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IL-11 neutralising therapies for the treatment of nonalcoholic steatohepatitis

ABSTRACT: IL-11 neutralising therapies for the treatment of nonalcoholic steatohepatitis

PROVIDER: PRJNA529419 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8792580_1.fastq.gz	Fastqsanger.gz
	SRR8792580_2.fastq.gz	Fastqsanger.gz
	SRR8792590_1.fastq.gz	Fastqsanger.gz
	SRR8792590_2.fastq.gz	Fastqsanger.gz
	SRR8792600_1.fastq.gz	Fastqsanger.gz

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IL-11 neutralising therapies for the treatment of nonalcoholic steatohepatitis

Project description:Background and aims: Here we investigate the role of IL-11 signalling in the pathogenesis of nonalcoholic steatohepatitis (NASH). Methods: HSCs or hepatocytes were stimulated with IL-11 and effects assessed using cellular and high content imaging, immunoblotting, ELISA and invasion assays. Genetic and pharmacological IL-11 gain- or loss-of-function experiments were performed in vitro and in vivo. IL-11 signaling was studied using ERK inhibitors. The effects of anti-IL-11 or anti-IL11RA therapy were assessed in three preclinical NASH models using methionine/choline deficient diets or a Western diet with liquid fructose. Phenotyping was performed using hydroxyproline assay, qPCR, RNA-seq, Western blotting, histology, CyTOF, lipid and metabolic biomarkers. Results: When stimulated with NASH factors HSCs secrete IL-11, which drives an autocrine, ERK-dependent signaling loop required for the HSC-to-myofibroblast transformation. IL-11 is upregulated in human and murine NASH, Il-11 injection causes liver damage, inflammation and fibrosis in mice and Il11ra1 deleted mice are protected from NASH in two preclinical models. Therapeutic antibodies against IL11RA or IL-11 consistently inhibit and reverse fibrosis and steatosis in three murine NASH models. Unexpectedly, IL-11 causes hepatocyte damage and promotes stromal-mediated inflammation and anti-IL-11 therapies reverse NASH-associated hepatotoxicity and hepatitis. Genetic or pharmacologic inhibition of IL-11 signaling in NASH is associated with lower serum triglyceride, cholesterol and glucose. Conclusion: We show an unappreciated and central role for IL-11 in liver pathobiology. Targeting IL-11 signalling with neutralizing antibodies reverses fibrosis, steatosis, hepatocyte death and inflammation across the spectrum of NASH. This novel therapeutic approach is associated with a favorable cardiometabolic profile.

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Nonalcoholic steatohepatitis in adolescents undergoing bariatric surgery

Project description:The genomic landscape of hepatic tissue affected by nonalcoholic steatohepatitis (NASH) in severely obese adolescents undergoing bariatric surgery is unknown. Our purpose here was to uncover genomic profiles of obese controls, and obese cases with nonalcoholic fatty liver disease (NAFLD), borderline nonalcoholic steatohepatitis, and definite nonalcoholic steatohepatitis, in order to clarify molecular functions, biological processes, and pathways that are dysregulated in nonalcoholic steatohepatitis in the severely obese adolescent. In a prospective observational cohort study, we have intra-operatively obtained 165 liver samples; of these 67 were submited for microarray analysis. Through ANOVA, we found 8648 genes with differential regulation between the four histologies; from these, we uncovered gene signatures shared between borderline and definite nonalcoholic steatohepatitis, and gene sets with differential effects between borderline and definite.

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Bardoxolone methyl improves nonalcoholic steatohepatitis through inhibition of macrophage recruitment

Project description:Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease caused by excess fat accumulation, closely associated with obesity and metabolic syndrome.Bardoxolone methyl (2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester, CDDO-Me) is a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2). Some clinical trials of CDDO-Me were conducted for chronic kidney diseases and pulmonary arterial hypertension, whereas the hepatoprotective effect of CDDO-Me on nonalcoholic steatohepatitis (NASH) has not yet been elucidated. The purpose of this study was to determine the hepatoprotective potential and mechanisms of CDDO-Me in a diet-induced NASH mouse model. Whole transcriptome analysis revealed that CDDO-Me markedly inhibited the expressions of chemokine ligands, Ccl3 and Ccl4, and the chemokine receptors, Ccr1 and Ccr5 that increased in NASH mice while activating Nrf2-dependent pathway. Serum protein levels of CCL3 and CCL4 upregulated in NASH mice were inhibited in a dose-dependent manner by treatment with CDDO-Me. CDDO-Me inhibited the expression levels of Ccr1 and Ccr5, and simultaneously blocked Ccl3 and Ccl4 the ligands of the receptors, respectively in RAW264.7 cell line. Taken together with the observations, CDDO-Me directly inhibits the expression of CCL3-CCR1 and CCL4-CCR5 axes in macrophages of NASH mice, which might contribute to the improvement of nonalcoholic steatohepatitis and fibrosis through the interference of monocyte-derived macrophage migration.

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SOX9 ameliorates nonalcoholic steatohepatitis through activating AMPK pathway

Project description:SOX9 ameliorates nonalcoholic steatohepatitis through activating AMPK pathway

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