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CYR61 orchestrates NASH fibrosis through SYK-NFκB-PDGF signaling in monocyte-derived macrophages [bulk RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE199637 | GEO | 2023/10/02

REPOSITORIES: GEO

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CYR61 orchestrates NASH fibrosis through SYK-NFκB-PDGF signaling in monocyte-derived macrophages [HIVE single-cell RNA-seq]

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.

2023-10-02 | GSE199639 | GEO

CYR61 orchestrates NASH fibrosis through SYK-NFκB-PDGF signaling in monocyte-derived macrophages [10X single-cell RNA-seq]

2023-10-02 | GSE199638 | GEO

Transcriptional analysis of non-fibrotic NAFLD progression

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.

2020-07-08 | GSE151158 | GEO

BET Inhibition Improves NASH and Liver Fibrosis

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.

2018-11-27 | GSE114261 | GEO

Post-transplant (non-alcoholic steatohepatitis) NASH compared with transplanted normal controls

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.

2022-05-09 | E-MTAB-11688 | biostudies-arrayexpress

Macrophage-derived thrombospondin1 promotes obesity-associated non-alcoholic fatty liver disease

Project description:Thrombospondin 1 (TSP1) is a multifunctional matricellular protein. Previously we have shown that TSP1 plays an important role in obesity-associated metabolic complications including inflammation, insulin resistance, cardiovascular and renal disease. However, its contribution to obesity-associated non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) remains largely unknown and is determined in this study. High fat diet or AMLN diet-induced obese and insulin resistant NAFLD/NASH mouse models were utilized. In addition, tissue specific TSP1 knockout mice were utilized to determine the contribution of different cellular sources of obesity-induced TSP1 to NAFLD/NASH development. The data demonstrated that liver TSP1 levels were increased in experimental obese and insulin resistant NAFLD/NASH mouse models as well as in human obese NASH patients. Moreover, TSP1 deletion in hepatocyte or adipocytes did not protect mice from diet-induced NAFLD/NASH. However, myeloid/macrophage-specific TSP1 deletion protected mice against obesity-associated liver injury, accompanied by reduced liver inflammation and fibrosis. Importantly, this protection is independent of the levels of obesity and hepatic steatosis. Mechanistically, through an autocrine effect, macrophage-derived TSP1 suppressed SMPDL3B expression in liver, which amplified liver pro-inflammatory signaling (TLR4 signal pathway) and promoted NAFLD progression. Together, out data suggest that macrophage-derived TSP1 is a significant contributor to obesity-associated NAFLD/NASH development and progression and may serve as a therapeutic target for this disease.

2020-12-07 | GSE155973 | GEO

Cyclo(His-Pro): A further step in the management of steatohepatitis

Project description:Non-alcoholic fatty liver disease (NAFLD) is now considered to be the most common liver disease in the world, and despite this has no approved therapy. The naturally occurring compound Cyclo (His-Pro) (CHP) has been described as having anti-inflammatory and hypoglycemic properties. We show that CHP administration in a mouse model of NAFLD/NASH protects against disease progression. Based on our study, CHP prevents overall lipid accumulation, reducing body weight and fat mass. The treatment lowers systemic inflammation and prevents the development of insulin resistance. Specifically, the effect of CHP in the liver is remarkable, it reduces the steatosis while preventing inflammation and fibrosis, typical features of NADLF/NASH progression. The analysis of the liver transcriptome underscores the anti-fibrotic and anti-inflammatory effects of the treatment, supported by histology results. CHP, which has an excellent safety record, may hence represent a novel approach to manage NAFLD.

2023-08-14 | GSE200750 | GEO

Cyclo (His-Pro): a further step in the prevention of steatohepatitis

2023-08-14 | GSE230745 | GEO

Gene expression in liver of morbidly obese patients

Project description:Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of liver disease affecting 20-30% of the population in developed countries. NAFLD is strongly associated with abdominal obesity and is recognized as the hepatic manifestation of the metabolic syndrome. In a subgroup of patients with NAFLD inflammation and fibrosis develops, this so-called Non-Alcoholic Steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma. A multi-hit hypothesis has been proposed in which during the first “hit” fat accumulation occurs in hepatocytes from excessive delivery of fatty acids from adipose tissue, in addition there is an imbalance in lipid synthesis and export. However, the reason why fat accumulation is subsequently followed by inflammation and fibrosis in some patients is poorly understood. We studied the role of gene expression at the transcriptional level using microarray in bariatric patients from whom the liver histology was available. Patients scheduled for bariatric surgery were recruited in Pretoria/South-Africa. At the time of the procedure, tissue samples of the visceral and subcutaneous fat were taken for molecular analysis as well as liver tissue for histology, also full biochemical data was collected. Patients were grouped according histology: group I (<5% steatosis), group II (NAFLD, 30-50% steatosis) and group III (NASH). The 15 samples were used for microarray (nr patients respectively for stages I-II-III: 6-4-5).This dataset is part of the TransQST collection.

2015-07-02 | E-GEOD-59045 | biostudies-arrayexpress

Microarray analysis among non-alcoholic fatty liver, non-alcoholic steatohepatitis, and type 2 diabetes mellitus rats

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.

2015-01-23 | E-GEOD-65220 | biostudies-arrayexpress

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