Visitors Talk: Anna Hadjihambi, King’s College London

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic multisystem disease that affects ~30% of the general population and >80% of obese individuals. It is often accompanied by cardiovascular disease, diabetes, and cancer, contributing to a global health crisis of multimorbidity. Whilst hepatic encephalopathy is strongly associated with advanced liver disease, recent evidence suggests that neurocognitive impairment and accelerated brain ageing also occur in earlier stages of MASLD. However, the mechanisms underlying the associated cerebral alterations, or whether they can be reversed following disease resolution, are largely unknown.

In this talk, I will present preliminary data from male C57BL/6NTac mice fed a control diet (CD) or a high-fat, high-cholesterol diet (HFHC) for 26 weeks to induce MASLD. Half of the mice in each group were then switched to a low-fat diet (LFD) until 18 months of age to evaluate the additional impact of ageing, as well as the potential of this dietary intervention as a neuroprotective approach. However, liver histology indicated that the LFD did not achieve liver disease reversal when accompanied by ageing. Both HFHC and aged HFHC-LFD mice exhibited anxiety-like behaviour, while aged CD-LFD and HFHC-LFD mice showed memory impairment. HFHC, aged HFHC-LFD, and CD-LFD mice had lower partial pressure of oxygen and reduced brain tissue oxygen saturation at baseline, monitored under anaesthesia by a fluorescence method and optoacoustic tomography, respectively. However, cerebrovascular reactivity in response to systemic hypercapnia (10% CO₂) was maintained. Decreased cortical vascular density was observed in HFHC and aged HFHC-LFD mice, while vascular diameter was reduced in all groups compared to CD. HFHC and aged HFHC-LFD mice had increased cortical microglial density, coverage, and volume, indicating reactivity.

These data suggest that reduced brain tissue oxygenation and increased inflammation are potential contributors to MASLD-induced brain dysfunction. As the LFD did not reverse MASLD or the associated brain alterations in ageing mice, alternative dietary interventions that achieve liver disease resolution, as well as mechanisms acting on the liver–brain axis (including liver disease–induced autonomic dysfunction), are currently being investigated. This work will increase our understanding of the long-term effects that may persist in the brain even after liver disease resolution, as well as the impact of MASLD on the natural ageing process.