Hörnblad, A. | bioRxiv Science

bioRxiv2024

AMPK-activator ATX-304 reduces oxidative stress and improves MASLD via metabolic switching

AbstractMetabolic dysfunction-Associated Steatotic Liver Disease (MASLD) is the most common chronic liver disease worldwide for which there are no approved treatments. Adenosine monophosphate-activated protein kinase (AMPK) is an interesting therapeutical target since it acts as a central regulator of cellular metabolism. Despite efforts to target the AMPK, no direct activators has yet been approved for treatment of this disease. This study investigates the effect of AMPK activator ATX-304 in a preclinical mouse model of progressive fatty liver disease. The data demonstrate that ATX-304 diminishes body fat mass, lowers blood cholesterol levels, mitigates liver steatosis, and ameliorates the development of liver fibrosis. The beneficial effects of ATX-304 treatment are accompanied by a shift in the liver metabolic program, including increased lipid oxidation, reduced lipid synthesis, as well as remodeling of cholesterol and lipid transport. We also observed variations in lipid distribution among liver lobes in response to ATX-304, and a shift in the zonal distribution of lipid droplets upon treatment. Taken together, our data suggest that ATX-304 holds promise as a potential treatment for Metabolically Associated Fatty Liver Disease (MAFLD), including in human patients.

molecular biology↗

bioRxiv2023

Diet-induced rewiring of the Wnt gene regulatory network connects aberrant splicing to fatty liver and liver cancer in DIAMOND mice

Background & AimsThis study aimed to provide a comprehensive understanding of the regulatory and transcriptional landscape in liver tumours from DIAMOND mice, a mouse model that mimics human hepatocellular carcinoma (HCC) in the context of metabolic associated fatty liver disease (MAFLD). MethodsRNA-sequencing and ChIP-sequencing were used to study the gene expression and regulatory changes in DIAMOND liver tumours. RNA in situ hybridisation splice variant analysis was used to study {beta}-catenin exon 3 exclusion in tumours at cellular resolution. Sequencing data on {beta}-catenin exon 3 splicing in DIAMOND tumours was compared to data from human patients and cell lines. ResultsThe study found an increase in Wnt/{beta}-catenin-signalling accompanied by rewiring of the Wnt/{beta}-catenin regulatory network in DIAMOND tumours. Changes include switching in the expression of the canonical TCF/LEF downstream effectors and associated chromatin remodelling. In addition, a large subset of DIAMOND tumours showed aberrant splicing of {beta}-catenin, which generate an mRNA isoform that encodes an oncogenic protein. Similar splicing events were found in a fraction of human HCC and hepatoblastoma samples. ConclusionsThis study provides evidence that western diet induces aberrant genome-wide splicing in DIAMOND livers, and in particular of the {beta}-catenin gene in a subset of DIAMOND liver tumours. This mechanism is distinct from previously reported activation of {beta}-catenin in HCC and mouse models, since it is independent on mutations in the locus. Our data suggests that metabolic input modulates gene regulatory network responses to active Wnt-signalling, which will be an important consideration also in the human setting. Lay summarySequencing data generated in this study highlights the effect of diet in modulating oncogenic gene expression and underscores an alternative mutation-independent mechanism leading to constitutive activation of {beta}-catenin, a well-known driver of liver cancer.

cancer biology↗