Effect of hepatocytic RKIP depletion on HFD-induced MASLD
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE300123 | GEO | 2025/09/03
REPOSITORIES: GEO
Similar Datasets
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) embraces different conditions, including metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The landscape of cellular abnormalities occurring in the different stages of MASLD as well as the processes which drive MASLD evolution are not completely clarified. We used single cell RNAsequencing (scRNAseq) to unravel cellular heterogeneity affecting livers during the switching from simple steatosis towads MASH and and MASH-fibrosis.
2025-02-28 | GSE284186 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD), closely associated with obesity, can progress to metabolic dysfunction-associated steatohepatitis when the liver undergoes overt inflammatory damage. A-kinase anchoring protein 1 (AKAP1) has been shown to control lipid accumulation in brown adipocytes. However, the role of AKAP1 signaling in hepatic lipid metabolism and MASLD remains poorly understood. Here, we showed that hepatocyte-specific AKAP1 deficiency exacerbated hepatic steatosis and steatohepatitis in male mice subjected to a high-fat diet and fast-food diet, respectively. Mechanistically, AKAP1 directly phosphorylated and inactivated glycerol-3-phosphate acyltransferase 1 (GPAT1) in a PKA-dependent manner, thus suppressing lysophosphatidic acid (LPA) production. Increased endogenous LPA in hepatocytes promoted hepatocellular triglyceride (TG) synthesis and initiated pronounced inflammatory response in Kupffer cells. Restoring hepatic AKAP1 or repressing LPA levels via GPAT1 knockdown alleviated MASLD exacerbation. Overall, AKAP1 plays a protective role against MASLD by inhibiting GPAT1 activity, highlighting the potential of targeting AKAP1/PKA/GPAT1 signalosome for MASLD therapy.
2025-05-26 | PXD062388 | Pride
Project description:Although maternal obesity is an independent risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), the pathogenesis remains unclear. We aimed to evaluate the effect and mechanisms of multigenerational maternal western diet (WD) on MASLD progression, and test drug candidates in a preclinical model. Female mice were fed WD from 8 weeks before breeding initiation with a normal chow (NC)-fed male, throughout pregnancy and lactation. Male offspring were weaned onto NC or WD and assessed at the age of 16 weeks. Maternal WD feeding aggravated body weight gain, insulin resistance, steatosis and inflammation. Fibrosis was only observed in offspring exposed to maternal WD. Mechanistically, the latter exhibited reduced OXPHOS activity. Maternal WD aggravates MASLD in male offspring, with mitochondrial dysfunction contributing to disease severity.
2025-06-18 | GSE291363 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with obesity. The use of animal models fed Western-style diets is vital for investigating the molecular mechanisms contributing to metabolic dysregulation and for facilitating novel drug target identification. However, the sex- and age-associated mechanisms underlying the pathophysiology remain poorly understood. Here we show distinct responses to a HFD between males and females. Our study underscores the need for utilizing both sexes in drug target identification studies, and characterizing the molecular mechanisms contributing to the MASLD pathophysiology in aging animals. Hepatology Communications 2024
2024-09-03 | GSE274914 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) liver biopsies were analyzed using spatial single-cell transcriptomics (CosMx Spatial Molecular Imager, NanoString) to elucidate molecular alterations associated with hepatic fibrosis morphology, as quantified by the artificial intelligence-based FibroNest algorithm (PharmaNest). This analysis identified distinct morphological fiber phenotypes (FibroPCs), among which FibroPC4, characterized by reticular fiber structures, was associated with a hepatic stellate cell (HSC) phenotype that promotes hepatocellular carcinoma (HCC). This HCC-promoting HSC phenotype was driven by insulin-like growth factor-binding protein 7 (IGFBP-7) secreted from senescent periportal endothelial cells.
2025-08-20 | GSE292268 | GEO
Project description:Hepatic fibrosis is the strongest contributor to hepatocarcinogenesis in metabolic dysfunction-associated steatotic liver disease (MASLD); however, the underlying mechanisms have yet to be fully elucidated. In 94 human MASLD biopsy samples, artificial intelligence-based morphological phenotyping of hepatic fiber and multi-omics analyses revealed that insulin growth factor-binding protein 7 (IGFBP-7) secreted from senescent periportal endothelial cells might transform stellate cells into a hepatocarcinogenesis-promoting phenotype. To test the effect of IGFBP-7 on HSC, a hepatic stellate cell line, LX-2, was cultured with recombinant IGFBP-7 (100ng/mL), resulting in their transformation to a more activated form than the control.
