Increasing BMI is associated with reduced expression of P-glycoprotein (ABCB1 gene) in the human brain with a stronger association in African Americans than Caucasians

J Vendelbo,J K Lauridsen,T M Hyde,J Rungby,R H Olesen,J E Kleinman,A Larsen

doi:10.1038/tpj.2016.74

J Vendelbo, J K Lauridsen + Show 5 more

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https://doi.org/10.1038/tpj.2016.74

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Abstract

The efflux pump, p-glycoprotein, controls bioavailability and excretion of pharmaceutical compounds. In the blood–brain barrier, p-glycoprotein regulates the delivery of pharmaceutical substances to the brain, influencing efficacy and side effects for some drugs notably antipsychotics. Common side effects to antipsychotics include obesity and metabolic disease. Polymorphisms in the ABCB1 gene coding for p-glycoprotein are associated with more severe side effects to neuro-pharmaceuticals as well as weight gain, indicating a potential link between p-glycoprotein function and metabolic regulation. Using microarray data analysis from 145 neurologically sound adults, this study investigated the association between body mass index (BMI) and ABCB1 expression in the frontal cortex. Increasing BMI values were associated with a statistically significantly reduced expression of ABCB1. Investigation of DNA methylation patterns in a subgroup of 52 individuals found that the methylation/expression ratios of ABCB1 were unaffected by increasing BMI values. Interestingly, the effect of BMI on ABCB1 expression appeared stronger in African Americans than in Caucasians.

Highlights

The human brain is a closed and highly regulated microenvironment
P-gp gene expression is reduced with increasing body mass index (BMI)—indications of a stronger effect in African Americans
The association between P-gp expression and BMI values was stronger in African Americans when looking separately at African Americans (P = 0.0055) and Caucasians (P = 0.2881)

Summary

Introduction

The human brain is a closed and highly regulated microenvironment. Intracerebral homeostasis is maintained by the blood–brain barrier (BBB), that is, endothelial cells in the tunica intima of the small blood vessels kept together by tight junctions supported by a underlying layer of astrocytic foot processes.[1]. Substrates transported by P-gp include pharmacological agents and toxins[5] as well as certain endogenous substances including lipids and hormones requiring tight regulation.[6]

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