Transcriptional analysis of non-fibrotic NAFLD progression
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ABSTRACT: 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.
Project description:Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease that ranges from simple steatosis, to inflammatory form non-alcoholic steatohepatitis (NASH), cirrhosis, and up to hepatocellular carcinoma. While NASH usually takes decades to develop at a rate of one stage per seven years, in the case of post-trasplant NASH (pt-NASH) develops fibrosis much more rapidly, with almost 50% of liver transplant recipients presenting stage 3 fibrosis by 5 years post-transplant. Archived fresh-frozen transplanted liver biopsy samples from four liver biopsy samples with evidence of NASH (2 recurrent and 2 de novo), two with simple steatosis (both de novo), and five with normal histology as controls had their transcriptome sequenced in two batches for deeper coverage.
Project description:Obesity is increasing worldwide and leads to a multitude of metabolic diseases including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatosis (NASH). Here we examine the role of CYR61 in liver fibrosis and inflammation and its potential as a therapeutic target. Loss of CYR61 during NASH injury improves glucose tolerance, decreases liver inflammation and reduces fibrosis. CYR61 activates signaling in monocytes and monocyte-derived macrophages promoting a pro-inflammatory/pro-fibrotic phenotype through a CYR61/SYK/NFKB signaling cascade. In vitro, CYR61 activates Pdgfa and Pdgfb expression in macrophages in a NFκB-dependent manner. Ultimately, we identify a potential therapeutic for NASH: a CYR61-blocking antibody that reduces fibrotic injury and CYR61-driven signaling in macrophages in vitro and in vivo. This study demonstrates that CYR61 is a key driver of liver inflammation and fibrosis and a strong therapeutic target for treatment of NAFLD/NASH.
Project description:Obesity is increasing worldwide and leads to a multitude of metabolic diseases including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatosis (NASH). Here we examine the role of CYR61 in liver fibrosis and inflammation and its potential as a therapeutic target. Loss of CYR61 during NASH injury improves glucose tolerance, decreases liver inflammation and reduces fibrosis. CYR61 activates signaling in monocytes and monocyte-derived macrophages promoting a pro-inflammatory/pro-fibrotic phenotype through a CYR61/SYK/NFKB signaling cascade. In vitro, CYR61 activates Pdgfa and Pdgfb expression in macrophages in a NFκB-dependent manner. Ultimately, we identify a potential therapeutic for NASH: a CYR61-blocking antibody that reduces fibrotic injury and CYR61-driven signaling in macrophages in vitro and in vivo. This study demonstrates that CYR61 is a key driver of liver inflammation and fibrosis and a strong therapeutic target for treatment of NAFLD/NASH.
Project description:Obesity is increasing worldwide and leads to a multitude of metabolic diseases including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatosis (NASH). Here we examine the role of CYR61 in liver fibrosis and inflammation and its potential as a therapeutic target. Loss of CYR61 during NASH injury improves glucose tolerance, decreases liver inflammation and reduces fibrosis. CYR61 activates signaling in monocytes and monocyte-derived macrophages promoting a pro-inflammatory/pro-fibrotic phenotype through a CYR61/SYK/NFKB signaling cascade. In vitro, CYR61 activates Pdgfa and Pdgfb expression in macrophages in a NFκB-dependent manner. Ultimately, we identify a potential therapeutic for NASH: a CYR61-blocking antibody that reduces fibrotic injury and CYR61-driven signaling in macrophages in vitro and in vivo. This study demonstrates that CYR61 is a key driver of liver inflammation and fibrosis and a strong therapeutic target for treatment of NAFLD/NASH.
Project description:Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease with large unmet need. Non-alcoholic steatohepatitis (NASH), a progressive variant of NAFLD, can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. To identify potential new therapeutics for NASH, we used a computational approach based on Connectivity Map (CMAP) analysis, which pointed us to a potential application of bromodomain and extra-terminal motif (BET) inhibitors for treating NASH. To experimentally validate this hypothesis, we tested a small-molecule inhibitor of the BET family of proteins, GSK1210151A (I-BET151), in the STAM mouse NASH model at two different dosing timepoints (onset of NASH and onset of fibrosis) to assess its potential effectiveness for the treatment of NASH and liver fibrosis. I-BET151 decreased the non-alcoholic fatty liver disease activity score (NAS), a clinical endpoint for assessing the severity of NASH, as well as progression of liver fibrosis and interferon-γ expression. Transcriptional characterization through RNA-sequencing pointed to alterations in molecular mechanisms related to interferon signaling and cholesterol biosynthesis following treatment, as well as reversal of gene expression patterns linked to fibrotic markers. Altogether, these results suggest that inhibition of BET proteins may present a novel therapeutic opportunity in the treatment of NASH and liver fibrosis.
