Pan AMPK-activator O304 ameliorates oxidative stress in MASLD, reverses lipid zonation and reveal lobular metabolic heterogeneitites in the murine live
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ABSTRACT:
PROVIDER: PRJNA1108647 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR28925654_1.fastq.gz | Fastqsanger.gz | |||
| SRR28925654_2.fastq.gz | Fastqsanger.gz | |||
| SRR28925655_1.fastq.gz | Fastqsanger.gz | |||
| SRR28925655_2.fastq.gz | Fastqsanger.gz |
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Project description:Therapeutic activators of the AMP-Activated Protein Kinase (AMPK) have been proposed as a potential treatment for metabolic dysfunction-associated steatotic liver disease, the most common chronic liver disease worldwide. This study investigates the effect of pan-AMPK activator O304 in a preclinical mouse model of progressive fatty liver disease and demonstrate that O304 reduces body fat mass, blood cholesterol and liver steatosis, as well as ameliorate development of liver fibrosis. These beneficial effects are accompanied by a shift in the metabolic program of the liver including increased lipid oxidation, reduced lipid synthesis, as well as changes in cholesterol and lipid transport. In addition, we detect lobular heterogeneities in the response to O304 and a consistent switch in the zonal distribution of lipid droplets upon treatment. Taken together, our data suggest that O304 is a promising candidate for treatment of MASLD also in human patients
2025-04-16 | GSE266874 | GEO
Project description:Energy homeostasis plays a key role in retarding aging, and mitochondria are responsible for energy production.AMPK plays a central role in maintaining energy homeostasis and mitochondrial homeostasis, and commands autophagy, a clearing and recycling process to maintain cellular homeostasis. However, the effect of AMPK activators on kidney aging has not been fully elucidated. We testified the effects of O304, a novel direct AMPK activator, in naturally aging mice model and D-galactose (D-gal)-treated renal tubular cell culture. We identified that O304 perfectly protects against cellular senescence and aged-related fibrosis in kidneys. Also, O304 restored energy metabolism, promoted autophagy, and preserved mitochondrial homeostasis. Transcriptomic sequencing also proved that O304 induced fatty acid metabolism, mitochondrial biogenesis and ATP process, and downregulated cell aging, DNA damage response and collagen organization. All these results suggest that O304 has a strong potential to retard aged kidney injury through regulating AMPK-induced multiple pathways.
2022-01-27 | GSE192512 | GEO
Project description:AMP-activated protein kinase (AMPK) have an important role in cellular energy homeostasis and has emerged as a promising target for treatment of Type 2 Diabetes (T2D) due to its beneficial effects on insulin sensitivity and glucose homeostasis. O304 is a pan-AMPK activator that has been shown to improve glucose homeostasis in both mouse models of diabetes and in human T2D subjects. Here, we describe the genome-wide transcriptional profile and chromatin landscape of pancreatic islets following O304 treatment of mice fed high-fat diet (HFD). O304 largely prevented genome-wide gene expression changes associated with HFD feeding in CBA mice and these changes were associated with remodelling of active and repressive chromatin marks. In particular, the increased expression of the β-cell stress marker Aldh1a3 in islets from HFD mice is completely abrogated following O304 treatment, which is accompanied by loss of active chromatin marks in the promoter as well as distant non-coding regions upstream of the Aldh1a3 gene. Moreover, O304 treatment restored dysfunctional glucose homeostasis as well as expression of key markers associated with β-cell function in mice with already established obesity. Our findings provide preclinical evidence that O304 is a promising therapeutic compound not only for T2D remission but also for restoration of β-cell function following remission of T2D diabetes.
2021-12-20 | GSE190812 | GEO
Project description:AMP-activated protein kinase (AMPK) have an important role in cellular energy homeostasis and has emerged as a promising target for treatment of Type 2 Diabetes (T2D) due to its beneficial effects on insulin sensitivity and glucose homeostasis. O304 is a pan-AMPK activator that has been shown to improve glucose homeostasis in both mouse models of diabetes and in human T2D subjects. Here, we describe the genome-wide transcriptional profile and chromatin landscape of pancreatic islets following O304 treatment of mice fed high-fat diet (HFD). O304 largely prevented genome-wide gene expression changes associated with HFD feeding in CBA mice and these changes were associated with remodelling of active and repressive chromatin marks. In particular, the increased expression of the β-cell stress marker Aldh1a3 in islets from HFD mice is completely abrogated following O304 treatment, which is accompanied by loss of active chromatin marks in the promoter as well as distant non-coding regions upstream of the Aldh1a3 gene. Moreover, O304 treatment restored dysfunctional glucose homeostasis as well as expression of key markers associated with β-cell function in mice with already established obesity. Our findings provide preclinical evidence that O304 is a promising therapeutic compound not only for T2D remission but also for restoration of β-cell function following remission of T2D diabetes.
