Cognitive dysfunction in early experimental metabolic dysfunction-associated steatotic liver disease is associated with systemic inflammation and neuroinflammation

BACKGROUND & AIMS: Cognitive dysfunction is an increasingly recognised manifestation of metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanistic link remains unclear. The aim of this study was to investigate the hypothesis that experimental MASLD leads to cognitive dysfunction via systemic inflammation and neuroinflammation. METHODS: Twenty male Sprague Dawley rats were randomised to a high-fat high-cholesterol (HFHC) diet to induce MASLD, or a standard diet (n = 10/group), for 16 weeks. Assessments included: MASLD severity (histology), neurobehaviour, inflammation (liver, plasma and cerebrospinal fluid), brain microglia and astrocyte activation, and synaptic density. RESULTS: The HFHC diet induced MASLD with extensive steatosis and lobular inflammation without fibrosis. Several plasma cytokines were elevated (CXCL1, IL-6, IL-17, MIP-1α, MCP-1, IL-10; all p <0.05) and correlated with increases in hepatic chemokine gene expression. Cerebrospinal fluid concentrations of CXCL1 were elevated ( p = 0.04). In the prefrontal brain cortex, we observed a 19% increase in microglial activation confirmed by Iba1 immunohistochemistry ( p = 0.03) and 3H-PK11195 autoradiography ( p <0.01). In parallel, synaptic density was reduced to 92%, assessed by 3H-UCB-J autoradiography ( p <0.01). MASLD animals exhibited impaired memory to previously encountered objects in the novel object recognition test ( p = 0.047) and showed depression-like behaviour evidenced by increased immobility time ( p <0.01) and reduced swimming time ( p = 0.03) in the forced swim test. CONCLUSIONS: Experimental non-fibrotic MASLD, as a model to reflect the early stage of human disease, results in cognitive impairment and depression-like behaviour. This is associated with an inflammatory phenotype not only in the liver but also in the plasma and brain, which together with diminished synaptic density, provides a pathophysiological link between liver disease and cognitive dysfunction in MASLD. IMPACT AND ...