AdipoR1/AdipoR2 dual agonist recovers nonalcoholic steatohepatitis and related fibrosis via endoplasmic reticulum-mitochondria axis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE158951 | GEO | 2020/10/03
REPOSITORIES: GEO
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Project description:Chronic nonalcoholic steatohepatitis (NASH) is a metabolic disorder that often leads to liver fibrosis, a condition with limited therapy options. Adiponectin is an adipocytokine that regulates glucose and lipid metabolism via binding to its receptors AdipoR1 and AdipoR2, and AdipoRs signaling is reported to enhance fatty acid oxidation and glucose uptake. Here, we synthesize and report an adiponectin-based agonist JT003, which potently improves insulin resistance in high fat diet induced NASH mice and suppresses hepatic stellate cells (HSCs) activation in CCl4 induced liver fibrosis. Mechanistic studies indicate that JT003 simultaneously stimulates AdipoR1- and AdipoR2- mediated signaling pathways as well as the PI3K-Akt pathway. Moreover, JT003 treatment significantly improves ER-mitochondrial axis function, which contributes to the reduced HSCs activation. Thus, the AdipoR1/AdipoR2 dual agonist improves both NASH and fibrosis in mice models, which provides the pharmacological and biological foundation for developing AdipoRs-based therapeutic agents on liver fibrosis.
| S-EPMC7669869 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease worldwide, with 25% of these patients developing nonalcoholic steatohepatitis (NASH). NASH significantly increases the risk of cirrhosis and decompensated liver failure. Past studies in rodent models have shown the knockout of glycine-N-methyltransferase (GNMT) results in rapid pro-gression of steatosis, fibrosis, and hepatocellular carcinoma. However, the attenuation of GNMT in subjects with NASH and the molecular basis for its impact on the disease process are still unclear. To address this knowledge gap, we show the reduction of GNMT protein levels in the liver of NASH subjects compared to healthy controls. To gain insight into the impact of decreased GNMT in the disease process, we performed global label-free proteome studies on the livers from a murine Western diet-based model of NASH. Histological and molecular characterization of the animal model demonstrate high resemblance to the human disease.
2022-04-04 | PXD030781 | Pride
Project description:Non‑alcoholic steatohepatitis (NASH) is a pathological condition of the liver in which hepatocyte steatosis, invasion of inflammatory cells and hepatic injury occur without alcohol abuse. Despite the known risk of liver cancer and liver fibrosis that may progress to liver cirrhosis that exists with NASH, an understanding of related gene expression and associated functional changes remains insufficient. The present study used a mouse model of NASH induced by a high‑fat diet to examine gene expression in the liver and to search for transcripts that could predict early liver fibrosis in the future. Mice fed a high‑fat diet for 2 weeks showed typical NASH liver histology by hematoxylin and eosin staining, and increased fibrosis was confirmed by Sirius red staining after 6 weeks. Functional changes associated with liver damage, liver inflammation, liver steatosis and liver fibrosis were predicted by toxicological ontology analysis using Ingenuity Pathways Analysis. Downregulated microRNA (miR)‑21 and upregulated collagen type III α1 mRNA in the liver and upregulated exosomal miR‑21 in serum of mice fed a high‑fat diet for 1 and/or 2 weeks were confirmed by reverse transcription‑quantitative PCR, suggesting that these changes occur prior to histological confirmation of fibrosis. Therefore, it may be possible to predict future liver fibrosis by analyzing fibrosis‑related genes that shift prior to pathological findings.
2022-06-01 | GSE200409 | GEO
Project description:Objective: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here we aim to investigate the interaction between adipose tissue and liver in NAFLD, and identify potential early plasma markers that predict NASH. Research Design and Methods: C57Bl/6 mice were chronically fed a high fat diet to induce NAFLD and compared with mice fed low fat diet. Extensive histological and phenotypical analyses coupled with a time-course study of plasma proteins using multiplex assay was performed. Results: Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into 4 subgroups: LF-low (LFL) responders displaying normal liver morphology, LF-high (LFH) responders showing benign hepatic steatosis, HF-low (HFL) responders displaying pre-NASH with macrovesicular lipid droplets, and HF-high (HFH) responders exhibiting overt NASH characterized by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells. Compared to HFL responders, HFH mice gained weight more rapidly and exhibited adipose tissue dysfunction characterized by decreased final fat mass, enhanced macrophage infiltration and inflammation, and adipose tissue remodelling. Plasma haptoglobin, IL-1β, TIMP-1, adiponectin and leptin were significantly changed in HFH mice. Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin and MIP-1α early in the intervention were positively associated with liver triglycerides. Intermediate prognostic markers of liver triglycerides included IL-18, IL-1β, MIP-1γ and MIP-2, whereas insulin, TIMP-1, GCP-2 and MPO emerged as late markers. Conclusions: Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH. Keywords: Expression profiling by array Male wildtype C57Bl/6 mice were fed LFD or HFD for 21 weeks. Mice were divided into 4 groups based on liver histology.
