Inhibiting hepatic LPCAT3 ameliorates alcoholic liver injury through regulating NAMPT and PTLP signaling
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ABSTRACT:
PROVIDER: PRJNA1141368 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30017622_1.fastq.gz | Fastqsanger.gz | |||
| SRR30017622_2.fastq.gz | Fastqsanger.gz | |||
| SRR30017623_1.fastq.gz | Fastqsanger.gz | |||
| SRR30017623_2.fastq.gz | Fastqsanger.gz | |||
| SRR30017624_1.fastq.gz | Fastqsanger.gz |
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Project description:Background and Aims: Lysophosphatidylcholine acyltransferase 3 (LPCAT3), a key molecule regulating intracellular phospholoesters has abundantly expression level in metabolic tissues including liver, intestine and adipose. And it is considered to be directly related to the biosynthesis of inflammatory lipid mediators in humans. However, the mechanism of LPCAT3 in alcoholic liver disease (ALD) is unclear. Approach and Results: Liver-specific LPCAT3 liver knockout (LPCAT3-LKO) mice were established using CRISPR/Cas9, and then an ALD model followed by NIAAA modele was established. After LPCAT3-specific knockout of liver tissue, ALT, AST, TG, TC and liver TG, TC in ALD mice were reduced. Our group found that three downstream targets of LPCAT3, namely phospholipid transfer protein (PLTP) and nicotinamide phosphoribosyltransferase (NAMPT) and elongation of long-chain fatty acids family member 5 (ELOVL5) through RNA sequencing and the unbiased systematic investigative approach. In addition, our experimental data indicated that LPC and PC metabolism were altered in ALD mice by using targeted metabolomics. PCR and WB showed that PLTP and NAMPT protein expression levels were ascended in the LKO_x005F_x0002_EtOH group than Flox-EtOH group in the ALD model group. At the same time, in ethanol-induced cell models, LPCAT3 overexpression upregulated ALT and TG levels, aggravated hepatocytes, damage and lipid production, and reduced the expression of PLTP and NAMPT. Conclusions: The results provide novel views on the significance of LPCAT3 in regulating liver phospholipid synthesis in the pathogenesis of ALD. Reduction of LPCAT3 in liver tissue is able to mitigate alcohol-induced hepatocyte damage and lipid production by regulating PLTP and NAMPT.
2025-01-10 | GSE273289 | GEO
Project description:FABP4 deficiency ameliorates alcoholic steatohepatitis in mice
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Project description:Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease associated with metabolic disorders such as obesity, diabetes, and high cholesterol. It results in inflammation and fibrosis of liver tissue, eventually leading to cirrhosis and liver cancer. While LPCAT3 has been linked to the formation of fat cells, its role in the development of NASH is not yet fully understood. The purpose of this study was to gain insights into the mechanisms that accelerate NASH induced by LPCAT3. We utilized a genetic engineering rodent model and transcriptomics sequencing approach to explore the role and regulatory mechanism of LPCAT3 in the development of NAFLD. Approach & Results: We studied the impact of Lpcat3 deficiency on NASH progression using three distinct Lpcat3 liver-specific knockout mouse (LKO) models and conducted RNA sequencing, lipidomics, and metabolomics studies on liver samples. Human samples were obtained and analyzed for LPCAT3 expression in patients with NASH to determine its correlation with disease severity. The HepG2 and Huh-7 cell lines were utilized for in vitro analyses. We discovered that LPCAT3 expression was elevated in human NASH livers, and its expression correlated with NAFLD activity score and fibrosis stage. Lpcat3 deficiency in the mouse liver slows the development of diet-induced NASH. Lpcat3 deficiency mechanistically reduces lipid production by inhibiting lipid metabolic pathwaysDeletion of Lpcat3 significantly improved lipid accumulation in NASH mice, possibly due to the involvement of sult1e1 in lipogenesis and oxidation regulation. Moreover, the hepatic overexpression of Lpcat3 significantly intensified lipid buildup in steatotic cells, indicating that LPCAT3 plays a crucial role in the progression of NASH. Conclusions: The findings indicate that LPCAT3 regulates the participation of sult1e1 in both adipogenesis and oxidation, leading to enhanced NASH outcomes.
