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Partial MCT1 invalidation protects against diet-induced non-alcoholic fatty liver disease and the associated brain dysfunction

Hadjihambi, Anna; Konstantinou, Christos; Klohs, Jan; Monsorno, Katia; Le Guennec, Adrien; Donnelly, Chris; Cox, Jane; ... Pellerin, Luc; + view all (2022) Partial MCT1 invalidation protects against diet-induced non-alcoholic fatty liver disease and the associated brain dysfunction. Journal of Hepatology 10.1016/j.jhep.2022.08.008. (In press). Green open access

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Abstract

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has been associated with mild cerebral dysfunction and cognitive decline, although the exact pathophysiological mechanism remains ambiguous. Using a diet-induced model of NAFLD and monocarboxylate transporter-1 haploinsufficient mice (MCT1+/-), which resist high fat diet (HFD)-induced hepatic steatosis, we investigated the hypothesis that NAFLD leads to an encephalopathy by altering cognition, behaviour, and cerebral physiology. We also proposed that global MCT1 downregulation offers cerebral protection. METHODS: Behavioural tests were performed in mice following 16-weeks of control diet (NC) or HFD with high fructose/glucose in water (HFDHF/HG). Tissue oxygenation, cerebrovascular reactivity, and cerebral blood volume (CBV) were monitored under anaesthesia by multispectral optoacoustic tomography and optical fluorescence. Cortical mitochondrial oxygen consumption and respiratory capacities were measured using ex vivo high-resolution respirometry. Microglial and astrocytic changes were evaluated by immunofluorescence and 3D reconstructions. Body composition was assessed by EchoMRI and liver steatosis was confirmed by histology. RESULTS: NAFLD concomitant with obesity is associated with anxiety and depression related behaviour. Low-grade brain tissue hypoxia was observed, likely attributed to the low-grade brain inflammation, and decreased CBV, accompanied by microglial and astrocytic morphological and metabolic alterations (higher oxygen consumption), suggesting the early stages of an obesogenic diet-induced encephalopathy. Haploinsufficient MCT1 mice, despite fat accumulation in adipose tissue, were protected from NAFLD and associated cerebral alterations. CONCLUSIONS: This study provides evidence of compromised brain health in obesity and NAFLD, emphasising the importance of the liver-brain axis. The observation of the protective effect of MCT1 haploinsufficiency points to this protein as a novel therapeutic target for preventing and/or treating NAFLD and the associated brain dysfunction. LAY SUMMARY: Fat accumulation in the liver following consumption of a diet rich in fat and sugar is accompanied by signs of brain dysfunction. A partial reduction in the global expression of MCT1, a transporter of energy substrates, is sufficient to prevent both the fatty liver and brain alterations in mice. These results highlight the importance of protecting the liver to maintain brain health.

Type: Article
Title: Partial MCT1 invalidation protects against diet-induced non-alcoholic fatty liver disease and the associated brain dysfunction
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jhep.2022.08.008
Publisher version: https://doi.org/10.1016/j.jhep.2022.08.008
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: Anxiety, astrocytes, brain inflammation, cerebral oxygenation, cerebral protection, depression, hepatic encephalopathy, metabolism, microglia, monocarboxylate transporter 1, non-alcoholic fatty liver disease
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10154247
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