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β-Cryptoxanthin suppresses inflammatory gene expression in diet-induced nonalcoholic steatohepatitis in mice

ABSTRACT: To evaluate the effect of β-cryptoxanthin on diet-induced NASH, we fed a high-cholesterol and high-fat diet (CL diet) with or without 0.003% β-cryptoxanthin to C56BL/6J mice for 12 weeks. After feeding, β-cryptoxanthin attenuated fat accumulation, increases in Kupffer and activated stellate cells, and fibrosis in CL diet-induced NASH in the mice. Comprehensive gene expression analysis showed that although β-cryptoxanthin histochemically reduced steatosis, it was more effective in inhibiting inflammatory gene expression change in NASH. β-Cryptoxanthin reduced the alteration of expression of genes associated with cell death, inflammatory responses, infiltration and activation of macrophages and other leukocytes, quantity of T cells, and free radical scavenging. However, it showed little effect on the expression of genes related to cholesterol and other lipid metabolism. The expression of markers of M1 and M2 macrophages, T helper cells, and cytotoxic T cells was significantly induced in NASH and reduced by β-cryptoxanthin. β-Cryptoxanthin suppressed the expression of lipopolysaccharide (LPS)-inducible and/or TNFα-inducible genes and the antioxidant enzyme glutathione peroxidase 1 in NASH. Thus, β-cryptoxanthin suppresses inflammation and the resulting fibrosis probably by primarily suppressing the increase and activation of macrophages and other immune cells. Reducing oxidative stress is likely to be a major mechanism of inflammation and injury suppression in the livers of mice with NASH.

ORGANISM(S): Mus musculus

PROVIDER: GSE51432 | GEO | 2014/05/28

SECONDARY ACCESSION(S): PRJNA223165

REPOSITORIES: GEO

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M-NM-2-Cryptoxanthin suppresses inflammatory gene expression in diet-induced nonalcoholic steatohepatitis in mice

Project description:To evaluate the effect of M-NM-2-cryptoxanthin on diet-induced NASH, we fed a high-cholesterol and high-fat diet (CL diet) with or without 0.003% M-NM-2-cryptoxanthin to C56BL/6J mice for 12 weeks. After feeding, M-NM-2-cryptoxanthin attenuated fat accumulation, increases in Kupffer and activated stellate cells, and fibrosis in CL diet-induced NASH in the mice. Comprehensive gene expression analysis showed that although M-NM-2-cryptoxanthin histochemically reduced steatosis, it was more effective in inhibiting inflammatory gene expression change in NASH. M-NM-2-Cryptoxanthin reduced the alteration of expression of genes associated with cell death, inflammatory responses, infiltration and activation of macrophages and other leukocytes, quantity of T cells, and free radical scavenging. However, it showed little effect on the expression of genes related to cholesterol and other lipid metabolism. The expression of markers of M1 and M2 macrophages, T helper cells, and cytotoxic T cells was significantly induced in NASH and reduced by M-NM-2-cryptoxanthin. M-NM-2-Cryptoxanthin suppressed the expression of lipopolysaccharide (LPS)-inducible and/or TNFM-NM-1-inducible genes and the antioxidant enzyme glutathione peroxidase 1 in NASH. Thus, M-NM-2-cryptoxanthin suppresses inflammation and the resulting fibrosis probably by primarily suppressing the increase and activation of macrophages and other immune cells. Reducing oxidative stress is likely to be a major mechanism of inflammation and injury suppression in the livers of mice with NASH. Eight-week old male C57BL/6J mice were fed for 12 weeks on a CRF-1 standard chow (control), a high-cholesterol and high-fat diet (CL diet; 38.23% CRF-1, 60% cocoa butter, 1.25% cholesterol, 0.5% sodium cholate) or a CL diet containing 0.003% M-NM-2-cryptoxanthin.

