Similar Datasets
Project description:Background and Aims: Host-cell factor 1 (HCF-1), encoded by the ubiquitously expressed X linked gene Hcfc1, is an epigenetic co-regulator important for mouse development and cell proliferation, including during liver regeneration. Here, we examine the role of HCF-1 in adult tissue physiology using, as model, the resting mouse liver. Methods: We used a hepatocyte-specific inducible Hcfc1 knock-out allele (called Hcfc1hepKO), to induce HCF-1 loss in hepatocytes of hemizygous Hcfc1 hepKO/Y males by four days. In heterozygous Hcfc1hepKO/+ females, owing to random X-chromosome inactivation, upon Hcfc1hepKO allele induction, a 50/50 mix of HCF-1 positive and negative hepatocyte clusters is engineered. Results: The livers with Hcfc1hepKO/Y hepatocytes displayed a 21 24-day terminal non-alcoholic fatty liver (NAFL) followed by non-alcoholic steatohepatitis (NASH) disease progression typical of severe NAFL disease (NAFLD). In contrast, in livers with heterozygous Hcfc1hepKO/+ hepatocytes, HCF-1-positive hepatocytes replaced HCF-1-negative hepatocytes and revealed only mild-NAFL development. Loss of HCF-1 led to loss of PGC1 alpha protein levels, probably owing to its destabilization, and deregulation of gene expression particularly of genes involved in mitochondrial structure and function, likely explaining the severe Hcfc1hepKO/Y liver pathology. Interestingly, although HCF-1 binds to over 5000 transcriptional start sites in the resting liver, expression of only a minor subset of the associated genes was affected by HCF-1 loss. Conclusion: HCF-1 is essential for proper liver physiology likely playing both transcriptional and non-transcriptional roles. These genetically-engineered loss-of-HCF-1 mice represent models for the study of NASH and NAFLD resolution.
2019-02-27 | GSE115767 | GEO
Project description:Background and Aims: Host-cell factor 1 (HCF-1), encoded by the ubiquitously expressed X linked gene Hcfc1, is an epigenetic co-regulator important for mouse development and cell proliferation, including during liver regeneration. Here, we examine the role of HCF-1 in adult tissue physiology using, as model, the resting mouse liver. Methods: We used a hepatocyte-specific inducible Hcfc1 knock-out allele (called Hcfc1hepKO), to induce HCF-1 loss in hepatocytes of hemizygous Hcfc1 hepKO/Y males by four days. In heterozygous Hcfc1hepKO/+ females, owing to random X-chromosome inactivation, upon Hcfc1hepKO allele induction, a 50/50 mix of HCF-1 positive and negative hepatocyte clusters is engineered. Results: The livers with Hcfc1hepKO/Y hepatocytes displayed a 21–24-day terminal non-alcoholic fatty liver (NAFL) followed by non-alcoholic steatohepatitis (NASH) disease progression typical of severe NAFL disease (NAFLD). In contrast, in livers with heterozygous Hcfc1hepKO/+ hepatocytes, HCF-1-positive hepatocytes replaced HCF-1-negative hepatocytes and revealed only mild-NAFL development. Loss of HCF-1 led to loss of PGC1 alpha protein levels, probably owing to its destabilization, and deregulation of gene expression particularly of genes involved in mitochondrial structure and function, likely explaining the severe Hcfc1hepKO/Y liver pathology. Interestingly, although HCF-1 binds to over 5000 transcriptional start sites in the resting liver, expression of only a minor subset of the associated genes was affected by HCF-1 loss. Conclusion: HCF-1 is essential for proper liver physiology likely playing both transcriptional and non-transcriptional roles. These genetically-engineered loss-of-HCF-1 mice represent models for the study of NASH and NAFLD resolution.
2019-02-27 | GSE115766 | GEO
Project description:Rapid recapitulation of non-alcoholic steatohepatitis upon loss of HCF-1 function in mouse hepatocytes
| PRJNA475971 | ENA
Project description:Host-cell factor 1 (HCF-1), encoded by the ubiquitously expressed X-linked gene Hcfc1, is an epigenetic coregulator important for mouse development and cell proliferation, including during liver regeneration. We used a hepatocyte-specific inducible Hcfc1 knock-out allele (called Hcfc1hepKO), to induce HCF-1 loss in hepatocytes of hemizygous Hcfc1hepKO/Y males by four days. In heterozygous Hcfc1hepKO/+ females, owing to random X-chromosome inactivation, upon Hcfc1hepKO allele induction, a 50/50 mix of HCF-1 positive and negative hepatocyte clusters is engineered. The livers with Hcfc1hepKO/Y hepatocytes displayed a 21-24-day terminal non-alcoholic fatty liver (NAFL) followed by non-alcoholic steatohepatitis (NASH) disease progression typical of severe NAFL disease (NAFLD). In contrast, in livers with heterozygous Hcfc1hepKO/+ hepatocytes, HCF-1-positive hepatocytes replaced HCF-1-negative hepatocytes and revealed only mild-NAFL development. Loss of HCF-1 led to loss of PGC1α protein, probably owing to its destabilization, and deregulation of gene expression particularly of genes involved in mitochondrial structure and function, likely explaining the severe Hcfc1hepKO/Y liver pathology. Thus, HCF-1 is essential for hepatocyte function, likely playing both transcriptional and non-transcriptional roles. These genetically-engineered loss-of-HCF-1 mice can be used to study NASH as well as NAFLD resolution.
