Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1242093 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32862158_1.fastq.gz | Fastqsanger.gz | |||
| SRR32862158_2.fastq.gz | Fastqsanger.gz | |||
| SRR32862159_1.fastq.gz | Fastqsanger.gz | |||
| SRR32862159_2.fastq.gz | Fastqsanger.gz | |||
| SRR32862160_1.fastq.gz | Fastqsanger.gz |
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Project description:The transcription factor Forkhead box protein O1 (FoxO1) is a well-established regulator of glucose and lipid metabolism, yet its role in metabolic dysfunction-associated steatohepatitis (MASH) pathogenesis remains debated. This study investigates hepatocyte-specific FoxO1 mechanisms driving hepatic inflammation in MASH. Using hepatocyte-specific FoxO1-knockout (KO) mice fed a methionine-choline-deficient diet and LPS-treated FoxO1-KO cells, we demonstrate FoxO1 depletion exacerbates hepatic inflammation, ballooning degeneration, and upregulates TNF-alpha, CXCL8, and CXCL2 in vivo and in vitro. Transcriptomics linked FoxO1 deficiency to enriched pro-inflammatory pathways and suppressed cysteine/methionine metabolism.
2025-07-30 | GSE293003 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) remains a significant health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption and pharmacological inhibition of SMPD3 alleviate MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. While healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses SIRT1, triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes MASH progression by enhancing caveolae-dependent lipid uptake in hepatocytes and extracellular vesicle secretion from steatotic hepatocytes to worsen inflammation and fibrosis. Thus, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid balance and holds great promise for developing novel MASH therapies.
2025-02-26 | GSE271336 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) remains a significant health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption and pharmacological inhibition of SMPD3 alleviate MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. While healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses SIRT1, triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes MASH progression by enhancing caveolae-dependent lipid uptake in hepatocytes and extracellular vesicle secretion from steatotic hepatocytes to worsen inflammation and fibrosis. Thus, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid balance and holds great promise for developing novel MASH therapies.
2025-02-26 | GSE271335 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) remains a significant health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption and pharmacological inhibition of SMPD3 alleviate MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. While healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses SIRT1, triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes MASH progression by enhancing caveolae-dependent lipid uptake in hepatocytes and extracellular vesicle secretion from steatotic hepatocytes to worsen inflammation and fibrosis. Thus, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid balance and holds great promise for developing novel MASH therapies.
2025-02-26 | GSE271333 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) remains a significant health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption and pharmacological inhibition of SMPD3 alleviate MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. While healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses SIRT1, triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes MASH progression by enhancing caveolae-dependent lipid uptake in hepatocytes and extracellular vesicle secretion from steatotic hepatocytes to worsen inflammation and fibrosis. Thus, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid balance and holds great promise for developing novel MASH therapies.
2025-02-26 | GSE286433 | GEO
Project description:Understanding mechanisms causing MAFLD (Metabolic Associated Fatty Liver Disease) and its progression to MASH (metabolic dysfunction-associated steatohepatitis) is clinically important and scientifically challenging. Hepatic insulin resistance is a common component in the progression of MAFLD in patients and experimental animals; however, hepatic steatosis caused by the HFD45% (high-fat diet) decreases during chronic hepatic IR generated by inactivation of Irs1/2 (LDKO), AKT1/2, or InsR 1-3—which is inconsistent with the expected relationship between IR and MAFLD in humans4. Here we found that complete hepatic insulin resistance promotes the fructose-enriched GAN diet-induced MAFLD, including acute inflammation and MASH in LDKO mice. Unexpectedly, fructose phosphorylation catalyzed by hepatic Khk (ketohexokinase) was not required as acute MAFLD progressed strongly in LDKOKhkL/L mice fed the GAN diet. FoxO1 activated during hepatic IR induces Fst (Follistatin) expression and secretion from the liver of LDKO mice. Inactivation of hepatic FoxO1 in LTKO mice (LDKO•FoxO1L/L) or Fst in LDKOFstKO mice prevented acute MAFLD during the GAN diet. Consistently, overexpression of hepatic Fst promoted GAN diet-induced MAFLD/MASH and hepatic carcinoma. Mechanistically, circulating Fst promoted adipose tissue IR and lipolysis, which can deliver FFA (free fatty acid) to the liver for esterification with excess Gro3P (glycerol 3-phosphate) generated by fructose metabolism, although hepatic DNL (de novo lipogenesis) decreased strongly in LDKO mice while. Since circulating FST correlates positively with both T2D and MAFLD in humans, our results suggests that hepatic FST induced by progressive hepatic IR might promote MAFLD/MASH during the consumption of sugar-sweetened food and beverages consumed frequently by people and animals with T2D.
