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Multiomics analysis of concurrent MASH and atherosclerosis in male and female mice

ABSTRACT: Metabolic dysfunction-associated steatohepatitis (MASH) has reached epidemic proportions with limited therapies available. Surprisingly, the leading cause of death in these patients is atherosclerotic cardiovascular disease. No pharmacological therapy exists to treat MASH and atherosclerosis simultaneously, which is attributed to the lack of translational mouse models, particularly in females. Herein, we have utilized both male and female atheroprone mice, combined with different high-fat diets containing physiologically relevant cholesterol levels, to model concurrent MASH-atherosclerosis. Upon phenotypic characterization using standard histopathology, immunohistochemistry, and biochemical assays on liver, cardiovascular, and plasma samples, we report the first female MASH-atherosclerosis model. Furthermore, we conducted a multi-omics exploration of metabolomic, lipidomic, and transcriptomic profiles altered within these groups, and found metabolic and genomic signatures comparable to the human disease. These models will facilitate future cardiometabolic research to unravel the molecular and metabolic underpinnings at the intersection of MASH and atherosclerosis, which must be pharmacologically targeted.

ORGANISM(S): Mus musculus

PROVIDER: GSE280888 | GEO | 2025/12/05

REPOSITORIES: GEO

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Project description:Background: Immune cell-driven inflammation is a key mediator of metabolic dysfunction-associated steatohepatitis (MASH) progression. We have previously demonstrated that pharmacological sphingosine 1-phosphate (S1P) receptor modulation ameliorates MASH and is associated with attenuated accumulation of intrahepatic macrophage and T cell subsets. Although S1P receptors are expressed on several immune cell types, given the prominent role of monocyte-derived recruited macrophages in the sterile inflammation of MASH, we hypothesized that deletion of S1P receptor 1 (S1P1) on myeloid cells may ameliorate MASH by reducing the accumulation of proinflammatory monocyte-derived macrophages into the liver. Methods: The LyzMCre approach was used to generate myeloid cell-specific knockout mice, termed S1pr1MKO. Littermate S1pr1loxp/loxp mice were used as wild-type (WT) controls. MASH was established by feeding mice a high-fat, fructose, and -cholesterol (FFC) diet for 24 weeks which leads to the development of steatohepatitis and MASH-defining cardiometabolic risk factors. Liver injury and inflammation were determined by histological and gene expression analyses. Intrahepatic leukocyte populations were analyzed by mass cytometry and immunohistochemistry. Results: Histological examination demonstrated a reduction in liver inflammatory infiltrates and fibrosis in FFC-fed S1pr1MKO compared to WT. There was a corresponding reduction in alanine aminotransferase, a sensitive marker for liver injury. As determined by mass cytometry, a significant decrease in recruited macrophages was noted in the livers of FFC-fed S1pr1MKO mice compared to WT. Gene ontology pathway analysis revealed a significant suppression of the peroxisome proliferator-activated receptor gamma (PPARγ) and mitogen activated protein kinase (MAPK) pathways in S1pr1MKO consistent with attenuated MASH in mice. Conclusion: Deletion of S1P1 in myeloid cells is sufficient to attenuate intrahepatic accumulation of monocyte-derived macrophages and ameliorate murine MASH.

Project description:Fibroblast growth factor 21 (FGF21) is a promising target for treatment of obesity-associated diseases including metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis. We evaluated the effects of the bispecific anti-FGF21-β klotho (KLB) agonist antibody bFKB1 in a preclinical model of MASH and atherosclerosis. Low-density lipoprotein receptor knockout (Ldlr−/−).Leiden mice received a high-fat diet for 20 weeks, followed by treatment with an isotype control antibody or bFKB1 for 12 weeks. Effects on plasma risk markers and (histo)pathology of liver, adipose tissue, and heart were evaluated alongside hepatic transcriptomics analysis. bFKB1 lowered body weight (−21%) and adipose tissue mass (−22%) without reducing food intake. The treatment also improved plasma insulin (−80%), cholesterol (−48%), triglycerides (−76%), alanine transaminase (ALT: −79%), and liver weight (−43%). Hepatic steatosis and inflammation were strongly reduced (macrovesicular steatosis −34%; microvesicular steatosis −100%; inflammation −74%) and while the total amount of fibrosis was not affected, bFKB1 did decrease new collagen formation (−49%). Correspondingly, hepatic transcriptomics and pathway analysis revealed the mechanistic background underlying these histological improvements, demonstrating broad inactivation of inflammatory and profibrotic transcriptional programs by bFKB1. In epididymal white adipose tissue, bFKB1 reduced adipocyte size (−16%) and inflammation (−52%) and induced browning, signified by increased uncoupling protein-1 (UCP1) protein expression (8.5-fold increase). In the vasculature, bFKB1 had anti-atherogenic effects, lowering total atherosclerotic lesion area (−38%). bFKB1 has strong beneficial metabolic effects associated with a reduction in hepatic steatosis, inflammation, and atherosclerosis. Analysis of new collagen formation and profibrotic transcriptional programs indicate that bFKB1 treatment may have antifibrotic potential in a longer treatment duration as well.

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Multiomics analysis of concurrent MASH and atherosclerosis in male and female mice

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