A preclinical mouse model of nonalcoholic steatohepatitis and hepatocellular cancer that mimics human disease
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE67680 | GEO | 2016/07/25
SECONDARY ACCESSION(S): PRJNA280621
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-07-25 | E-GEOD-67680 | biostudies-arrayexpress
Project description:A preclinical mouse model of nonalcoholic steatohepatitis and hepatocellular cancer that mimics human disease
| PRJNA280621 | ENA
Project description:Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease and second indication for liver transplantation in the Western world. Effective therapy is still not available. Previously we showed a critical role for caspase-2 in the pathogenesis of nonalcoholic steatohepatitis (NASH), the potentially progressive form of NAFLD. An imbalance between free coenzyme A (CoA) and acyl-CoA ratio is known to induce caspase-2 activation.We aimed to evaluate CoA metabolism and the effects of supplementation with CoA precursors, pantothenate and cysteine, in mouse models of NASH.CoA metabolism was evaluated in methionine-choline deficient (MCD) and Western diet mouse models of NASH. MCD diet-fed mice were treated with pantothenate and N-acetylcysteine or placebo to determine effects on NASH.Liver free CoA content was reduced, pantothenate kinase (PANK), the rate-limiting enzyme in the CoA biosynthesis pathway, was down-regulated, and CoA degrading enzymes were increased in mice with NASH. Decreased hepatic free CoA content was associated with increased caspase-2 activity and correlated with worse liver cell apoptosis, inflammation, and fibrosis. Treatment with pantothenate and N-acetylcysteine did not inhibit caspase-2 activation, improve NASH, normalize PANK expression, or restore free CoA levels in MCD diet-fed mice.In mice with NASH, hepatic CoA metabolism is impaired, leading to decreased free CoA content, activation of caspase-2, and increased liver cell apoptosis. Dietary supplementation with CoA precursors did not restore CoA levels or improve NASH, suggesting that alternative approaches are necessary to normalize free CoA during NASH.
| S-EPMC4703517 | biostudies-literature
Project description:Aim:Worldwide, hepatocellular cancer (HCC) is the fourth leading cause of cancer death and occurs 3 times more commonly in males than females. Current surveillance practices do not fully address gender differences in HCC.Methods:Clinical characteristics and survival were compared between males and females using a prospectively collected database of HCC patients.Results:In a cohort of 1206 patients, 307 (25%) were female who presented with older age, more non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), family history of HCC, and hypertension. Males (75%) were more likely to use alcohol and cigarettes. Females were more likely to undergo HCC surveillance, have smaller tumor size at diagnosis, and less vascular involvement. Males who met Milan criteria were more likely to undergo liver transplant than women who met the criteria. Median/mean survival was similar between the genders. Multivariate analysis showed that NAFLD/NASH was predictive of mortality for both males and females, age and smoking were predictive of mortality for males, and transplant was predictive of survival for males.Conclusion:Gender differences in HCC appear related to both behavioral risk factors and biologic factors. Older females with HCC have more NAFLD/NASH and may be overlooked by current surveillance guidelines. These gender disparities may lend support to future studies of gender-based HCC screening.
| S-EPMC6347119 | biostudies-other
Project description:Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), causes hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The patatin-like phospholipase-3 (PNPLA3) I148M sequence variant is one of the strongest genetic determinants of NAFLD/NASH. PNPLA3 is an independent risk factor for HCC among patients with NASH. The obesity epidemic is closely associated with the rising prevalence and severity of NAFLD/NASH. Furthermore, metabolic syndrome exacerbates the course of NAFLD/NASH. These factors are able to induce apoptosis and activate immune and inflammatory pathways, resulting in the development of hepatic fibrosis and NASH, leading to progression toward HCC. Small intestinal bacterial overgrowth (SIBO), destruction of the intestinal mucosa barrier function and a high-fat diet all seem to exacerbate the development of hepatic fibrosis and NASH, leading to HCC in patients with NAFLD/NASH. Thus, the intestinal microbiota may play a role in the development of NAFLD/NASH. In this review, we describe recent advances in our knowledge of the molecular mechanisms contributing to the development of hepatic fibrosis and HCC in patients with NAFLD/NASH.
| S-EPMC7073210 | biostudies-literature
Project description:This study employed low and high-fat purified diets containing two levels of added dietary cholesterol in conventionally raised, specific-pathogen free (SPF) mice harboring a full microbial community as compared to germ-free (GF) mice raised in complete absence of gut microbes on disease outcomes. It was hypothesized that FF-diets would lead to an earlier onset of gut dysbiosis, corresponding with elevated biomarkers of NAFLD and NASH. In the present study, we aimed to dissect the role of FF diet induced gut dysbiosis in order to mechanistically identify the underlying mechanism that influences gut-liver crosstalk between specific diet-induced bacterial populations and hepatic tissue to drive NAFLD/NASH onset and progression
2023-04-27 | GSE190982 | GEO
Project description:The natural polyphenol compound resveratrol (RSV) is considered to have a broad spectrum of beneficial biological activities upon human health. However, the exact effect of RSV on steatosis (a phenotype of non-alcoholic fatty liver [NAFL]) or fibrosis and inflammation (major phenotypes of non-alcoholic steatohepatitis [NASH]) is not known. Our data showed that administration of RSV (2 or 20 mg/kg/day) did not suppress steatosis in a high-fat diet-induced model of NAFL in mice. In contrast, identical concentrations of RSV dramatically inhibited inflammation and fibrosis in a low-dose lipopolysaccharide-induced model of NASH. These data suggested that RSV administration-mediated improvement of inflammation and fibrosis was due to the inhibition of LPS reactivity controlled by CD14 expression in Kupffer cells. These findings suggest that RSV could be a candidate agent for the treatment of NASH.
