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HSD17B13 liquid-liquid phase separation activates autocrine platelet-activating factor signaling in NASH

ABSTRACT: HSD17B13 liquid-liquid phase separation activates autocrine platelet-activating factor signaling in NASH

PROVIDER: PRJNA997902 | ENA |

REPOSITORIES: ENA

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HSD17B13 liquid-liquid phase separation activates autocrine platelet-activating factor signaling in NASH

Project description:Loss-of-function variants in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) are associated with decreased inflammation in human chronic liver disease. The underlying mechanism by which HSD17B13 promotes liver inflammation remains largely elusive. Here we find that HSD17B13 undergoes liquid-liquid phase separation (LLPS) around lipid droplets (LDs) in the liver of NASH patients. Dimerization of HSD17B13 drives LLPS formation and regulates its enzyme activity. HSD17B13 LLPS promotes leukocyte adhesion and fibrinogen expression in hepatocytes via activating autocrine platelet activating factor (PAF) signaling. Importantly, adeno-associated viral (AAV)-mediated xeno-expression of human HSD17B13 promotes liver inflammation in Hsd17b13-/- mice induced by high fat diet/carbon tetrachloride treatment. In conclusion, HSD17B13 LLPS triggers liver inflammation via promoting PAF-mediated leukocyte adhesion. Targeting HSD17B13 phase transition would be a promising approach to treat liver inflammation in chronic liver disease.

2024-12-19 | GSE238060 | GEO

Bacterial Heterochromatin Formation Through Liquid-Liquid Phase Separation

Project description:Bacterial Heterochromatin Formation Through Liquid-Liquid Phase Separation

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Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation [ChIP-seq]

Project description:CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia (AML) progress. Clarifying its functional implementation mechanism is of great significance for its further clinical application. Here, we show that C/EBPα regulates AML cell differentiation through liquid-liquid phase separation (LLPS), which can be disrupted by C/EBPα-p30. Considering that C/EBPα-p30 inhibits the functions of C/EBPα through the LZ region, a small peptide TAT-LZ that could instantaneously interfere with the homodimerization of C/EBPα-p42 was constructed, and dynamic inhibition of C/EBPα phase separation was observed, demonstrating the importance of C/EBPα-p42 homodimers for its LLPS. Mechanistically, homodimerization of C/EBPα-p42 mediated its phosphorylation at the novel phosphorylation site S16, which promoted LLPS and subsequent AML cell differentiation. Finally, decreasing the endogenous C/EBPα-p30/C/EBPα-p42 ratio rescued the phase separation of C/EBPα in AML cells, which provided a new insight for the treatment of the AML.

2023-11-08 | GSE243423 | GEO

Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation [RNA-seq]

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A mechanically regulated liquid-liquid phase separation of the transcriptional regulator Tono instructs muscle development

Project description:A mechanically regulated liquid-liquid phase separation of the transcriptional regulator Tono instructs muscle development

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NASH

Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that can progress from simple fatty liver disease to non-alcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism and excretion (ADME) of drugs. Differential gene expression between three clinically defined pathological groups; normal, steatosis and NASH was analyzed. The samples were diagnosed as normal, steatotic, NASH with fatty liver (NASH fatty) and NASH without fatty liver (NASH NF). Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChipM-. Human 1.0ST arrays

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Platelet-derived thrombospondin 1 promotes immune cell liver infiltration and exacerbates diet-induced steatohepatitis.

Project description:Background and Aims: Recent studies have implicated platelets, particularly α-granules, in the development of steatohepatitis (NASH). However, the specific mechanisms involved have yet to be determined. Notably, thrombospondin 1 (TSP1) is a major component of the platelet α-granules released during platelet activation. The role of platelet-derived TSP1 in NASH remains unknown and was investigated in this study. Approach and Results: Platelet-specific TSP1 knockout mice (TSP1Δpf4) and their wild type littermates (TSP1F/F) were used. NASH was induced by feeding the mice a diet enriched in fat, sucrose, fructose, and cholesterol (AMLN diet). A human liver NASH organoid model was also employed. Although TSP1 deletion in platelets did not affect diet-induced steatosis, TSP1Δpf4 mice exhibited attenuated NASH and liver fibrosis, accompanied by improvements in plasma glucose and lipid homeostasis. Moreover, intrahepatic platelet accumulation, activation and chemokine production were reduced in TSP1Δpf4 mice, which was correlated with decreased immune cell infiltration into the liver. Consequently, this leads to diminished pro-inflammatory signaling in the liver and mitigated the progression of NAFLD. Moreover, in vitro data revealed that co-culturing TSP1-deficient platelets in a human liver NASH organoid model attenuated hepatic stellate cell activation and NASH progression. Additionally, TSP1 deficient platelets play a role in regulating brown fat endocrine function, specifically affecting Nrg4 production. Crosstalk between brown fat and the liver may also influence NAFLD progression. Conclusions: These data suggest that platelet α-granule-derived TSP1 is a significant contributor to diet-induced NASH and fibrosis, and may serve as a new therapeutic target for this severe liver disease.

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Study on the effect and mechanism of c-Maf liquid-liquid separation in promoting MM cellular proliferation and drug resistance through Mtbp/c-Myc axis

Project description:Previous experiments have demonstrated that c-Maf can undergo liquid-liquid phase separation (LLPS) in MM. In order to search for the downstream target genes of c-Maf based on its LLPS regulation, we successfully constructed three kinds of cells with EV, c-Maf and already c-Maf-IDR mutation, and simultaneously subjected the three kinds of cells to ChIP sequencing (selecting the FLAG-tagged antibody), and then analysed them for the differential genes, thus screening the downstream targets of c-Maf based on its LLPS regulation.

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