2014-05-28 | E-GEOD-51432 | biostudies-arrayexpress

Hepatic transcriptome profiles of mice with diet-induced nonalcoholic steatohepatitis treated with astaxanthin and vitamin E

Project description:Astaxanthin alleviates hepatic lipid accumulation and peroxidation, inflammation, and fibrosis in mice with high-cholesterol, high-cholate, and high-fat (CL) diet-induced nonalcoholic steatohepatitis (NASH). It has been proposed as a potential new treatment to inhibit the progression of NASH in humans. Therefore, we compared hepatic gene expression profiles after treatment with astaxanthin or the antioxidant vitamin E in mice with CL diet-induced NASH. Comprehensive gene expression analyses of the livers of mice fed a standard, CL, or CL diet containing astaxanthin or vitamin E for 12 weeks were performed using a DNA microarray. Both astaxanthin and vitamin E effectively improved gene expression associated with eukaryotic initiation factor-2 (EIF2) signaling, which is suppressed in NASH by endoplasmic reticulum (ER) stress in the liver. Astaxanthin but not vitamin E was predicted to suppress the actions of ligand-dependent nuclear receptors peroxisome proliferator-activated receptors (PPAR) α and PPARδ and to affect related molecules. Establishing a new therapy using astaxanthin will require elucidation of astaxanthin’s molecular action on the functions of PPARα and related molecules in the livers of mice with diet-induced NASH.

2017-03-21 | GSE93819 | GEO

Dietary cholesterol promotes fatty liver-associated liver cancer by inducing aberrant genomic expression and mutations

Project description:We investigated the effects of cholesterol on nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) in diethylnitrosamine-injected mice fed high-fat high-cholesterol (HFHC) diet versus high-fat (HF) alone. mRNA microarray analysis was applied for expressional aberrations.

2018-09-27 | E-MTAB-6002 | biostudies-arrayexpress

Administration of glutaredoxin-1 attenuates liver fibrosis caused by aging and non-alcoholic steatohepatitis

Project description:Glutaredoxin-1 (Glrx) controls redox signaling and has an anti-apoptotic function. We evaluated the role of Glrx on hepatic cell damage and fibrosis induced by a high-fat diet. We fed mice a high-fat high-fructose diet to induce non-alcoholic steatohepatitis (NASH) and injected AAV-Glrx to express hepatocyte-specific Glrx in diet-induced NASH mice. AAV-Glrx suppressed fibrosis and improved liver function in the NASH liver. We used microarrays to profile gene expression in the NASH liver and find pathways that AAV-Glrx mediated to attenuate fibrosis and NASH progression.

2022-06-01 | GSE198961 | GEO

Platelet-derived thrombospondin 1 promotes immune cell liver infiltration and exacerbates diet-induced steatohepatitis.

Project description:Background and Aims: Recent studies have implicated platelets, particularly α-granules, in the development of steatohepatitis (NASH). However, the specific mechanisms involved have yet to be determined. Notably, thrombospondin 1 (TSP1) is a major component of the platelet α-granules released during platelet activation. The role of platelet-derived TSP1 in NASH remains unknown and was investigated in this study. Approach and Results: Platelet-specific TSP1 knockout mice (TSP1Δpf4) and their wild type littermates (TSP1F/F) were used. NASH was induced by feeding the mice a diet enriched in fat, sucrose, fructose, and cholesterol (AMLN diet). A human liver NASH organoid model was also employed. Although TSP1 deletion in platelets did not affect diet-induced steatosis, TSP1Δpf4 mice exhibited attenuated NASH and liver fibrosis, accompanied by improvements in plasma glucose and lipid homeostasis. Moreover, intrahepatic platelet accumulation, activation and chemokine production were reduced in TSP1Δpf4 mice, which was correlated with decreased immune cell infiltration into the liver. Consequently, this leads to diminished pro-inflammatory signaling in the liver and mitigated the progression of NAFLD. Moreover, in vitro data revealed that co-culturing TSP1-deficient platelets in a human liver NASH organoid model attenuated hepatic stellate cell activation and NASH progression. Additionally, TSP1 deficient platelets play a role in regulating brown fat endocrine function, specifically affecting Nrg4 production. Crosstalk between brown fat and the liver may also influence NAFLD progression. Conclusions: These data suggest that platelet α-granule-derived TSP1 is a significant contributor to diet-induced NASH and fibrosis, and may serve as a new therapeutic target for this severe liver disease.