2025-01-10 | GSE273291 | GEO
Project description:Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease associated with metabolic disorders such as obesity, diabetes, and high cholesterol. It results in inflammation and fibrosis of liver tissue, eventually leading to cirrhosis and liver cancer. While LPCAT3 has been linked to the formation of fat cells, its role in the development of NASH is not yet fully understood. The purpose of this study was to gain insights into the mechanisms that accelerate NASH induced by LPCAT3. We utilized a genetic engineering rodent model and transcriptomics sequencing approach to explore the role and regulatory mechanism of LPCAT3 in the development of NAFLD. Approach & Results: We studied the impact of Lpcat3 deficiency on NASH progression using three distinct Lpcat3 liver-specific knockout mouse (LKO) models and conducted RNA sequencing, lipidomics, and metabolomics studies on liver samples. Human samples were obtained and analyzed for LPCAT3 expression in patients with NASH to determine its correlation with disease severity. The HepG2 and Huh-7 cell lines were utilized for in vitro analyses. We discovered that LPCAT3 expression was elevated in human NASH livers, and its expression correlated with NAFLD activity score and fibrosis stage. Lpcat3 deficiency in the mouse liver slows the development of diet-induced NASH. Lpcat3 deficiency mechanistically reduces lipid production by inhibiting lipid metabolic pathwaysDeletion of Lpcat3 significantly improved lipid accumulation in NASH mice, possibly due to the involvement of sult1e1 in lipogenesis and oxidation regulation. Moreover, the hepatic overexpression of Lpcat3 significantly intensified lipid buildup in steatotic cells, indicating that LPCAT3 plays a crucial role in the progression of NASH. Conclusions: The findings indicate that LPCAT3 regulates the participation of sult1e1 in both adipogenesis and oxidation, leading to enhanced NASH outcomes.
2025-01-10 | GSE273290 | GEO
Project description:Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer
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Project description:Neural stem/progenitor cell (NSPC) proliferation and self-renewal, as well as insult-induced differentiation, decrease markedly with age, but the molecular mechanisms responsible for these declines remain unclear. Here we show that levels of NAD+ and nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in mammalian NAD+ biosynthesis, decrease with age in the hippocampus. Ablation of Nampt in adult NSPCs reduced their pool and proliferation in vivo. The decrease in the NSPC pool during aging can be rescued by enhancing hippocampal NAD+ levels. Nampt is the main source of NSPC NAD+ levels and required for G1/S progression of the NSPC cell cycle. Nampt is also critical for oligodendrocytic lineage fate decisions through a mechanism mediated redundantly by Sirt1 and Sirt2. Ablation of Nampt in the adult NSPCs in vivo reduced NSPC-mediated oligodendrogenesis upon injury. These phenotypes recapitulate defects in NSPCs during aging, implicating Nampt-mediated NAD+ biosynthesis as a mediator of these age-associated functional declines. Total RNA obtained from neurospheres derived from postnatal hippocampi subjected to 48 hours in vitro of incubation with Nampt-specific inhibitor FK866 (10 nM, 4 samples) or vehicle (DMSO, 1:1000, 4 samples).
2014-05-08 | E-GEOD-49784 | biostudies-arrayexpress
Project description:NAMPT is an enzyme in the mammalian NAD+ salvage pathway. Expression microarray analysis was used to study the effect of NAMPT knockdown on gene expression in MCF-7 breast cancer cells. Experiment Overall Design: Stable knockdown of NAMPT was achieved using a retroviral shRNA construct. An shRNA directed against Luciferase was used to generate the Luc control cells. Three independent biological replicates with matching Luc controls were analyzed using Affymetrix U133 A2.0 microarrays.
2009-06-08 | E-GEOD-13449 | biostudies-arrayexpress
Project description:We used microarray to analyze the global gene expression in crypts isolated from wild-type (Lpcat3F/F) and Lpcat3 tamoxifen inducible intestine-specific knockout (Lpcat3F/F, Villin-CreERT2) crypts. Phospholipid remodeling is a critical determinant of membrane composition and function. How membrane phospholipid composition affects tissue stem cell function and tumorigenesis is unknown. Here we demonstrate that Lpcat3-dependent phospholipid remodeling regulates intestinal stem cell (ISC) proliferation and promotes tumorigenesis in intestine. The objective of generating this dataset was to analyze the effects of Lpcat3 loss of function on gene expression in mouse intestine crypts.
2017-12-05 | GSE98516 | GEO
Project description:Fatty acid-binding protein 4 (FABP4) plays an essential role in metabolism and inflammatory. However, the role of FABP4 in alcoholic steatohepatitis (ASH) remains unclear. This study aimed to investigate the function of FABP4 and the underlying mechanisms in the progression of ASH.
2024-04-24 | GSE265758 | GEO
Project description:Hypothesis is that NAMPT overexpression alters liver transcriptomics in genetically diabetic, obese db/db mice. We treated db/db mice n = 4 with adenovirus encoding GFP or NAMPT by tail-vein delivery.
2022-08-01 | E-MTAB-10984 | biostudies-arrayexpress