Project description:We investigated the hepatic transcriptome of 58 biopsy-proven NAFLD patients at multiple stages of the disease (NAFL, NASH with mild fibrosis, NASH with advanced fibrosis) with the aim of describing the pathophysiological events driving the development and progression of NASH.
Project description:Non-alcoholic fatty liver (NAFL) has the potential to progress to non-alcoholic steatohepatitis (NASH) or to promote type 2 diabetes mellitus (T2DM). However, NASH and T2DM do not always develop coordinately. We established rat models of NAFL, NASH, and NAFL + T2DM to recapitulate different phenotypes associated with NAFLD and its progression. Microarrays were used to identify hepatic gene expression changes in each of these models. The goal is to identify a predictor of different NAFLD progressions. Non-alcoholic fatty liver disease (NAFLD) is recognized as a low-grade systemic inflammatory state with both hepatic and extra-hepatic manifestations. We aimed to identify common key regulators and adaptive pathways in different NAFLD phenotypes. NAFL, NASH and NAFL+T2DM rat models were used to represent simple fatty liver, fatty liver with severe hepatic manifestations, and fatty liver with severe metabolic manifestations, respectively. We applied microarray analysis to characterize the key regulators and adaptive pathways in different NAFLD phenotypes. There are 12 samples in our study which belonged to 4 groups, and each group contains 3 different samples.
Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that can progress from simple fatty liver disease to non-alcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism and excretion (ADME) of drugs. Differential gene expression between three clinically defined pathological groups; normal, steatosis and NASH was analyzed. The samples were diagnosed as normal, steatotic, NASH with fatty liver (NASH fatty) and NASH without fatty liver (NASH NF). Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChipM-. Human 1.0ST arrays
Project description:Global gene expression patterns of 2 human steatosis and 9 human non-alcoholic steatohepatitis (NASH) together with their respective control patterns were analyzed to define the non-alcoholic fatty liver disease (NAFLD) progression molecular characteristics and to define NASH early markers from steatosis. Human liver samples of steatosis and non-alcoholic steatohepatitis were selected for RNA extraction and hybridization on Affymetrix microarrays. This dataset is part of the TransQST collection.
Project description:Dyslipidemia and inflammation play key roles in the pathogenesis of both nonalcoholic fatty liver disease (NAFLD) and atherosclerosis. NAFLD, particularly its severe form nonalcoholic steatohepatitis (NASH) is associated with increased cardiovascular disease (CVD) risk. HDL (high density lipoprotein- also a CVD risk) are decreased in NAFLD but whether HDL function is abnormal in NAFLD is unknown. Furthermore, it is unknown whether dyslipidemia contributes to reduced HDL function in NAFLD and whether hepatic inflammation further impairs HDL function in patients with NASH. Therefore, the aim of this study was to investigate HDL function and to examine the effect of dyslipidemia and inflammation on HDL metabolism in patients with biopsy-proven simple steatosis (SS) and NASH. RESULTS: Compared to controls, SS and NASH subjects had significantly higher levels of plasma triglyceride, insulin, and were more insulin resistant (HOMA, P<0.05) with no differences in total cholesterol, HDL cholesterol, ApoB100 and ApoAI levels. NAFLD patients had increased production and degradation rates of both HDLc and ApoAI that resulted in their levels remaining stable. The degradation rates also were increased of other HDL proteins, including ApoAII, ApoAIV, vitamin D-binding protein, and complement 3 (all P<0.05). NAFLD patients had increased activities of LCAT and CETP, indicating altered HDL lipidation. NAFLD induced alterations in HDL metabolism were associated with reduced anti-oxidant but increased pro-inflammatory activity of HDL. However, no differences were observed in either HDL function or the kinetics of HDLc and HDL proteins between SS and NASH subjects.