Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA258077 | ENA |
REPOSITORIES: ENA
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Project description:Abnormalities in hepatic lipid metabolism are believed to play a critical role in the etiology of nonalcoholic steatohepatitis (NASH). Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol (TAG) synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis and knocking down Mogat1 improves insulin sensitivity, but whether increased MGAT activity plays a role in the etiology of NASH is unclear. To examine the effects of knocking down Mogat1 in the liver on the development of NASH, C57BL/6 mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were then injected with antisense oligonucleotides (ASO) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver, attenuated weight gain, improved glucose tolerance, and decreased hepatic TAG content compared to control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic DAG, cholesterol, or free fatty acid content, improve histologic measures of liver injury, or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves glucose tolerance and hepatic TAG accumulation without attenuating liver inflammation and injury. Total RNA obtained from liver of 4 control vs. 4 Mogat1 ASO treated higf-fat diet (HFD) fed mice.
2014-11-05 | E-GEOD-60349 | biostudies-arrayexpress
Project description:Abnormalities in hepatic lipid metabolism are believed to play a critical role in the etiology of nonalcoholic steatohepatitis (NASH). Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol (TAG) synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis and knocking down Mogat1 improves insulin sensitivity, but whether increased MGAT activity plays a role in the etiology of NASH is unclear. To examine the effects of knocking down Mogat1 in the liver on the development of NASH, C57BL/6 mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were then injected with antisense oligonucleotides (ASO) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver, attenuated weight gain, improved glucose tolerance, and decreased hepatic TAG content compared to control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic DAG, cholesterol, or free fatty acid content, improve histologic measures of liver injury, or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves glucose tolerance and hepatic TAG accumulation without attenuating liver inflammation and injury.
2014-11-05 | GSE60349 | GEO
Project description:Macrophage PKM2 depletion ameliorates hepatic inflammation and acute liver injury in mice
| PRJNA1250415 | ENA
Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder with high morbidity and mortality. The current study aims to explore the role of Cullin-associated and neddylation-dissociated protein 1 (CAND1) in the development of NAFLD and the underlying mechanisms. CAND1 is reduced in the liver of NAFLD male patients and high fat diet (HFD)-fed male mice. CAND1 alleviates palmitate (PA) induced lipid accumulation in vitro. Hepatocyte-specific knockout of CAND1 exacerbates HFD-induced liver injury in HFD-fed male mice, while hepatocyte-specific knockin of CAND1 ameliorates these pathological changes. Mechanistically, deficiency of CAND1 enhances the assembly of Cullin1, F-box only protein 42 (FBXO42) and acetyl-CoA acyltransferase 2 (ACAA2) complexes, and thus promotes the ubiquitinated degradation of ACAA2. ACAA2 overexpression abolishes the exacerbated effects of CAND1 deficiency on NAFLD. Additionally, androgen receptor binds to the -187 to -2000 promoter region of CAND1. Collectively, CAND1 mitigates NAFLD by inhibiting Cullin1/FBXO42 mediated ACAA2 degradation
2023-10-24 | PXD043719 | Pride
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:Inhibiting hepatic LPCAT3 ameliorates alcoholic liver injury through regulating NAMPT and PTLP signaling
| PRJNA1141368 | ENA
Project description:Cannabinoid 1 receptor (CB1R) expression is upregulated in hepatocytes during viral hepatitis, cirrhosis, and both alcoholic and non-alcoholic fatty liver disease (FLD), whereas its expression is muted under usual physiological conditions. Inhibiting CB1R has been shown to be beneficial in preserving hepatic function in FLD but it is unclear if inhibiting CB1R during an inflammatory response to an acute hepatic injury, such as toxin - induced injury, would also be beneficial. We tested if nullification of hepatocyte-specific CB1R (hCNR1-/-) in mice protects against concanavalin A (Con A) - induced liver injury. We looked for evidence of liver damage and markers of inflammation in response to Con A by measuring liver enzyme levels and proinflammatory cytokines (e.g., TNF-α, IL-1β, IL-6, IL-17) in serum collected from hCNR1-/- and control mice. We observed a shift to the right in the dose-response curve for liver injury and inflammation in hCNR1-/- mice. We also found less inflammatory cell infiltration and focal necrosis in livers of hCNR1-/- mice compared to controls, resulting from downregulated apoptotic markers. This anti-apoptotic mechanism results from increased activation of nuclear factor kappa B (NF-κB), especially membrane-bound TNF-α, via downregulated TNF-α receptor 2 (TNFR2) transcription levels. We also found that CB1R in hepatocytes regulated liver inflammation - related gene transcription. Collectively, these findings provide insight into involvement of CB1R in the pathogenesis of acute liver injury.