2025-08-20 | GSE278593 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are characterized by excessive triglyceride accumulation in the liver. However, due to an incomplete understanding of its pathogenesis, more efforts are still needed to identify specific and effective treatments. N4-acetylcytidine (ac4C) is a newly discovered RNA modification to regulate mRNA stability post-transcriptionally. N-acetyltransferase 10 (NAT10), the sole enzyme catalyzing mRNA acetylation, has not been fully explored in human diseases, especially in MASLD and MASH. In the current study, abundant RNA acetylation was found in lipid metabolism-related genes in the livers of leptin receptor-deficient (db/db) mice. Besides, hepatic NAT10 expression is significantly increased in multiple mouse models of MASLD and MASH. NAT10 expression is also elevated in patients with MASLD and positively correlated with clinical characteristics. Genetic NAT10 knockdown protects against diet-induced hepatic steatosis and steatohepatitis in mice, while its overexpression exacerbates steatosis. Mechanistically, NAT10 could bind to Srebp-1c mRNA to promote its stability and expression, thereby upregulating lipogenic enzymes. In addition, the translational significance of our findings is that treatment of Remodelin, an NAT10 inhibitor, could improve liver steatosis and dyslipidemia in a preclinical mouse model. Together, these findings highlight the significance of ac4C modification and NAT10 in MASLD and MASH, offering a potential therapeutic target for disease treatment.
2024-09-22 | GSE275576 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are characterized by excessive triglyceride accumulation in the liver. However, due to an incomplete understanding of its pathogenesis, more efforts are still needed to identify specific and effective treatments. N4-acetylcytidine (ac4C) is a newly discovered RNA modification to regulate mRNA stability post-transcriptionally. N-acetyltransferase 10 (NAT10), the sole enzyme catalyzing mRNA acetylation, has not been fully explored in human diseases, especially in MASLD and MASH. In the current study, abundant RNA acetylation was found in lipid metabolism-related genes in the livers of leptin receptor-deficient (db/db) mice. Besides, hepatic NAT10 expression is significantly increased in multiple mouse models of MASLD and MASH. NAT10 expression is also elevated in patients with MASLD and positively correlated with clinical characteristics. Genetic NAT10 knockdown protects against diet-induced hepatic steatosis and steatohepatitis in mice, while its overexpression exacerbates steatosis. Mechanistically, NAT10 could bind to Srebp-1c mRNA to promote its stability and expression, thereby upregulating lipogenic enzymes. In addition, the translational significance of our findings is that treatment of Remodelin, an NAT10 inhibitor, could improve liver steatosis and dyslipidemia in a preclinical mouse model. Together, these findings highlight the significance of ac4C modification and NAT10 in MASLD and MASH, offering a potential therapeutic target for disease treatment.
2024-09-22 | GSE275575 | GEO
Project description:Uric acid has garnered increasing attention for its association with metabolic dysfunction-associated steatotic liver disease (MASLD) in recent cross-sectional studies, although detailed understanding of its involvement remains limited. This study confirms a strong association between urate levels and elevated risk of both MASLD and type 2 diabetes (T2D) through a large-scale observational analysis of UK Biobank data. However, Mendelian randomization (MR) analysis involving over 2 million samples identified only causal effects of urate on serum triglyceride levels and the risk of T2D. Additionally, a targeted metabolomics study involving elderly Chinese participants revealed that, rather than UA, allantoin—a byproduct of UA oxidation—was significantly elevated in individuals with dyslipidemia or T2D. Notably, a significant negative correlation was found between serum allantoin level and fasting glucose, as well as serum triglyceride and cholesterol levels. Animal studies demonstrated that allantoin exacerbates hepatic lipid accumulation and glucose intolerance in mice fed a high-fat diet, which was accompanied by increased hepatic lipid biogenesis and reduced bile acid production. Interestingly, our findings indicate that allantoin exhibits a strong binding affinity for PPARα, suggesting that it may act as an inhibitor of PPARα, thereby promoting the progression of MASLD. These results underscore the critical role of allantoin, rather than UA, in the development of MASLD, offering valuable insights for the prediction and management of hepatic metabolic disorders.
2025-06-04 | GSE283505 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease globally. Abnormal crosstalk between hepatocytes and hepatic stellate cells (HSCs) leads to liver fibrosis and aggravates MASLD. We explored the role of the RNA-binding protein Pumilio in this process.
2025-04-27 | GSE295362 | GEO