Mid-Lobular Hepatocytes Exhibit Transient Proliferation Pause and Stress Response through Atf4-Ddit3 axis in Early Acute Liver Injury
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE272566 | GEO | 2024/09/17
REPOSITORIES: GEO
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Project description:Liver zonation remains a critical aspect of understanding its response to acute injury. This study investigates the impact of acetaminophen-induced acute liver injury on zonal heterogeneity during early phases of injury. Through Ki67 staining, we observed a transient pause in proliferation specifically among mid-lobular hepatocytes during the initiation phase. Using spatial transcriptomics, immunostaining, and in vivo assays, we elucidated that mid-lobular hepatocytes upregulate the Atf4-Ddit3 axis, offering temporary protection at the cost of reduced proliferation mediated by Btg2. Our findings underscore the unique zonal metabolism of acetaminophen as a determinant of differential tissue responses across lobular regions. This study highlights how distinct liver zones exhibit varied responses during the early stages of acute injury, with mid-lobular hepatocytes showing an integrated stress response characterized by protective mechanisms that temporarily suppress proliferation.
2024-09-17 | GSE272565 | GEO
Project description:Liver zonation remains a critical aspect of understanding its response to acute injury. This study investigates the impact of acetaminophen-induced acute liver injury on zonal heterogeneity during early phases of injury. Through Ki67 staining, we observed a transient pause in proliferation specifically among mid-lobular hepatocytes during the initiation phase. Using spatial transcriptomics, immunostaining, and in vivo assays, we elucidated that mid-lobular hepatocytes upregulate the Atf4-Ddit3 axis, offering temporary protection at the cost of reduced proliferation mediated by Btg2. Our findings underscore the unique zonal metabolism of acetaminophen as a determinant of differential tissue responses across lobular regions. This study highlights how distinct liver zones exhibit varied responses during the early stages of acute injury, with mid-lobular hepatocytes showing an integrated stress response characterized by protective mechanisms that temporarily suppress proliferation.
2024-09-17 | GSE272564 | GEO
Project description:Mid-Lobular Hepatocytes Exhibit Transient Proliferation Pause and Stress Response through Atf4-Ddit3 axis in Early Acute Liver Injury
| PRJNA1137352 | ENA
Project description:Mid-Lobular Hepatocytes Exhibit Transient Proliferation Pause and Stress Response through Atf4-Ddit3 axis in Early Acute Liver Injury (10x Visium)
| PRJNA1137353 | ENA
Project description:Mid-Lobular Hepatocytes Exhibit Transient Proliferation Pause and Stress Response through Atf4-Ddit3 axis in Early Acute Liver Injury (CUT&Run)
| PRJNA1137355 | ENA
Project description:Prohibitin 1 (PHB1) is a mitochondrial chaperone that regulates cell growth. Phb1 knock-out mice exhibit liver injury and hepatocellular carcinoma (HCC). Phb1 knock-out livers show induction of tumor growth-associated genes, H19 and insulin-like growth factor 2 (Igf2). These genes are controlled by the imprinting control region (ICR) containing CCCTC-binding transcription factor (CTCF)-binding sites. Because Phb1 knock-out mice exhibited induction of H19 and Igf2, we hypothesized that PHB1-mediated regulation of the H19-Igf2 axis might control cell proliferation in normal hepatocytes. H19 and Igf2 were induced (8-20-fold) in 3-week-old Phb1 knock-out livers, in Phb1 siRNA-treated AML12 hepatocytes (2-fold), and HCC cell lines when compared with control. Phb1 knockdown lowered CTCF protein in AML12 by ∼30% when compared with control. CTCF overexpression lowered basal H19 and Igf2 expression by 30% and suppressed Phb1 knockdown-mediated induction of these genes. CTCF and PHB1 co-immunoprecipitated and co-localized on the ICR element, and Phb1 knockdown lowered CTCF ICR binding activity. The results suggest that PHB1 and CTCF cooperation may control the H19-Igf2 axis. Human HCC tissues with high levels of H19 and IGF2 exhibited a 40-50% reduction in PHB1 and CTCF expression and their ICR binding activity. Silencing Phb1 or overexpressing H19 in the mouse HCC cell line, SAMe-D, induced cell growth. Blocking H19 induction prevented Phb1 knockdown-mediated growth, whereas H19 overexpression had the reverse effect. Interestingly H19 silencing induced PHB1 expression. Taken together, our results demonstrate that the H19-Igf2 axis is negatively regulated by CTCF-PHB1 cooperation and that H19 is involved in modulating the growth-suppressive effect of PHB1 in the liver.
