The combination of plant-derived compounds with anti-diabetic agents to manage hepatic steatosis closely associated with diabetes mellitus may be a new therapeutic approach. Silymarin, a complex of bioactive substances extracted from Silybum marianum, evinces an antioxidative, anti-inflammatory, and hepatoprotective activity. In this study, we investigated whether metformin (300 mg/kg/day for four weeks) supplemented with micronized silymarin (600 mg/kg/day) would be effective in mitigating fatty liver disturbances in a pre-diabetic model with dyslipidemia. Compared with metformin monotherapy, the metformin-silymarin combination reduced the content of neutral lipids (TAGs) and lipotoxic intermediates (DAGs). Hepatic gene expression of enzymes and transcription factors involved in lipogenesis (Scd-1, Srebp1, Pparγ, and Nr1h) and fatty acid oxidation (Pparα) were positively affected, with hepatic lipid accumulation reducing as a result. Combination therapy also positively influenced arachidonic acid metabolism, including its metabolites (14,15-EET and 20-HETE), mitigating inflammation and oxidative stress. Changes in the gene expression of cytochrome P450 enzymes, particularly Cyp4A, can improve hepatic lipid metabolism and moderate inflammation. All these effects play a significant role in ameliorating insulin resistance, a principal background of liver steatosis closely linked to T2DM. The additive effect of silymarin in metformin therapy can mitigate fatty liver development in the pre-diabetic state and before the onset of diabetes.

• Klíčová slova
• combination therapy, liver steatosis, metformin, pre-diabetes, silymarin,
• Publikační typ
• časopisecké články MeSH

Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease worldwide and includes a broad spectrum of histologic phenotypes, ranging from simple hepatic steatosis or nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). While liver biopsy is the reference gold standard for NAFLD diagnosis and staging, it has limitations due to its sampling variability, invasive nature, and high cost. Thus, there is a need for noninvasive biomarkers that are robust, reliable, and cost effective. In this study, we measured 540 lipids and amino acids in serum samples from biopsy-proven subjects with normal liver (NL), NAFL, and NASH. Using logistic regression analysis, we identified two panels of triglycerides that could first discriminate between NAFLD and NL and second between NASH and NAFL. These noninvasive tests were compared to blinded histology as a reference standard. We performed these tests in an original cohort of 467 patients with NAFLD (90 NL, 246 NAFL, and 131 NASH) that was subsequently validated in a separate cohort of 192 patients (7 NL, 109 NAFL, 76 NASH). The diagnostic performances of the validated tests showed an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.88 ± 0.05, 0.94, and 0.57, respectively, for the discrimination between NAFLD and NL and 0.79 ± 0.04, 0.70, and 0.81, respectively, for the discrimination between NASH and NAFL. When the analysis was performed excluding patients with glucose levels >136 mg/dL, the area under the receiver operating characteristic curve for the discrimination between NASH and NAFL increased to 0.81 ± 0.04 with sensitivity and specificity of 0.73 and 0.80, respectively. Conclusion: The assessed noninvasive lipidomic serum tests distinguish between NAFLD and NL and between NASH and NAFL with high accuracy. (Hepatology Communications 2018;2:807-820).

• Publikační typ
• časopisecké články MeSH

BACKGROUND AND AIMS: Adefovir, an acyclic nucleotide reverse transcriptase inhibitor used to treat hepatitis B viral infection, is primarily eliminated renally through cooperation of glomerular filtration with active tubular transport. Nonalcoholic steatohepatitis is a variable in drug disposition, yet the impact on renal transport processes has yet to be fully understood. The goal of this study was to determine the effect of nonalcoholic steatohepatitis on the pharmacokinetics of adefovir in rats given a control or methionine and choline deficient diet to induce nonalcoholic steatohepatitis. METHODS: Animals received a bolus dose of 7mg/kg (35μCi/kg) [(3)H] adefovir with consequent measurement of plasma and urine concentrations. Inulin clearance was used to determine glomerular filtration rate. RESULTS: Methionine and choline deficient diet-induced nonalcoholic steatohepatitis prolonged the elimination half-life of adefovir. This observation occurred in conjunction with reduced distribution volume and hepatic levels of adefovir. Notably, despite these changes, renal clearance and overall clearance were not changed, despite markedly reduced glomerular filtration rate in nonalcoholic steatohepatitis. Alteration of glomerular filtration rate was fully compensated for by a significant increase in tubular secretion of adefovir. Analysis of renal transporters confirmed transcriptional up-regulation of Mrp4, the major transporter for adefovir tubular secretion. CONCLUSIONS: This study demonstrates changes to glomerular filtration and tubular secretion that alter pharmacokinetics of adefovir in nonalcoholic steatohepatitis. Nonalcoholic steatohepatitis-induced changes in renal drug elimination processes could have major implications in variable drug response and the potential for toxicity.

• Klíčová slova
• Adefovir, GFR, NASH, Renal elimination,
• MeSH
• adenin analogy a deriváty   farmakokinetika   MeSH
• cholin aplikace a dávkování   MeSH
• dieta MeSH
• hodnoty glomerulární filtrace MeSH
• inhibitory reverzní transkriptasy farmakokinetika   MeSH
• krysa rodu Rattus MeSH
• ledviny účinky léků   metabolismus   MeSH
• methionin aplikace a dávkování   MeSH
• nealkoholová steatóza jater metabolismus   MeSH
• organofosfonáty farmakokinetika   MeSH
• potkani Sprague-Dawley MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• adefovir MeSH Prohlížeč
• adenin MeSH
• cholin MeSH
• inhibitory reverzní transkriptasy MeSH
• methionin MeSH
• organofosfonáty MeSH

Non Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) are the hepatic manifestations of the metabolic syndrome; worrisome is the booming increase in pediatric age. To recreate the full spectrum of juvenile liver pathology and investigate the gender impact, male and female C57Bl/6 mice were fed with high fat diet plus fructose in the drinking water (HFHC) immediately after weaning (equal to 3-years old human), and disease progression followed for 16 weeks, until adults (equal to 30-years old human). 100% of subjects of both genders on HFHC diet developed steatosis in 4weeks, and some degree of fibrosis in 8weeks, with the 86% of males and 15% of females presenting a stage 2 fibrosis at 16weeks. Despite a similar final liver damage both groups, a sex difference in the pathology progression was observed. Alterations in glucose homeostasis, dyslipidemia, hepatomegaly and obese phenotype were evident from the very beginning in males with an increased hepatic inflammatory activity. Conversely, such alterations were present in females only at the end of the HFHC diet (with the exception of insulin resistance and the hepatic inflammatory state). Interestingly, only females showed an altered hepatic redox state. This juvenile model appears a good platform to unravel the underlying gender dependent mechanisms in the progression from NAFLD to NASH, and to characterize novel therapeutic approaches.

• MeSH
• dietní tuky škodlivé účinky   farmakologie   MeSH
• dospělí MeSH
• dyslipidemie chemicky indukované   metabolismus   patologie   patofyziologie   MeSH
• fruktosa škodlivé účinky   farmakologie   MeSH
• lidé MeSH
• modely nemocí na zvířatech * MeSH
• myši MeSH
• nealkoholová steatóza jater krev   chemicky indukované   patologie   patofyziologie   MeSH
• obezita krev   chemicky indukované   patologie   patofyziologie   MeSH
• pohlavní dimorfismus * MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dietní tuky MeSH
• fruktosa MeSH