Results: CDAA diet effectively induced NASH, and increased the hepatic expression of pro-inflammatory, pro-fibrotic genes and oxidative stress-associated genes. Hepatic MR mRNA levels were increased in NASH and signifi cantly correlated with the expression of pro-inflammatory and pro-fibrotic genes. Epleronone administration was associated to a reduction in the hepatic mRNA levels of the MR and significantly reduced HTC and steatosis and attenuated the development of liver fibrosis, which was associated to a significant decrease DMXAA mw in the expression of pro-fibrogenic genes and of the oxidative stress-associated
Nrf2 up-regulation. Eplerenone did not influence hepatic inflammation in the setting of NASH. Conclusion: the expression of MR correlates with inflammation and fibrosis development in experimental NASH. MR blockade with eplerenone has hepatic anti-steatotic and anti-fibrotic effects. Considering its safety and FDA-approved status, eplerenone, alone or in combination with other agents, should be tested in human NASH. Disclosures: The following people have nothing to disclose: Margarita Pizarro, Nancy Solis, Pablo Quintero,
Juan C. Roa, Rene Baudrand, Carlos B. Fardella, Arnoldo Riquelme, Marco Arrese BACKGROUND: Metabolic dysregulation can lead to the development of nonalcoholic fatty liver Selumetinib in vivo disease (NAFLD) which is histologically classified as nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Dysregulated amino acid metabolism can promote insulin resistance which is key to NAFLD pathophysiology. The plasma amino acid metabolome has not been characterized in NAFLD. AIMS:
(1) To define plasma amino acid metabolome in NAFL and NASH compared to controls, and (2) To determine pathway enrichment and impact distinguishing NAFL and NASH. METHODS: Plasma metabolomic profiling using mass spectrometry was performed Mephenoxalone in controls, NAFL and NASH subjects. Multiple comparisons ANOVA with Tukey’s post-hoc pairwise tests, partial least squares discriminant analysis (PLS-DA), volcano plots, variable importance projection (VIP) scores, pathway enrichment and impact analyses were performed. RESULTS: Three groups (controls, n=7; NAFL, n=13; and NASH, n=31 based on liver histology) were studied. Plasma amino acid metabo-lome: (1) Tryptophan pathway: Tryptophan betaine (p=0.04) showed 1.8 and 1.9-fold increase in NAFL vs. control subjects. C-glycosyltryptophan was increased in NASH subjects (1.12 fold, p=0.05 for NASH vs. NAFL). (2) Phenylalanine and tyrosine pathway: 3-phenylpropionate (hydrocinnamate) was decreased 0.41-fold in NASH vs. control subjects (p=0.02). (3) Alanine and aspartate pathway: N-acetyl-beta-alanine was 0.65 folds decreased in NAFL vs. controls (p=0.05). Asparag- ine levels were 0.63 fold lower in NASH (p=0.02, NASH vs. control). Beta-alanine was also decreased 0.60 fold in NASH (p=0.01, NASH vs. NAFL).
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