2024-03-13 | GSE250004 | GEO

RNAseq of livers of mice fed high fat high sugar diet and either untreated or treated with curcumin liposomes or calcitriol liposomes

Project description:Non-alcoholic fatty liver disease (NAFLD) is a common complication of obesity, where insulin resistance and hepatocyte fat deposition may progress to steatohepatitis (NASH) and fibrosis/ cirrhosis. NASH has no approved treatment. Consequent upon hepatic fat deposition, NF-κB activation in hepatic myeloid cells mediates inflammation and NASH progression. We delivered micro-doses of liposome-encapsulated lipophilic NF-κB inhibitors, curcumin or 1,25-dihydroxy-vitamin D3 (calcitriol), to the pro-fibrogenic inflammatory liver macrophages and dendritic cells (DCs) in diet-induced NASH. After i.v. administration, liver was the primary organ targeted. MHC class-II+ hepatic DCs taking up liposomes in mice and human were F4/80+ and CD14+ respectively, were lipid-laden and expressed pro-inflammatory genes. Curcumin or calcitriol liposomes suppressed hepatic inflammation, fibrosis and fat accumulation, and reduced insulin resistance associated with suppression of immune activation, cell cycle and collagen deposition pathways in vivo. Thus, hepatic inflammatory DCs passively targeted with liposomes encapsulating lipophilic NF-κB inhibitors are beneficial in NASH.

2020-01-22 | GSE94593 | GEO

RNAseq of liver dendritic cells targeted with empty liposomes or curcumin liposomes

2020-01-22 | GSE94592 | GEO

Impact of dietary cholesterol on Macrophages during non-alcoholic steatohepatitis progression

Project description:Inflammation, mediated by liver-resident Kupffer cells (KCs) and recruited infiltrating macrophages (IMs), plays a critical role in NAFLD pathogenesis. Cholesterol induces pro-inflammatory cytokine production by macrophages and has been identified as a key factor involved in progression from simple steatosis to NASH. In this study, using the fructose, palmitate, cholesterol & trans-fat (FPC) diet model which recapitulates human NAFLD, we aimed to determine the impact of cholesterol manipulation on NAFLD progression/regression and macrophage phenotype in vivo.The transcriptomic evaluation of hepatic macrophages from mice fed with FPC diet contained the highest concentration of cholesterol (1.25%) suggest these cells might contribute to liver inflammation, steatohepatitis, and hepatocarcinoma pathways during the progression phase.

2022-08-23 | GSE205776 | GEO

Effect of cholesterol overload on gene expression of RAW264 macrophages

Project description:Hepatocyte death plays a critical role in the disease progression from simple steatosis to non-alcoholic steatohepatitis (NASH). We have previously reported that hepatocyte death locally induces phenotypic changes in the macrophages surrounding the corpse and remnant lipids, thereby promoting liver fibrosis in a murine model of NASH. Here, we demonstrated free cholesterol was accumulated in macrophages around dead hepatocytes containing cholesterol crystals. In vitro experiments revealed that cholesterol-induced lysosomal stress triggered profibrotic activation in macrophages. This study provides evidence that dysregulated cholesterol metabolism in macrophages would be a novel mechanism of NASH.

2023-06-25 | GSE235222 | GEO

Effect of cholesterol overload on gene expression of hepatic macrophages isolated from normal and NASH livers.

Project description:Hepatocyte death plays a critical role in the disease progression from simple steatosis to non-alcoholic steatohepatitis (NASH). We have previously reported that hepatocyte death locally induces phenotypic changes in the macrophages surrounding the corpse and remnant lipids, thereby promoting liver fibrosis in a murine model of NASH. Here, we demonstrated free cholesterol was accumulated in macrophages around dead hepatocytes containing cholesterol crystals. In vitro experiments revealed that cholesterol-induced lysosomal stress triggered profibrotic activation in macrophages predisposed to the steatotic microenvironment. This study provides evidence that dysregulated cholesterol metabolism in macrophages would be a novel mechanism of NASH.

2023-06-20 | GSE235024 | GEO

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