2020-12-22 | GSE148309 | GEO
Project description:Here, we found that microRNA-223 (miR-223) was highly elevated in hepatocytes after high fat diet (HFD) feeding in mice and in human nonalcoholic steatohepatitis (NASH) samples. Genetic deletion of the miR-223 induced a full spectrum of nonalcoholic fatty liver disease (NAFLD) in mice after long-term (up to one year) HFD feeding including NASH-related steatosis, inflammation, fibrosis and HCC. To better explore the mechanisms underlying the abnormalities observed in HFD-fed miR-223KO mice, we examined hepatic gene expression in 3-month-HFD-fed WT and miR-223KO mice by microarray analysis. Finally, we revealed that miR-223 plays a key role in controlling steatosis-to-NASH progression by inhibiting hepatic Cxcl10 and Taz expression.
2019-03-30 | GSE129080 | GEO
Project description:Post-translational acetylation of proteins at lysine side chains by the central metabolite acetyl-CoA, is a crucial regulator of proteostasis. Ethanol metabolism in the liver induces protein acetylation and disrupts hepatic substrate metabolism. While acetylation can influence gene transcription, enzyme activity, and stability of proteins, the role of ethanol-induced acetylation in hepatic metabolism is still unclear. We used a 2H2O-based metabolic labeling approach to investigate the impact of ethanol-induced acetylation on liver metabolism in a murine model of chronic ethanol-induced liver injury. Mice were fed an ethanol containing diet for 25 days; liver proteins and acetylation patterns were monitored during the final 21 days of 2H2O labeling. The proteome, acetylome, and targeted metabolic profiling were conducted to evaluate ethanol-induced alterations in hepatic metabolism. Ethanol consumption induced hepatic steatosis, inflammation, and oxidative stress. It led to reduced turnover of mitochondrial proteins and increased turnover of cytosolic stress response proteins and metabolic enzymes. Ethanol elevated acetylation levels of mitochondrial metabolic enzymes and nuclear histones, with no significant changes in the cytosol. Acetylation stabilized mitochondrial proteins but destabilized histones. Ethanol-induced reduced mitochondrial protein turnover, linked to increased acetylation, led to hepatic protein accumulation. Impaired proteasomal and lysosomal degradation contributed to alcohol-induced hepatic proteopathy. These changes were associated with altered levels of acyl-CoAs and acyl-carnitines, amino acids, and tricarboxylic acid (TCA) cycle intermediates, reflecting impaired fatty acid oxidation, nitrogen disposal and citric acid cycle activities. In conclusion, ethanol-induced alterations in acetylome dynamics could modify hepatic substrate metabolism and contribute to liver injury in alcohol-associated liver disease through acetylation-dependent epigenetic changes and the regulation of metabolic enzymes.
2025-08-04 | PXD055349 | Pride
Project description:Epidemiological studies have showed that vitamin D deficiency was correlated with increased risk of insulin resistance and type 2 diabetes. Although immune cells triggered chronic inflammation as a central link between obesity and insulin resistance, how vitamin D affects metabolic remodeling in immune cells to control inflammation and insulin resistance has not been well characterized. Here we defined a critical role of 1α,25(OH)2D3 in regulating glycolysis metabolism, protecting against inflammation and alleviating insulin resistance. Mechanistically, 1α,25(OH)2D3-VDR promote fructose-1,6-bisphosphatase (FBP1) expression to repress glycolysis in γδ T cells, thereby inhibiting Akt/p38 MAPK phosphorylation and reducing inflammatory cytokines production. Notably, therapeutic administration of 1α,25(OH)2D3 restrains inflammation in adipose-resident γδ T cells and ameliorates systemic insulin resistance in obesity mice. Collectively, these findings show that 1α,25(OH)2D3 has an important role in maintaining γδ T cells homeostasis via orchestrating metabolic programs, and is highly promising target for preventing obesity, inflammation and insulin resistance.
2025-09-20 | GSE213910 | GEO