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. 2017 Jan;58(1):267-278.
doi: 10.1194/jlr.P071639. Epub 2016 Nov 3.

Defective cholesterol metabolism in amyotrophic lateral sclerosis

Jonas Abdel-Khalik  1 , Eylan Yutuc  1 , Peter J Crick  1 , Jan-Åke Gustafsson  2 , Margaret Warner  2 , Gustavo Roman  3 , Kevin Talbot  4 , Elizabeth Gray  4 , William J Griffiths  5 , Martin R Turner  6 , Yuqin Wang  5
Affiliations

Defective cholesterol metabolism in amyotrophic lateral sclerosis

Jonas Abdel-Khalik et al. J Lipid Res. 2017 Jan.

Abstract

As neurons die, cholesterol is released in the central nervous system (CNS); hence, this sterol and its metabolites may represent a biomarker of neurodegeneration, including in amyotrophic lateral sclerosis (ALS), in which altered cholesterol levels have been linked to prognosis. More than 40 different sterols were quantified in serum and cerebrospinal fluid (CSF) from ALS patients and healthy controls. In CSF, the concentration of cholesterol was found to be elevated in ALS samples. When CSF metabolite levels were normalized to cholesterol, the cholesterol metabolite 3β,7α-dihydroxycholest-5-en-26-oic acid, along with its precursor 3β-hydroxycholest-5-en-26-oic acid and product 7α-hydroxy-3-oxocholest-4-en-26-oic acid, were reduced in concentration, whereas metabolites known to be imported from the circulation into the CNS were not found to differ in concentration between groups. Analysis of serum revealed that (25R)26-hydroxycholesterol, the immediate precursor of 3β-hydroxycholest-5-en-26-oic acid, was reduced in concentration in ALS patients compared with controls. We conclude that the acidic branch of bile acid biosynthesis, known to be operative in-part in the brain, is defective in ALS, leading to a failure of the CNS to remove excess cholesterol, which may be toxic to neuronal cells, compounded by a reduction in neuroprotective 3β,7α-dihydroxycholest-5-en-26-oic acid.

Keywords: bile acids and salts/biosynthesis; brain lipids; cholestenoic acids; cytochrome P450; mass spectrometry; neurodeneneration.; nuclear receptors/LXR; oxysterols.

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Figures

Fig. 1.
Fig. 1.
Concentration of 25-D3 and cholesterol metabolites in serum. Box and whiskers plots showing the concentrations (ng/ml) of 25-D3 (A), 7α-HC (B), 7α-HCO (C), 7α,25-diHCO (D), 26-HC (E), and 3β-HCA (F) in serum from ALS (n = 35) and PLS (n = 6) patients and healthy controls (n = 24). The bottom and top of the box are the first and third quartiles, and the band inside the box represents the median. The whiskers extend to the most extreme data points, which are no more than 1.5 times the range between first and third quartile distant from the box. Points beyond that are plotted individually. Data for other sterols can be found in supplemental Table S1. Univariate t tests were performed against the control group. * P < 0.05; ** P < 0.01.
Fig. 2.
Fig. 2.
Pathways of cholesterol metabolism initiated by the enzymes cholesterol 25-hydroxylase (CH25H) and CYP46A1. Changes in sterols concentration in CSF and serum are indicated by blue and red arrows, respectively. The direction of change corresponds to the direction of the arrow. Enzymes catalyzing the indicated reactions are shown where known. Univariate t tests were performed against the control group. * P < 0.05; ** P < 0.01.
Fig. 3.
Fig. 3.
Pathway of cholesterol metabolism initiated by the enzymes CYP7A1 and CYP27A1. Changes in sterols concentration in CSF and serum are indicated by blue and red arrows, respectively. The direction of change corresponds to the direction of the arrow. Enzymes catalyzing the indicated reactions are shown where known. Enzyme abbreviations used are as follows: ACOX2, acyl-CoA oxidase 2, branched chain; AMACR, α-methylacyl-CoA racemase; BACS, bile acyl-CoA synthetase; DBP, D-bifunctional protein or multifunctional enzyme type 2 (HSD17B4); SCPx, sterol carrier protein x; VLCS, very long chain acyl-CoA synthetase. Univariate t tests were performed against the control group. * P < 0.05; ** P < 0.01.
Fig. 4.
Fig. 4.
Concentration of cholesterol and its precursors in CSF. Box and whisker plots showing concentrations (ng/ml) of 24-DHC (A), 7-DHC + 8-DHC (B), and cholesterol (C) in CSF from ALS (n = 20) patients and healthy controls (n = 15). Box and whiskers are as described in the Fig. 1 legend. Data for other sterols can be found in supplemental Table S3. Univariate t tests were performed against the control group. * P < 0.05; ** P < 0.01.
Fig. 5.
Fig. 5.
Concentration of CYP7A1, CYP46A1, and CH25H pathway metabolites in CSF. Box and whisker plots showing concentrations (ng/µg cholesterol) of 7α-HC (A), 7β-HC (B), 7O-C (C), 24S-HC (D), 7α,25-diHCO (E), and 7α,26-diHCO (F) in CSF from ALS (n = 20) patients and healthy controls (n = 15). Box and whiskers are as described in the Fig. 1 legend. Data for other sterols can be found in supplemental Table S4. Univariate t tests were performed against the control group. * P < 0.05; ** P < 0.01.
Fig. 6.
Fig. 6.
Concentration of acidic pathway metabolites in CSF. Box and whisker plots showing concentrations (ng/µg cholesterol) of 3β-HCA (A), 3β,7α-diHCA (B), 7αH,3O-CA (C), 3β,7β-diHCA (D), 7α,24-diH,3O-CA (E), and 7αH,26-nor-C-3,24-diO (F) in CSF from ALS (n = 20) patients and healthy controls (n = 15). Box and whiskers are as described in the Fig. 1 legend. Data for other sterols can be found in supplemental Table S4. Univariate t tests were performed against the control group. * P < 0.05; ** P < 0.01.
Fig. 7.
Fig. 7.
Hypothetical model of cholesterol homeostasis in neurons and astrocytes. Neurons import cholesterol from astrocytes mediated by apolipoprotein (APO) E (green circle) (53). Neurons dispose of cholesterol by ATP-binding cassette (ABC) transporters (blue circle) and APOA1 (red circle), by the formation of 24S-HC, or via return to astrocytes via an unknown mechanism (broken arrow). Activation of LXRβ by oxysterols or cholestenoic acids leads to increased expression of ABC transporters and increased sterol release. Impaired metabolism of cholesterol in astrocytes as suggested in the present study of ALS patients may result in a greater flux of cholesterol out of astrocytes into the CSF and also into neurons. A reduction of metabolism of cholesterol to cholestenoic acids will result in a decrease in LXRβ ligands in astrocytes and lower amounts transported to neurons (broken arrow depicts unknown mechanism). A consequence will be increased cellular levels of cholesterol in neurons and reduced antiinflammatory signaling by LXRβ.
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