| S-EPMC5104939 | biostudies-literature
Project description:To characterize transcriptome changes uopn ATF4 or DDIT3 in maturing cardiomyocytes
2022-05-21 | GSE179944 | GEO
Project description:BackgroundStudies have indicated vascular smooth muscle cells (VSMCs) played a crucial role in atherosclerosis and microRNAs (miRNAs) played key roles in biological functions of VSMCs. Whereas, the potential function and mechanism of miR-552 in VSMCs remains unclear. Our aim was to explore the role of miR-552 on VSMCs and underlying mechanism.Material/methodsMTT assay and transwell assay were used to measure the proliferation, invasion, and migration of human brain VSMCs (HBVSMCs) and mice VSMCs (mVSMCs), respectively. Bioinformatics tools and luciferase assay were adopted to verify the association between miR-552 and SKI. Rescue experiments were employed to assess the interaction of miR-552 and SKI in modulating biological functions in HBVSMCs and mVSMCs. The expression level of transcription factors (TFs)was measured via qRT-PCR assay. The effect of ATF4 on miR-552 and SKI expression was tested by qRT-PCR or western blot assay. Finally, chromatin immunoprecipitation (ChIP) assay and JASPAR databases were used to analyze the regulatory linkage between ATF4 and miR-552.ResultsWe found that miR-552 was upregulated in HBVSMCs treated with PDGF-bb and miR-552 overexpression could promote proliferation, invasion, and migration of HBVSMCs and mVSMCs, whereas, miR-552 knockdown had the opposite impact. In addition, we also found that SKI was a direct target of miR-552, which reversed miR-552-mediated proliferation, invasion, and migration in HBVSMCs and mVSMCs. Furthermore, we also discovered that miR-552 overexpression promoted the effects of ATF4 elevation on proliferation, migration and invasion of HBVSMCs and mVSMCs, but, miR-552 decline had the opposite impact.ConclusionsATF4-miR-552-SKI axis played critical roles in the proliferation and migration of HBVSMCs and mVSMCs, which were closely involved in atherosclerosis (AS). Therefore, our findings might offer a novel therapeutic target for AS.
| S-EPMC9299314 | biostudies-literature
Project description:Activating transcription factor (ATF) 4 is involved in the regulation of oxidative stress in fibroblasts and neurons. The role of ATF4 in hepatocytes, however, is unknown. The aim of this study was to investigate the role of ATF4 in hepatocytes in oxidative stress under a high-fat diet (HFD). Here, we showed that palmitate-stimulated reactive oxygen species (ROS) production and triglyceride (TG) accumulation is blocked by ATF4 deficiency in primary hepatocytes. Consistently, HFD-induced oxidative stress, TG accumulation and expression of cytochrome P450, family 2, subfamily, polypeptide 1 (CYP2E1) are also blocked by knocking down ATF4 expression in the mouse liver. This suggests that ATF4 might regulate oxidative stress via CYP2E1 under an HFD. In addition, we observed that expression of CYP2E1 is indirectly regulated by ATF4 in a cAMP-responsive element binding protein (CREB)-dependent manner, which can directly activate the CYP2E1 promoter activity. Notably, ATF4-stimulated ROS production is inhibited in vivo by treatment with diallyl sulphide, a selective CYP2E1 inhibitor. Finally, we showed that ATF4 expression in the liver is responsible for the protective effects against HFD-induced CYP2E1 expression, oxidative stress, and TG accumulation. Taken together, these observations suggest that ATF4 is a novel regulator of oxidative stress as well as accumulation of TG in response to HFD.
| S-EPMC3916120 | biostudies-literature
Project description:Here we studied the relevance and modulation of aldehyde dehydrogenase (ALDH) expression in malignant pleural mesothelioma (MPM) chemoresistant cell subpopulations (ALDH(bright) cells), which survive pemetrexed + cisplatin treatment in vitro and in vivo. Expression of the ALDH1A3 isoform was invariably enriched in purified ALDH(bright) cells from multiple MPM cell lines and accounted for the enzymatic activity of those cells. RNAi mediated downregulation of ALDH1A3 reduced the survival of the ALDH(bright) cells at steady state and, much more, after pemetrexed + cisplatin treatment. We demonstrated, for the first time, that a pSTAT3(tyr705)-NFkB(p65) complex is required for the repression of DDIT3 mRNA and this ensures high levels of CEBPβ-dependent ALDH1A3 promoter activity. Inhibition of STAT3-NFkB activity allowed high levels of DDIT3 expression with increased formation of a DDIT3-CEBPβ complex. This reduced the occupancy of the ALDH1A3 promoter by CEBPβ, thus largely reducing the ALDH1A3 expression. Consequently, survival of ALDH(bright) cells in pemetrexed + cisplatin-treated cultures was impaired, following increased apoptosis. We show that such a mechanism is relevant in vivo and underlies the action of butein, a dual STAT3-NFkB inhibitor capable of abating the chemoresistance of mesothelioma cells in vivo. The possible broad translational relevance of the described mechanism is discussed.
| S-EPMC4494963 | biostudies-literature