Dietary cholesterol-induced NASH-HCC
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ABSTRACT:
PROVIDER: PRJEB22176 | ENA |
REPOSITORIES: ENA
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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
Project description:To identify miRNAs that play important roles in the liver carcinogenesis from NASH, miRNA expression profiles were examined. Some miRNAs showed aberrant expression in HCC (Hepatocellular carcinoma) from NASH (non-alcoholic steatohepatitis). These miRNAs were regulated by DNA methylation, and could be potential therapeutic targets for HCC (Hepatocellular carcinoma) from NASH (non-alcoholic steatohepatitis).
2014-12-01 | GSE52821 | GEO
Project description:Impact of dietary cholesterol on Macrophages during non-alcoholic steatohepatitis progression
| PRJNA847573 | ENA
Project description:The study evaluated effects of dietary cholesterol (1.5%) in Atlantic salmon fed a plant based diet for 77 days. Cholesterol supplementation did not affect growth or organ weights of Atlantic salmon, but promoted induction of cholesterol and plant sterol efflux in the intestine, whereas sterol uptake was suppressed. Microarray analyses in the liver indicated decreased cholesterol biosynthesis and enhanced conversion to bile acids. The marked effect of cholesterol on bile acid synthesis suggests that dietary cholesterol can be used to stimulate bile acid synthesis in fish. The study clearly demonstrated how Atlantic salmon adjusted metabolic functions in response to the dietary load of cholesterol, and has expanded our understanding of sterol metabolism and turnover that adds to the knowledge of these processes in fish. Atlantic salmon received feeds based on plant ingredients with (CH) and without (K) supplementation of cholesterol. Liver samples were collected after 77 days. Five individuals from each group were analyzed with microarrays, pooled liver sample of salmon fed with commerical fish meal based feed was used as a reference.
2013-10-31 | E-GEOD-51887 | biostudies-arrayexpress
Project description:Intestinal cholesterol absorption is an important determinant of systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1), the target of the drug ezetimibe, is a critical player in dietary cholesterol uptake. But how cholesterol moves within the cell downstream of NPC1L1 is unknown. Here we show that the nonvesicular sterol transporters Aster-B and -C cooperate with NPC1L1 to deliver dietary cholesterol from the gut lumen to the enterocyte ER for chylomicron packaging. Aster proteins are recruited to the enterocyte plasma membrane (PM) in response to NPC1L1-dependent cholesterol accumulation. Mice lacking Asters in intestine have impaired cholesterol absorption, and reduced plasma cholesterol. NanoSIMS imaging and tracer studies reveal delayed lipid trafficking into chylomicrons in Aster-deficient enterocytes. Interestingly, in addition to potently blocking NPC1L1, ezetimibe is also a low-affinity inhibitor of Aster-B and -C but not -A, and the structure of the Aster-C-ezetimibe complex reveals the basis for this selectivity. Our findings support a model in which NPC1L1 enriches dietary cholesterol at the apical PM, and ASTERs subsequently traffic this cholesterol to the ER. The findings identify the enterocyte Aster pathway as potential target for treatment of hypercholesterolemia. Alessandra Ferrari, PhD
2023-12-21 | GSE206780 | GEO
Project description:The association of nonalcoholic steatohepatitis (NASH) with obesity and type 2 diabetes is a major determinant factor for the continued rise of NASH-driven HCC. Unfortunately, the mechanisms underlying the progression from NASH to HCC are not well-understood. Steatosis is characterized by the accumulation of different lipid species, and cholesterol has emerged as an important player in NASH development, which has been shown to promote NASH-driven HCC. However, recent findings indicated a tumor suppressor role of cholesterol in liver carcinogenesis and HCC development. Thus, we examined the contribution of hepatic steatosis with or without cholesterol accumulation induced by dietary or genetic approaches in liver tumorigenesis and whether the role of cholesterol in NASH-driven HCC is species-dependent. While diethylnitrosamine (DEN) treatment to rats or mice fed a choline-deficient diet decreased the hepatic steatosis, feeding an atherogenic diet enriched in cholesterol potentiated the liver tumor markers. Similar effects were observed in DEN-treated transgenic SREBP-2 mice but not wild-type (WT) mice fed a regular chow diet. Remarkably, long-term feeding of a high-fat high-cholesterol diet (HFHC) but not a high-fat diet (HFD) to WT mice caused severe NASH with spontaneous progression to HCC. A similar outcome was observed in MUP-uPA transgenic mice fed a HFHC diet, which resulted in increased liver tumors and expression of the genes involved in the immune checkpoints. Ezetimibe treatment ameliorated chronic liver disease and, more importantly, tumor multiplicity in HFHC-fed MUP-uPA mice or DEN-treated WT mice. Thus, these results revealed a differential role of steatosis and cholesterol in NASH-driven HCC and indicated that the tumor-promoter role of cholesterol is species-independent and associated with impaired immunosurveillance.
| S-EPMC8393403 | biostudies-literature
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
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
Project description:Non-alcoholic steatohepatitis (NASH) has emerged as a major challenge for public health because of high global prevalence and lack of evidence-based therapies. Most animal models of NASH lack sufficient validation regarding disease progression and pharmacological treatment. The Gubra-Amylin NASH (GAN) diet-induced obese (DIO) mouse demonstrate clinical translatability with respect to disease etiology and hallmarks of NASH. This study aimed to evaluate disease progression and responsiveness to clinically effective interventions in GAN DIO-NASH mice. Disease phenotyping was performed in male C57BL/6J mice fed the GAN diet high in fat, fructose and cholesterol for 28-88 weeks. GAN DIO-NASH mice with biopsy-confirmed NASH and fibrosis received low-caloric dietary intervention, semaglutide (30 nmol/kg/day, s.c.) or lanifibranor (30 mg/kg/day, p.o.) for 8 and 12 weeks, respectively. Within-subject change in NAFLD Activity Score (NAS) and fibrosis stage was evaluated using automated deep learning-based image analysis. GAN DIO-NASH mice showed clear and reproducible progression in NASH, fibrosis stage and tumor burden with high incidence of hepatocellular carcinoma. Consistent with clinical trial outcomes, semaglutide and lanifibranor improved NAS, while only lanifibranor induced regression in fibrosis stage. Dietary intervention also demonstrated substantial benefits on metabolic outcomes and liver histology. Differential therapeutic efficacy of dietary intervention, semaglutide and lanifibranor was supported by quantitative histology, RNA sequencing, and blood/liver biochemistry. In conclusion, the GAN DIO-NASH mouse model recapitulates various histological stages of NASH and faithfully reproduces histological efficacy profiles of compounds in advanced clinical development for NASH. Collectively, these features highlight the utility of GAN DIO-NASH mice in preclinical drug development.
2022-02-21 | GSE196908 | GEO
Project description:The mechanisms by which cholesterol promotes NAFLD remain far less clear. Animal models are necessary to explore the pathogenesis and therapies of NAFLD. Several previous studies have shown that pig breeds can differ in their metabolic phenotype in response to high-energy diet. To investigate whether genetic background has profound effects on pig NAFLD phenotype and their metabolic response to dietary cholesterol intake, we performed RNA-Seq on liver tissues from two miniature pig breeds fed either standard or a high-fat and high-cholesterol diet for 6 months.
2022-12-15 | GSE142346 | GEO