Metabolic dysfunction-associated steatotic liver disease is associated with effects on cerebral perfusion and white matter integrity

Abstract

It is unclear whether early metabolic and inflammatory aberrations in the liver are associated with detrimental changes in brain structure and cognitive function. This cross-sectional study examines putative associations between metabolic dysfunction-associated steatotic liver disease (MASLD) and brain health in 36-55 year-old participants with obesity (n = 70) from the BARICO study (BAriatric surgery Rijnstate and Radboudumc neuroImaging and Cognition in Obesity). The participants underwent brain magnetic resonance imaging to study brain volumes and cortical thickness (3T MRI including T1-weighted magnetization-prepared rapid gradient-echo sequence), cerebral blood perfusion (arterial spin labeling) and white matter integrity (diffusion weighted imaging to assess mean-skeletonized mean diffusivity and fluid-attenuated inversion recovery to detect the presence of white matter hyperintensities (WMH)). The participants additionally performed neuropsychological tests to assess global cognition, working and episodic memory, verbal fluency and the ability to shift attention. Liver biopsies were collected and liver dysfunction was examined with histopathological, biochemical, and gene expression analyses. Linear regression analyses were performed between liver and brain parameters and the influence of body-mass index, diabetes and hypertension was explored. Early stages of liver disease were not associated with cognitive status but with cerebrovascular changes independently of age, sex, BMI, diabetes and hypertension: hepatic fibrosis development was associated with higher spatial coefficient of variation (sCoV) in the nucleus accumbens (NAcc), reflecting greater variations in cerebral perfusion and reduced vascular efficiency. Elevated hepatic levels of free cholesterol and cholesteryl esters were associated with increased WMH, indicating cerebral small vessel disease. RNA-seq and pathway analyses identified associations between sCoV in NAcc and WMH and the expression of hepatic genes involved in inflammation and cellular stress. Additionally, sCoV in NAcc correlated with plasma IL-6 levels suggesting that systemic-low grade inflammation may, at least partly, mediate this relationship. In conclusion, this study demonstrates that specific features of liver dysfunction (e.g. free cholesterol, onset of fibrosis) are associated with subtle cerebrovascular impairments, when changes in cognitive performance are not yet noticeable. These findings highlight the need for future research on therapeutic strategies that normalize metabolic-inflammatory aberrations in the liver to reduce the risk of cognitive decline.

Keywords: Brain health; MASLD; Metabolism; Systemic inflammation.

Graphical abstract

Fig. 1

Variation in liver steatosis and intrahepatic lipids between the participants. (A) Representative photomicrographs of mild, moderate, and severe liver steatosis in patients undergoing brain MRI. (B) Liver steatosis, (C) liver inflammation, (D) liver fibrosis and (E) liver lipids. Each dot represents one subject and the black line indicates the mean. Abbreviations: (DAG) diacylglycerols, (CE) cholesteryl esters, (FC) free cholesterol, (TG) triglycerides.

Fig. 2

Identified canonical pathways and upstream regulators using hepatic genes correlating with NAcc sCoV or WMH count. Illustrative picture depicting (A) low and high NAcc sCoV (average of n = 6 participants each), and (B) low and high WMH count (n = 1 representative participant each, for the complete 3D view see video S1). Hepatic genes of which the expression correlated respectively with NAcc sCoV or WMH count were used as input for pathway enrichment analysis. Significantly enriched canonical pathways in the liver (-log(p-value)≥2) for (C) NAcc sCoV and (D) WMH count. Top-25 liver upstream regulators enriched for (E) NAcc sCoV and (F) WMH count.

figs1