Aberrant basement membrane production by hepatic stellate cells in MASLD is attenuated by the bile acid analog INT-767
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PROVIDER: PRJNA1153020 | ENA |
REPOSITORIES: ENA
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Project description:Background: The farnesoid X receptor (FXR) is a leading therapeutic target for MASH-related fibrosis. INT-767, a potent FXR agonist, has shown promise in preclinical models. We aimed to define the mechanisms of INT-767 activity in experimental MASH and dissect cellular and molecular targets of FXR agonism in human disease. Methods: Leptin-deficient ob/ob mice were fed a MASH-inducing diet for 15 weeks prior to study start. After baseline liver biopsy and stratification, mice were allocated to INT-767 (10 mg/kg/day) or vehicle treatment for 8 weeks, either alongside ongoing MASH diet (progression) or following conversion to normal chow (reversal). Effects on extracellular matrix remodelling were analyzed histologically and by RNA-sequencing. Serum fibrosis biomarkers were measured longitudinally. Human liver samples were investigated using bulk and single-cell RNA-sequencing, histology, and cell culture assays. Results: INT-767 treatment was antifibrotic during MASH progression but not reversal, attenuating accumulation of type I collagen and basement membrane proteins (type IV collagen, laminin). Circulating levels of PRO-C4, a type IV collagen formation marker, were reduced by INT-767 treatment and correlated with fibrosis. Expression of basement membrane constituents also correlated with fibrosis severity and adverse clinical outcomes in human MASH. Single-cell RNA-sequencing analysis of mouse and human livers, and immunofluorescence staining colocalized FXR and basement membrane expression to myofibroblasts within the fibrotic niche. Treatment of culture-activated primary human hepatic stellate cells with INT-767 decreased expression of basement membrane components. Conclusion: These findings highlight the importance of basement membrane remodelling in MASH pathobiology and as a source of circulating biomarkers. Basement membrane deposition by activated hepatic stellate cells is abrogated by INT-767 treatment and measurement of basement membrane molecules should be included when determining the therapeutic efficacy of FXR agonists.
2025-08-19 | GSE275813 | GEO
Project description:This study aimed to establish and characterize an in vitro model of human intestinal organoids isolated from duodenal samples of patients with non-fibrotic MASLD and those with MASLD-cirrhosis. Whole transcriptome analysis and the energetic and redox status of the organoids were assessed to characterize intestinal functional impairment in the context of MASLD. We used microarrays to detail the whole transcriptome dysregulation underlying intestinal dysfunction in organoids isolated from chirrotic versus non-fibrotic MASLD patients.
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Project description:HBV-KMT2B integrated human induced pluripotent stem cell-derived hepatic progenitor cells (KMT2B-Int HPCs) vs heterozygous mutated KMT2B human induced pluripotent stem cell-derived hepatic progenitor cells (KMT2B-HT HPCs) vs original human induced pluripotent stem cell-derived hepatic progenitor cells (KMT2B-WT HPCs) Transcriptional profiling of all KMT2B-WT, HT, and Int HPCs. KMT2B-HT and Int iPSCs were generated by gene editing using CRISPR/Cas9 and Cre recombinase technologies. iPSCs were differentiated into a hepatic lineage. On Day14 of hepatic differentiation, CD13 high and C133 high hepatic cells were sorted by fluorescence-activated cell sorter (FACS) on feeder mouse embryonic fibroblasts (MEFs). HPCs forms colony on MEFs and were stably cultured with maintaining their hepatic phenotype.
2025-01-01 | GSE217993 | 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:Allantoin promotes MASLD progression
| PRJNA1194129 | ENA
Project description:Pharmacological treatments for non-alcoholic steatohepatitis (NASH) are still unsatisfactory. Fibrosis is the most significant predictor of mortality and many anti-fibrotic agents are under evaluation. Herein, we assessed in vitro the effects of the FXR agonist obeticholic acid (OCA) and the dual FXR/TGR5 agonist INT-767 in a well-established co-culture NASH model. Co-cultures of human hepatoma and hepatic stellate (HSCs) cells were exposed to free fatty acids (FFAs) alone or in combination with OCA or INT-767. mRNA expression of HSCs activation markers and FXR engagement were evaluated at 24, 96 and 144 hours. Collagen deposition and metalloproteinase 2 and 9 (MMP2-9) activity were compared to tropifexor and selonsertib. FFAs induced collagen deposition and MMP2-9 activity reduction. Co-treatment with OCA or INT-767 did not affect ACTA2 and COL1A1 expression, but significantly reduced FXR and induced SHP expression, as expected. OCA induced a dose-dependent reduction of collagen and induced MMP2-9 activity. Similarly, INT-767 induced collagen reduction at 96 h and a slight increase in MMP2-9. Tropifexor and Selonsertib were also effective in collagen reduction but showed no modulation of MMP2-9. All tested compounds reduced collagen deposition. OCA exerted a more potent and long-lasting effect, mainly related to modulation of collagen turn-over and MMP2-9 activity.
| S-EPMC6997404 | biostudies-literature
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Project description:High-fat diet (HFD) is a risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), yet the molecular pathways that connect dietary fats to liver dysfunction remain unclear. Hepatocyte-specific RKIP depletion in male mice exacerbates ER stress, resulting in lipid droplets accumulation and MASLD progression.
2025-09-03 | GSE300123 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by imbalance of lipid metabolism and autoimmune inflammation. The relationship between Hypoxia-inducible Factor 2α (HIF-2α) and the progression of MASLD has been well-documented. However, the mechanistic linkage between HIF-2α and steatohepatitis progression remains largely elusive. Here, hepatocyte-specific HIF-2α knockout mice were used to identify underlying pathophysiological relevance in MASLD. Through multiple gain- and loss-of-function experiments in primary hepatocytes and established human hepatocyte cell lines to investigate the molecular mechanism of HIF-2α in MASLD progression. Compared to their wild-type littermates, hepatocyte-specific HIF-2α knockout mice exhibited a substantial reduction in hepatic steatosis and inflammatory pathway induced by high fat diet (HFD). Furthermore, the HIF-2ɑ deficiency in primary hepatocytes and both L02 and MIHA cell lines markedly inhibited the lipid accumulation, inflammation and endoplasmic reticulum stress in vitro under FFAs challenge. Mechanistically, HIF-2 directly bound to the promoter region of protein kinase RNA-like ER kinase (PERK), leading to the activation of the activating transcription Factor 4 (ATF4) signaling under metabolic stress, thereby aggravating lipogenesis while inhibiting lipid oxidation in hepatocytes.These data indicate that HIF-2α acts as a contributing factor to MASLD progression via ATF4 signaling.
2025-12-10 | GSE267155 | GEO