Cholesterol metabolism in neurons and astrocytes

Abstract

Cells in the mammalian body must accurately maintain their content of cholesterol, which is an essential membrane component and precursor for vital signalling molecules. Outside the brain, cholesterol homeostasis is guaranteed by a lipoprotein shuttle between the liver, intestine and other organs via the blood circulation. Cells inside the brain are cut off from this circuit by the blood–brain barrier and must regulate their cholesterol content in a different manner. Here, we review how this is accomplished by neurons and astrocytes, two cell types of the central nervous system, whose cooperation is essential for normal brain development and function. The key observation is a remarkable cell-specific distribution of proteins that mediate different steps of cholesterol metabolism. This form of metabolic compartmentalization identifies astrocytes as net producers of cholesterol and neurons as consumers with unique means to prevent cholesterol overload. The idea that cholesterol turnover in neurons depends on close cooperation with astrocytes raises new questions that need to be addressed by new experimental approaches to monitor and manipulate cholesterol homeostasis in a cell-specific manner. We conclude that an understanding of cholesterol metabolism in the brain and its role in disease requires a close look at individual cell types.

Introduction

Cholesterol is an indispensible component of biological membranes and precursor to numerous signalling molecules including steroid hormones. Its provision and disposal in all organs of the mammalian body – except for the brain – relies on dietary uptake by the intestine, on de novo synthesis in every organ, and on lipoprotein-mediated transport via the blood circulation. Cells in the brain are cut off from this elaborate system by the blood–brain barrier, which prevents lipoprotein exchange [1], [2]. Therefore, cells in the brain have implemented their specific way to handle cholesterol turnover. Here, we summarize current knowledge of cholesterol metabolism in the central nervous system (CNS) with a focus on two cell types, namely neurons and astrocytes (Fig. 1). Their cooperation is essential for normal brain function, and a disturbance of their interactions can provoke pathologic changes. Complementary overviews focus on cholesterol metabolism in the nervous system [3], [4], [5], [6], [7], [8] and possible links to brain injury and diseases [4], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18].