2010-09-09 | E-GEOD-24031 | biostudies-arrayexpress
Project description:Background and aims: NASH, characterized by inflammation and fibrosis, is emerging as a leading etiology of HCC. Lipidomics analyses in the liver have shown that the levels of polyunsaturated phosphatidylcholine (PC) are decreased in patients with NASH, but the roles of membrane PC composition in the pathogenesis of NASH have not been investigated. Lysophosphatidylcholine acyltransferase 3 (LPCAT3), a phospholipid (PL) remodeling enzyme that produces polyunsaturated PLs, is a major determinant of membrane PC content in the liver. Approach and results: The expression of LPCAT3 and the correlation between its expression and NASH severity were analyzed in human patient samples. We examined the effect of Lpcat3 deficiency on NASH progression using Lpcat3 liver-specific knockout (LKO) mice. RNA sequencing, lipidomics, and metabolomics were performed in liver samples. Primary hepatocytes and hepatic cell lines were used for in vitro analyses. We showed that LPCAT3 was dramatically suppressed in human NASH livers, and its expression was inversely correlated with NAFLD activity score and fibrosis stage. Loss of Lpcat3 in mouse liver promotes both spontaneous and diet-induced NASH/HCC. Mechanistically, Lpcat3 deficiency enhances reactive oxygen species production due to impaired mitochondrial homeostasis. Loss of Lpcat3 increases inner mitochondrial membrane PL saturation and elevates stress-induced autophagy, resulting in reduced mitochondrial content and increased fragmentation. Furthermore, overexpression of Lpcat3 in the liver ameliorates inflammation and fibrosis of NASH. Conclusions: These results demonstrate that membrane PL composition modulates the progression of NASH and that manipulating LPCAT3 expression could be an effective therapeutic for NASH.
2024-06-05 | GSE218075 | GEO
Project description:Nonalcoholic steatohepatitis (NASH), characterized by inflammation and fibrosis, is emerging as a leading etiology of hepatocellular carcinoma (HCC). However, the mechanisms underlying the pathogenesis of NASH are not well understood. Here, we show that membrane phospholipid (PL) composition determined by a remodeling process modulates the progression of NASH. The expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), a PL remodeling enzyme that produces polyunsaturated PLs, is dramatically suppressed in human NASH livers compared to controls. LPCAT3 expression is inversely correlated with NAFLD activity score and fibrosis stage. Loss of Lpcat3 in mouse liver promotes the development of both spontaneous and diet-induced NASH/HCC. Mechanistically, Lpcat3 deficiency increases reactive oxygen species production, likely due to impaired mitochondrial homeostasis as demonstrated by reduced mitochondrial DNA content and fragmented mitochondrial morphology. Overexpressing Lpcat3 in the liver ameliorates inflammation and fibrosis of NASH. These results suggest that manipulating LPCAT3 expression may be an effective therapeutic strategy for NASH.
2024-06-05 | GSE218074 | GEO
Project description:Nonalcoholic steatohepatitis (NASH), characterized by inflammation and fibrosis, is emerging as a leading etiology of hepatocellular carcinoma (HCC). However, the mechanisms underlying the pathogenesis of NASH are not well understood. Here, we show that membrane phospholipid (PL) composition determined by a remodeling process modulates the progression of NASH. The expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), a PL remodeling enzyme that produces polyunsaturated PLs, is dramatically suppressed in human NASH livers compared to controls. LPCAT3 expression is inversely correlated with NAFLD activity score and fibrosis stage. Loss of Lpcat3 in mouse liver promotes the development of both spontaneous and diet-induced NASH/HCC. Mechanistically, Lpcat3 deficiency increases reactive oxygen species production, likely due to impaired mitochondrial homeostasis as demonstrated by reduced mitochondrial DNA content and fragmented mitochondrial morphology. Overexpressing Lpcat3 in the liver ameliorates inflammation and fibrosis of NASH. These results suggest that manipulating LPCAT3 expression may be an effective therapeutic strategy for NASH.
2024-06-05 | GSE218073 | GEO
Project description:Our objective is to determine the role of myeloid FoxO1 in regulating hepatic lipid metabolism and its contribution to nonalcoholic steatohepatitis (NASH) in mice. We generated mice with conditional FoxO1 depletion in myeloid cells, using the FoxO1-LoxP/LysM-Cre system. We then fed myeloid cell-conditional FoxO1-knockout and wild-type male mice a NASH-inducing diet for 25 weeks. Then mice in both groups were euthanized and the liver tissues were procured for the preparation of total RNAs, which were subjected to RNA-seq assay. While myeloid FoxO1 was upregulated in animal models and human subjects with NASH, the underlying mechanism is poorly understood. We found that myeloid cell conditional FoxO1-knockout mice were protected from developing NASH, culminating in the reduction of hepatic inflammation, steatosis and fibrosis. Mechanistically, FoxO1 counteracts Stat6 to skew macrophage polarization from M2 toward M1 signatures to perpetuate hepatic inflammation in NASH. FoxO1 appears as a pivotal mediator of macrophage activation in response to overnutrition and a therapeutic target for ameliorating hepatic inflammation to stem the disease progression from benign steatosis to NASH.
2022-05-24 | GSE203227 | GEO
Project description:In this study Guo et al. revealed an endocrine pathway regulated by skeletal muscle IRF4 that manipulates liver pathology. Mice with skeletal muscle specific ablation of IRF4 show ameliorated liver steatosis, inflammation, and fibrosis, without changes in body weight on nonalcoholic steatohepatitis (NASH) diet. Proteomics analysis of mouse serum suggested that follistatin-like protein 1 (FSTL1) might link the communication between muscle and liver. Dual luciferase assays showed that IRF4 could transcriptionally regulate FSTL1 and reconstitution of FSTL1 expression in muscle of F4MKO mice was sufficient to restore the liver pathology. Furthermore, co-culture experiments verified that FSTL1 exerts its function in hepatocyte, macrophage, and hepatic satellite cells through CD14 and DIP2A, CD14, DIP2A, respectively. In human, serum FSTL1 is increased in NASH patients, but the mRNA level of Fstl1 and its receptors are decreased in NASH liver biopsy, suggesting the increased serum FSTL1 is from skeletal muscle as studied in F4MKO mice. These data unveiled a signaling pathway from skeletal muscle to liver via IRF4-FSTL1-DIP2A/CD14 in the pathogenesis of NASH.
2023-09-13 | PXD045324 | Pride
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.
2019-06-22 | GSE128940 | GEO