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Differential effects of a glucagon-like peptide 1 receptor agonist in NAFLD and in response to hepatectomy

ABSTRACT: The genomic analysis of liver from mice fed with standard or MCD diet and treated with FC-GLP-1 during two weeks before 70%partial hepatectomy (PH) and after 2 weeks PH resulted in a set of genes regulated by diet and other set regulated differentially by treatment in MCD treated animals. These genes are apparently responsible for the reversion and prevention of NAS and improvement in hepatic regeneration induced by drug treatment

ORGANISM(S): Mus musculus

PROVIDER: GSE119725 | GEO | 2018/09/11

REPOSITORIES: GEO

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Effects of dual agonist of GLP1 and GCGR on animal model of NAS (MCD diet) and hepatic regeneration

Project description:The genomic analysis of liver from mice fed with standard or methyl and choline deficient (MCD) diet and treated with dual agonist of GLP1R/GCGR during two weeks before 70% partial hepatectomy (PH) and after 2 weeks PH resulted in a set of genes regulated by diet and other set regulated differentially by treatment in MCD treated animals. These genes are apparently responsible for the reversion and prevention of NAS and improvement in hepatic regeneration induced by drug treatment

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Project description:Background: Extended hepatectomies may result in post-hepatectomy liver failure, a condition with a high mortality. The main purpose of the present study was to investigate and compare the gene expression profiles in rats subjected to increasing size of partial hepatectomy. Methods: 40 Wistar rats were subjected to 30%, 70%, or 90% partial hepatectomy, sham operation or no operation. 24 hours following resection, liver tissue was harvested and genome-wide expression analysis was performed. Results: Cluster analysis revealed 2 main groupings, one containing the PH(90%) and one containing the remaining groups (baseline, sham, PH(30%) and PH(70%)). Categorization of specific affected molecular pathways in the PH(90%) group revealed a downregulation of cellular homeostatic functions degradation and biosynthesis, whereas proliferation, cell growth, and cellular stress and injury were upregulated in the PH(90%) group. After PH(90%), the main upregulated pathways were mTOR and ILK. The main activated upstream regulators were hepatocyte growth factor and transforming growth factor. Conclusion: With decreasing size of the future liver remnant, the liver tended to prioritize expression of genes involved in cell proliferation and differentiation at the expense of genes involved in metabolism and body homeostasis. This prioritizing may be an essential molecular explanation for post-hepatectomy liver failure.

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Project description:Background & Aims: Non-alcoholic steatohepatitis (NASH), a subtype of non-alcoholic fatty liver disease (NAFLD) that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma, is characterized by hepatic inflammation. Despite evolving therapies aimed to ameliorate inflammation in NASH, the transcriptional changes that lead to inflammation progression in NAFLD remain poorly understood. The aim of this study is to define transcriptional changes in early, non-fibrotic NAFLD using a biopsy-proven non-fibrotic NAFLD cohort. Methods: We extracted RNA from liver tissue of 40 patients with biopsy-proven NAFLD based on NAFLD Activity Score (NAS) (23 with NAS ≤3, 17 with NAS ≥5) and 21 healthy controls and compared changes in expression of 594 genes involved in innate immune function. Results: Compared to healthy controls, NAFLD patients with NAS ≥5 had differential expression of 211 genes, while those with NAS ≤3 had differential expression of only 14 genes. Notably, osteopontin (SPP1) (3.74-fold in NAS ≤3, 8.28-fold in NAS ≥5) and CXCL10 (2.27-fold in NAS ≤3, 8.28-fold in NAS ≥5) gene expression were significantly upregulated with histologic progression of NAFLD.

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Genome wide analysis of liver histone H3K9 acetylation after partial hepatectomy in glucose-treated and control mice.

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mRNA profile between 1/3 partial hepatectomy (PH) and 2/3 PH at 24 hours

Project description:Six rats underwent partial hepatectomy (PH) (3, 1/3PH; 3, 2/3PH). The total mRNA of three rats each group were pooled and compared by microarray to selected the mRNA which differs between between 2/3PH with robust DNA replication and 1/3PH with a minimal replicative response.

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Effects of NAFLD/NASH on hepatic gene expression.

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