Cardiac remodelling in a mouse model of progressive metabolic dysfunction-associated steatotic liver disease

Background The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), and its progressive subtype, metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, establishes MASLD as a major cardiometabolic disorder. Growing evidence has strongly documented a complex, bidirectional crosstalk between the liver and heart as a central driver of cardiometabolic disease, including hypertension and atherogenic dyslipidaemia. Human and preclinical studies recently indicated that, beyond endothelial dysfunction and atherosclerosis, MASLD can be associated with adverse cardiac remodelling, including cardiac hypertrophy. Aims In this study, we aimed to evaluate the pattern of pathological cardiac remodelling in a mouse model of early-established progressive MASLD to investigate the relationship between liver and cardiac tissue damage. Methods A MASLD mouse model was established using streptozotocin combined with a high-fat (SHF) diet and compared with standard chow-fed controls (CTRL). Mice from both groups were sacrificed at 8, 16, and 20 weeks old to assess disease progression. Biochemical and metabolic parameters were measured by colorimetric assays, while hepatic and cardiac tissue damage were evaluated on FFPE sections by haematoxylin/eosin and Masson's trichrome staining. Gene expression analysis was performed by qRT-PCR to assess alterations in hepatic lipid metabolism and fibrogenesis and to identify markers of cardiac remodelling. Results Anthropometric and biochemical analyses revealed a progressive disease phenotype in SHF mice, characterised by increased body and liver weights, elevated metabolic parameters and elevated liver enzymes compared with CTRL. Histological staining showed a progressive increase in steatosis and fibrosis across all SHF groups compared with their respective CTRL groups. Interestingly, the progressive liver damage was parallel to cellular and structural changes occurring in cardiac tissue, such as signs of hypertrophy with irregular vacuolization, evidence of ectopic lipid accumulation, extensive disorganisation and an increase in collagen deposition. These findings were confirmed by gene expression data, including upregulation of the Collagen type 1 (Col1a1) and 3 (Col3a1) and Fatty acid synthase (Fasn) mRNA levels in both hepatic and cardiac tissues of SHF mice. The hypertrophic remodelling was confirmed by increased expression of natriuretic peptide A (Nppa), B (Nppb), and beta-myosin heavy chain (Myh7) and decreased expression of alpha-myosin heavy chain (Myh6). Conclusions Overall, our preliminary data suggest that hepatometabolic dysfunction during MASLD progression is associated with cardiac hypertrophy, a fibrotic phenotype and altered lipid metabolism, supporting lipotoxicity as a potential driver of cardiomyocyte remodelling that warrants further exploration to elucidate the causal connection between dual organ damage.