2024-06-23 | GSE270246 | GEO
Project description:Our objective is to determine the role of myeloid FoxO1 in regulating hepatic lipid metabolism and its contribution to nonalcoholic steatohepatitis (NASH) in mice. We generated mice with conditional FoxO1 depletion in myeloid cells, using the FoxO1-LoxP/LysM-Cre system. We then fed myeloid cell-conditional FoxO1-knockout and wild-type male mice a NASH-inducing diet for 25 weeks. Then mice in both groups were euthanized and the liver tissues were procured for the preparation of total RNAs, which were subjected to RNA-seq assay. While myeloid FoxO1 was upregulated in animal models and human subjects with NASH, the underlying mechanism is poorly understood. We found that myeloid cell conditional FoxO1-knockout mice were protected from developing NASH, culminating in the reduction of hepatic inflammation, steatosis and fibrosis. Mechanistically, FoxO1 counteracts Stat6 to skew macrophage polarization from M2 toward M1 signatures to perpetuate hepatic inflammation in NASH. FoxO1 appears as a pivotal mediator of macrophage activation in response to overnutrition and a therapeutic target for ameliorating hepatic inflammation to stem the disease progression from benign steatosis to NASH.
2022-05-24 | GSE203227 | GEO
Project description:Hepatocyte caspase-8 is elevated in MASH and promotes fibrosis independently of apoptosis changes. To investigate how hepatocyte caspase-8 might drive liver fibrosis progression in MASH, we focused on activated hepatic stellate cells (HSCs), which are the primary source of collagen-producing myofibroblasts and central players in MASH fibrosis. To assess a potential link between hepatocyte caspase-8 and HSC activation, we used an ex vivo model where primary murine HSCs were cultured with conditioned media from siCasp8-treated or control primary hepatocytes. Supporting our hypothesis, HSC activation markers were reduced in HSCs exposed to conditioned media from Casp8-silenced AML12 hepatocytes compared to controls. To pinpoint caspase-8-dependent secretory proteins that could activate HSCs, we conducted LC-MS/MS on conditioned media from these cells, identifying secretory proteins reduced in Casp8-silenced AML12 hepatocytes.
2025-07-09 | PXD057540 | Pride
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease strongly associated with cardiometabolic risk factors. Semaglutide, a glucagon-like peptide-1 receptor agonist, improves liver histology in MASH, but the underlying signals and pathways driving semaglutide-induced MASH resolution are not well understood. We show that, in two preclinical MASH models, semaglutide improved histological markers of fibrosis and inflammation, and reduced hepatic expression of fibrosis- and inflammation-related gene pathways.
2025-04-25 | GSE294630 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) is an advanced form of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by accumulation of fats in liver, chronic inflammation, hepatocytic ballooning, and fibrosis. This study investigates role of endogenous Aryl hydrocarbon Receptor (AhR) agonist, cinnabarinic acid (CA) in protection against in vivo mouse model of MASH. To analyze the transcriptomic changes in response to CA treatment, male AhRfl/fl (AhR-floxed) mice were subjected to control diet (CD), high-fat high-fructose high-cholesterol diet (MASH diet, MD), and fed with MASH diet and treated with CA thrice a week for 20-week period. RNA sequencing revealed altered expression of multiple genes involved in fatty acid metabolism and inflammation in response to CA treatment. Gene set enrichment analysis indicated enrichment of AMPK among other kinases. Subsequent immunoblotting and immunofluorescence studies performed on CA-treated livers and primary hepatocytes confirmed activated AMPK signaling. Moreover, in a hepatocyte-specific AhR knockout mice livers (AhR-hKO, constructed by crossing AhRfl/fl with alb-Cre), CA failed to phosphorylate AMPK strongly indicating that CA-induced AMPK mediated protection against lipotoxicity in MASH is dependent on hepatic AhR signaling.
2025-07-23 | GSE277498 | GEO