| S-EPMC6379584 | biostudies-literature
Project description:Rapid recapitulation of non-alcoholic steatohepatitis upon loss of HCF-1 function in mouse hepatocytes [ChIP-seq]
| PRJNA475975 | ENA
Project description:Rapid recapitulation of non-alcoholic steatohepatitis upon loss of HCF-1 function in mouse hepatocytes [RNA-seq]
| PRJNA475976 | ENA
Project description: Not available
| S-EPMC6497995 | biostudies-literature
Project description:While non-alcoholic steatohepatitis is a slowly progressive disease, patients may rarely present in acute liver failure. We describe six patients who developed severe hepatic dysfunction following rapid weight loss or malnutrition. Rapid weight loss (18 to 91?kg) occurred after Roux-en-Y gastric bypass in four patients and starvation-like dieting or hypoalbuminemia was noted in two patients. Four patients either died or received an urgent liver transplant. Pathologic findings were characterized by advanced alcoholic steatohepatitis-like features, including extensive/circumferential centrizonal pericellular fibrosis, central scar with perivenular sclerosis/veno-occlusion with superimposed hepatocellular dropout, abundant/prominent hepatocellular balloons, and numerous Mallory-Denk bodies, but there was no history of excess alcohol consumption. This study characterizes clinicopathologic features of aggressive non-alcoholic steatohepatitis following rapid weight loss or malnutrition, which should be included in the differential diagnosis with alcohol when a patient is considered for liver transplantation. The mechanism of liver injury in aggressive steatohepatitis is unknown, but rapid fat mobilization in obese patients may potentially cause oxidative stress to the liver and further study is needed to determine if there is a genetic predisposition to this form of injury and if antioxidants may protect the liver during rapid weight loss/malnutrition.
| S-EPMC5935795 | biostudies-literature
Project description:Incomplete understanding of how hepatosteatosis transitions to fibrotic non-alcoholic steatohepatitis (NASH) has limited therapeutic options. Two molecules that are elevated in hepatocytes in human NASH liver are cholesterol, whose mechanistic link to NASH remains incompletely understood, and TAZ, a transcriptional regulator that promotes fibrosis but whose mechanism of increase in NASH is unknown. We now show that increased hepatocyte cholesterol upregulates TAZ and promotes fibrotic NASH. ASTER-B/C-mediated internalization of plasma membrane cholesterol activates soluble adenylyl cyclase (sAC; ADCY10), triggering a calcium-RhoA-mediated pathway that suppresses β-TrCP/proteasome-mediated TAZ degradation. In mice fed with a cholesterol-rich NASH-inducing diet, hepatocyte-specific silencing of ASTER-B/C, sAC, or RhoA decreased TAZ and ameliorated fibrotic NASH. The cholesterol-TAZ pathway is present in primary human hepatocytes, and associations among liver cholesterol, TAZ, and RhoA in human NASH liver are consistent with the pathway. Thus, hepatocyte cholesterol contributes to fibrotic NASH by increasing TAZ, suggesting new targets for therapeutic intervention.
| S-EPMC7313619 | biostudies-literature
Project description:Ectopic lipid accumulation and inflammation are the essential signs of NASH. However, the molecular mechanisms of ectopic lipid accumulation and inflammation during NASH progression are not fully understood. Here we reported that hepatic Wilms' tumor 1-associating protein (WTAP) is a key integrative regulator of ectopic lipid accumulation and inflammation during NASH progression. Hepatic deletion of Wtap leads to NASH due to the increased lipolysis in white adipose tissue, enhanced hepatic free fatty acids uptake and induced inflammation, all of which are mediated by IGFBP1, CD36 and cytochemokines such as CCL2, respectively. WTAP binds to specific DNA motifs which are enriched in the promoters and suppresses gene expression (e.g., Igfbp1, Cd36 and Ccl2) with the involvement of HDAC1. In NASH, WTAP is tranlocated from nucleus to cytosol, which is related to CDK9-mediated phosphorylation. These data uncover a mechanism by which hepatic WTAP regulates ectopic lipid accumulation and inflammation during NASH progression.
| S-EPMC9352699 | biostudies-literature