, for 7 weeks to generate an NAFLD model. Then, the rats were treated with VD and a PPARα antagonist (MK886) for 7 weeks. Tissue and serum were collected and assessed by biochemical assays, morphological analysis, histological analysis, and western blot analysis. In vitro, HepG2 cells were incubated with oleic acid (OA) to induce steatosis, which was evaluated by staining. HepG2 cells were pretreated with MK886 followed by calcitriol treatment, and differences in lipid metabolism-related proteins were detected by western blot.ResultsNAFLD patients were characterized by impaired liver function, dyslipidemia, and insulin resistance. Serum 25(OH)D3 was negatively associated with alanine aminotransferase (ALT) in NAFLD. VD deficiency was a risk factor for patients with no advanced fibrosis. Adequate VD status (25(OH)D3 >20 ng/mL) had a protective effect in patients after adjustment for confounding variables. NAFLD rats showed hyperlipidemia with severe hepatic steatosis, systematic inflammation, and lower serum 25(OH)D3. VD treatment ameliorated hepatic steatosis both in NAFLD rats and OA-induced HepG2 cells. Further, MK886 inhibited the anti-steatosis effect of VD.ConclusionThe study revealed that an adequate VD level may act as a protective factor in NAFLD and that VD may alleviate hepatic steatosis via the PPARα signaling pathway.

Project description:ObjectivesTo assess whole-liver texture analysis on T1 maps for risk stratification of advanced fibrosis in patients with suspected nonalcoholic fatty liver disease (NAFLD).MethodsThis retrospective study included 53 patients. Histogram and texture parameters (volume, mean, SD, median, 5th percentile, 95th percentile, skewness, kurtosis, diff-entropy, diff-variance, contrast, and entropy) of T1 maps were calculated based on the semi-automatically segmented whole-liver volume. A two-step approach combining the Nonalcoholic Fatty Liver Disease Fibrosis Score (NFS) and Fibrosis-4 Index (FIB-4) with the liver stiffness measurement (LSM) for the risk stratification was used. Univariate analysis was performed to identify significant parameters. Logistic regression models were then run on the significant features. Diagnostic performance was evaluated with receiver operating characteristic (ROC) analysis.ResultsIn total, 33 (62%) subjects had a low risk and 20 (38%) subjects had an intermediate-to-high risk of advanced fibrosis. The following significantly different parameters with the best performance were diff-entropy, entropy, and diff-variance, with AUROC 0.837 (95% CI 0.73-0.95), 0.821 (95% CI 0.71-0.94), and 0.807 (95% CI 0.69-0.93). The optimal combination of median, 5th percentile, and diff-entropy as a multivariate model improved the diagnostic performance to diagnose an intermediate-to-high risk of advanced fibrosis with AUROC 0.902(95% CI 0.79-0.97).ConclusionsParameters obtained by histogram and texture analysis of T1 maps may be a noninvasive analytical approach for stratifying the risk of advanced fibrosis in NAFLD.Key points• Variable flip angle (VFA) T1 mapping can be used to acquire 3D T1 maps within a clinically acceptable duration. • Whole-liver histogram and texture parameters on T1 maps in patients with NAFLD can distinguish those with an intermediate-to-high risk of advanced fibrosis. • The multivariate model of combination of texture parameters improved the diagnostic performance for a high risk of advanced fibrosis and clinical parameters offer no added value to the multivariate model.

Dataset Information

Combination Treatment with Hydroxytyrosol and Vitamin E Improves NAFLD-Related Fibrosis.

Publications

Combination Treatment with Hydroxytyrosol and Vitamin E Improves NAFLD-Related Fibrosis.

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