2021-12-20 | GSE190810 | GEO
Project description:In Type 2 diabetes, insulin resistance elicits compensatory insulin hypersecretion, provoking β-cell stress and eventually compensatory failure. In insulin deficient STZ treated diabetic mice the dual AMPK activator and mitochondrial uncoupler O304 stimulates insulin independent glucose uptake and utilization in skeletal muscle and heart in vivo, thus improving glucose homeostasis. In obese In type 2 diabetic db/db mice, O304 additionally preserves β-cell function by preventing decline in insulin secretion, β-cell mass, and pancreatic insulin content. It remains however unclear whether these effects of O304 is mediated by a direct protective effect on β-cells, or indirectly by improving glucose homeostasis thereby inducing β-cell rest. To investigate the ability of O304 to directly mitigate the detrimental effect of hyperglycemia on β-cell function, we exposed isolated islets ex vivo to normoglycemic and hyperglycemic comdition in the abscence or prescene of O304.
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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 | GSE272564 | 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 | GSE272565 | GEO
Project description:Human hepatocytes differ in gene expression and function across the hexagonal lobules of the tissue microarchitecture, a phenomenon referred to as liver zonation. Hepatocytes also display intra-lobular differences in cell size, but to what extent zonal expression and function correlate with cell size in isolated human hepatocytes is not entirely clear. Here, we first used our accumulated experience of nearly 100 hepatocyte isolations to assess the impact of donor background and process parameters on hepatocyte quality. We observed substantial inter-batch variability in cell size distributions and a tendency for overall cell size to affect the outcome of hepatocyte isolation and cryopreservation. We further separated cells into different size fractions and analyzed them with label-free quantitative proteomics. This showed that protein abundances in different hepatocyte size fractions recapitulated the in vivo expression patterns of well-known zonal markers. We also found that proteins with sequential enrichment across fractions largely represented biological processes with known zonal specificity. This was confirmed by differences in the metabolic activity of zonated CYP enzymes. Altogether, our results show that hepatocyte size corresponds to zonal origin, and that our size fractionation approach can be used to study zone-specific liver functions in vitro.
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Project description:Little is known about how liver fibrosis influences lobular zonation. To address this question, we used three mouse models of liver fibrosis, repeated CCl4 administration for 2, 6 and 12 months to induce pericentral damage, as well as bile duct ligation (21 days) and mdr2-/- mice to study periportal fibrosis. Analyses were performed by RNA-sequencing, immunostaining of zonated proteins and image analysis. RNA-sequencing demonstrated a significant enrichment of pericentral genes among genes downregulated by CCl4; vice versa, periportal genes were enriched among the upregulated genes. Immunostaining showed an almost complete loss of pericentral proteins, such as cytochrome P450 enzymes and glutamine synthetase, while periportal proteins, such as arginase 1 and CPS1 became expressed also in pericentral hepatocytes. This pattern of fibrosis-associated 'periportalization' was consistently observed in all three mouse models and led to complete resistance to hepatotoxic doses of acetaminophen (200 mg/kg). Characterization of the expression response identified the inflammatory pathways TGFβ, NFκB, TNFα, and transcription factors NFKb1, Stat1, Hif1a, Trp53, and Atf1 among those activated, while estrogen-associated pathways, Hnf4a and Hnf1a, were decreased. In conclusion, liver fibrosis leads to strong alterations of lobular zonation, where the pericentral region adopts periportal features. Beside adverse consequences, periportalization supports adaptation to repeated doses of hepatotoxic compounds.
| S-EPMC6953125 | biostudies-literature
Project description:The burden of senescent hepatocytes correlates with MASLD severity but mechanisms driving senescence, and how it exacerbates MASLD are poorly understood. Hepatocytes become senescent when Smoothened (Smo) is deleted to disrupt Hedgehog signaling. We aimed to determine if the secretomes of Smo-deficient hepatocytes perpetuate senescence to drive MASLD progression. RNA seq analysis confirmed that hepatocyte populations of MASLD livers are depleted of Smo(+) cells and enriched with senescent cells. When fed CDA-HFD, Smo(-) mice had lower antioxidant markers and developed worse DNA damage, senescence, MASH and liver fibrosis than Smo(+) mice. Sera and hepatocyte-conditioned medium from Smo(-) mice were depleted of thymidine phosphorylase (TP), a protein that maintains mitochondrial fitness. Treating Smo(-) hepatocytes with TP reduced senescence and lipotoxicity; inhibiting TP in Smo(+) hepatocytes had the opposite effects and exacerbated hepatocyte senescence, MASH, and fibrosis in CDA-HFD-fed mice.Therefore, we found that inhibiting Hedgehog signaling in hepatocytes promotes MASLD by suppressing hepatocyte production of proteins that prevent lipotoxicity and senescence.
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