| S-EPMC4766502 | biostudies-literature
Project description:Non-alcoholic steatohepatitis (NASH) is characterized by steatosis with lobular inflammation and hepatocyte injury. Pirfenidone (PFD) is an orally bioavailable pyridone derivative that has been clinically used for the treatment of idiopathic pulmonary fibrosis. However, it remains unknown whether PFD improves liver fibrosis in a mouse model with human NASH-like phenotypes. In this study, we employed melanocortin 4 receptor-deficient (MC4R-KO) mice as a mouse model with human NASH-like phenotypes to elucidate the effect and action mechanisms of PFD on the development of NASH. PFD markedly attenuated liver fibrosis in western diet (WD)-fed MC4R-KO mice without affecting metabolic profiles or steatosis. PFD prevented liver injury and fibrosis associated with decreased apoptosis of liver cells in WD-fed MC4R-KO mice. Pretreatment of PFD inhibited the tumor necrosis factor-α (TNF-α)-induced liver injury and fibrogenic responses associated with decreased apoptosis of liver cells in wild-type mice. PFD also prevented TNF-α-induced hepatocyte apoptosis in vitro with reduced activation of caspase-8 and -3. This study provides evidence for the antifibrotic effect of PFD in a mouse model of human NASH. The data of this study highlight hepatocyte apoptosis as a potential therapeutic target, and suggest that PFD can be repositioned as an antifibrotic drug for human NASH.
| S-EPMC5355985 | biostudies-literature
Project description:Nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, ranges from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which is a more aggressive form characterized by hepatocyte injury, inflammation, and fibrosis. Increasing evidence suggests that NASH is a risk factor for hepatocellular carcinoma (HCC), which is the fifth most common cancer worldwide and the second most common cause of cancer-related death. Recent studies support a strong mechanistic link between the NASH microenvironment and HCC development. The liver has a large capacity to remove circulating pathogens and gut-derived microbial compounds. Thus, the liver is a central player in immunoregulation. Altered immune responses are tightly associated with the development of NASH and HCC. The objective of this study was to differentiate the roles of specific immune cell subsets in NASH and HCC pathogenesis.
| S-EPMC8080649 | biostudies-literature
Project description:Nonalcoholic steatohepatitis (NASH) is a progressive liver disease projected to become the leading cause of cirrhosis and liver transplantation in the next decade. Cenicriviroc (CVC), a dual chemokine receptor 2 and 5 antagonist, prevents macrophage trafficking and is under clinical investigation for the treatment of human NASH fibrosis. We assessed the efficacy and durability of short and prolonged CVC therapy in a diet-induced mouse model of NASH, the choline deficient, L-amino acid-defined, high-fat diet (CDAHFD) model. C57BL/6 mice received 4 or 14 weeks of standard chow or the CDAHFD. CVC (10 mg/kg/day and 30 mg/kg/day for 4 weeks and 20 mg/kg/day and 30 mg/kg/day for 14 weeks) was initiated simultaneously with the CDAHFD. At 4 and 14 weeks, livers were harvested for histology and flow cytometric analyses of intrahepatic immune cells. High-dose CVC (30 mg/kg/day) therapy in CDAHFD mice for 4 or 14 weeks inhibited intrahepatic accumulation of Ly6Chigh bone marrow-derived macrophages. Prolonged CVC therapy (14 weeks) yielded no significant differences in the total intrahepatic macrophage populations among treatment groups but increased the frequency of intrahepatic anti-inflammatory macrophages in the high-dose CVC group. Despite ongoing steatohepatitis, there was significantly less fibrosis in CDAHFD mice receiving high-dose CVC for 14 weeks based on histologic and molecular markers, mirroring observations in human NASH CVC trials. CVC also directly inhibited the profibrotic gene signature of transforming growth factor-?-stimulated primary mouse hepatic stellate cells in vitro. Conclusion: CVC is a novel therapeutic agent that is associated with reduced fibrosis despite ongoing steatohepatitis. Its ability to alter intrahepatic macrophage populations and inhibit profibrogenic genes in hepatic stellate cells in NASH livers may contribute to its observed antifibrotic effect. (Hepatology Communications 2018;2:529-545).
| S-EPMC5944590 | biostudies-literature