P: 13 The Role of Monocarboxylate Transporter-1 and Lactate Metabolism on the Development of Cognitive Deficits During NAFLD

Abstract

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a major complication of obesity. Certain observations regarding NAFLD induced neuropsychiatric and neurochemical alterations have been reported but mechanisms are unknown (Seo, 2016). In this context, monocarboxylate transporter-1 (MCT1) haploinsufficient mice, which resist high fat diet (HFD) induced hepatic steatosis represent an interesting model (Carneiro, 2017). Using a mouse model of NAFLD (HFD+high fructose/high glucose in water [HF/HG]) we investigated the development of cognitive deficits and state of cerebral oxygenation and cerebrovascular reactivity. METHODS: Behavioural tests (open field/novel object recognition/forced swimming test [FST]) were performed in mice fed control diet (NC; WT + NC, MCT1 ± +NC) or HFD HF/HG (WT + HFD HF/HG, MCT1 ± +HFD HF/HG) for 16 weeks. Baseline PO2 (in somatosensory cortex) and in response to systemic hypercapnia (10% CO2) was monitored under anaesthesia by a fluorescence method (Oxylite™). Microelectrode biosensors were used for measurements of lactate release by cortical slices. EchoMRI was performed to assess lean/fat mass. RESULTS: Increased fat mass (not lean mass) was observed in WT and MCT1± mice (50% less) on HFD HF/HG compared to NC controls. Liver mass was only significantly higher in WT + HFD HF/HG mice compared to NC controls. Behavioural tests did not reveal any significant differences between groups except for FST, which indicated a depression-related behaviour in the WT + HFD HF/HG group compared to their controls. This was not observed with MCT1 ±+HFD HF/HG mice. WT+HFD HF/HG mice had a lower cerebral PO2 baseline and PO2 response induced by systemic hypercapnia compared to NC controls (although significance was not reached), while the MCT1± groups remained unchanged. Tonic lactate release was unaltered between all groups although the MCT1 ± +HFD HF/HG group indicated a trend of decreased lactate tone. CONCLUSIONS: Our results suggest that NAFLD is associated with a depression-related behaviour and a trend of decreased cerebral PO2 baseline. MCT1 haploinsufficient mice were resistant to the reported phenotypes, suggesting a link between liver metabolism and neuropathophysiological alterations in NAFLD.