Cholesterol 24-Hydroxylation by CYP46A1: Benefits of Modulation for Brain Diseases

Abstract

Cholesterol 24-hydroxylation is the major mechanism for cholesterol removal from the brain and the reaction catalyzed by cytochrome P450 46A1 (CYP46A1), a CNS-specific enzyme. This review describes CYP46A1 in the context of cholesterol homeostasis in the brain and summarizes available experimental data on CYP46A1 association with different neurologic diseases, including the mechanisms by which changes in the CYP46A1 activity in the brain could be beneficial for these diseases. The modulation of CYP46A1 activity by genetic and pharmacologic means is also presented along with a brief synopsis of the two clinical trials that evaluate CYP46A1 as a therapeutic target for Alzheimer's disease as well as Dravet and Lennox-Gastaut syndromes.

Keywords: 24-Hydroxycholesterol; CYP46A1; Cholesterol; Cholesterol turnover; Efavirenz; Neurodegeneration.

Fig. 1

Major pathways of cholesterol homeostasis in adult brain. Arrow thickness indicates the relative quantitative significance of the pathway in humans. Cholesterol (shown as a ball model in orange, the hydroxyl group is in red) is synthesized from acetyl-CoA in both neurons and astrocytes, and then could be effluxed from astrocytes by ABCA1 and transported on high-density lipoprotein (HDL)-like particles to neurons where it is taken up by a receptor-dependent mechanism. Once in neurons, CYP46A1 can convert cholesterol excess to 24-hydroxycholesterol (24HC, shown as a ball model in green, the hydroxyl groups are in red), which could rapidly diffuse to the CSF and then through the blood–brain barrier to the systemic circulation for delivery to the liver. Some of the HDL-like particles could travel to the cerebrospinal fluid (CSF) and then gain access to the systemic circulation via the receptor-mediated endocytosis. A small portion of cholesterol could be esterified by sterol-O-acetyltransferase 1 (SOAT1) to form cholesterol esters (CE)

Fig. 2

Major mechanisms whereby modulation of CYP46A1 activity can affect brain processes. The three major mechanisms are changes in the brain cholesterol levels, 24-hydroxycholesterol (24HC) levels, and cholesterol turnover. The brain cholesterol levels could modulate the progression of several neurodegenerative disorders. The 24HC cholesterol levels can affect the activation of N-methyl-d-aspartate receptors (NMDARs) involved in memory and cognition and the activation of liver X receptors (LXRs), important transcription factors controlling gene expression in multiple pathways. The brain cholesterol turnover can alter physicochemical properties of plasma and subcellular membranes and thereby synaptogenesis and synaptic processes as well as lead to lipid raft rearrangement. The latter can in turn alter phosphorylation and amyloid β production. In addition, the brain cholesterol turnover can determine the rate of cholesterol biosynthesis and hence the production of non-sterol isoprenoids required for protein prenylation. The question marks indicate the lack of sufficient experimental evidence

Fig. 3

Brain regions affected by Alzheimer’s, Huntington’s, and Parkinson’s diseases. The regions in color on sagittal sections are those that are mostly affected by the disease; the regions in gray are those that are affected to a lesser extent or at a later disease stage. Upward arrows, downward arrows, and left-right arrows indicate increase, decrease, and no change, respectively, in the levels of cholesterol (C, in orange) and 24-hydroxycholesterol (24HC, in green), and CYP46A1 (in magenta) in different regions of the disease-affected brain as discussed in the main text

Fig. 4

Plasticity of the CYP46A1 active site. The enclosed volumes of the CYP46A1 active site, substrate-free and in complex with different compounds, are shown as semitransparent surfaces. Compounds inside the active site are shown as stick models. The heme group, which is the site of catalysis in the P450 enzymes, is in red

Fig. 5

A comparative summary of the long-term efavirenz treatments of 5XFAD mice. Upward arrows, downward arrows, and left-right arrows indicate increase, decrease, and no change, respectively. The data are taken from Mast et al. (the 1st treatment paradigm) and will be published elsewhere (the 2nd treatment paradigm)