Cholesterol-24S-hydroxylase (CYP46A1) Is Specifically Expressed in Neurons of the Neural Retina

Abstract

Increasing biological findings argue for the importance of cholesterol-24S-hydroxylase (CYP46A1) in cholesterol homeostasis in cerebral structures. Based on the similarity between the brain and the neural retina, the aim of the current study was to evaluate the expression of CYP46A1 in the mammalian retina. RT-PCR analysis of CYP46A1 in bovine samples revealed the highest expression in the neural retina. The retinal pigment epithelium expressed CYP46A1 gene at a low level while the ciliary body showed no expression. Immunohistochemical evaluation of the posterior pole of rat retina showed that the protein is specifically expressed in neurons, whereas cone-rods photoreceptors were negative for CYP46A1 staining. The metabolite produced by CYP46A1, 24S-hydroxycholesterol, was almost exclusively found in neural retina, the concentration therein being more than 10-fold higher than in the retinal pigment epithelium or the ciliary body. The results of the current study are consistent with our primary hypothesis: the neural retina specifically expresses cholesterol-24S-hydroxylase, a metabolizing enzyme responsible for the removal of cholesterol in neurons. Based on the link between cholesterol-24S-hydroxylase, 24S-hydroxycholesterol, and neurologic disorders, CYP46A1 may be a valuable gene candidate for retinal pathologies like age-related macular degeneration or glaucomas, and 24S-hydroxycholesterol may be involved in the onset of the degenerative processes in these diseases.

Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration

“…27HCh has been found in high levels in macrophage foam cells and atherosclerotic plaques ( 39,40 ), but its presence in the retina has not been previously reported. 24HCh was reported in the retina in one study ( 45 ), and this will be discussed in more detail below. Our laboratory measured signifi cant levels of 7KCh in monkey retina ( 9 ) and rat retina ( 10 ) but did not report the levels of the side-chain hydroxylated oxysterols, because they were present only in trace amounts.…”

“…To our knowledge, the only cytochrome P450s reported in the retina that are capable of hydroxylating 7KCh are CYP27A1 ( 39,65 ) and CYP46A1 ( 45 ). CYP27A1 is a mitochondrial protein that can be readily detected in the retina by immunoblot and has been localized by immunofl uorescence ( 65 ).…”

“…This disease is characterized by cataracts as well as a series of neurological and systemic abnormalities ( 66 ).These patients also exhibit retinal abnormalities such as optic disc paleness and retinal senescence ( 67 ). CYP46A1 has been localized by immunofl uorescence in bovine retina ( 45 ) and by immunohistochemistry in mouse retina ( 68 ). No immunoblot for CYP46A1 in the retina has been published.…”

The ins and outs of cholesterol in the vertebrate retina

“…The brain has the highest cholesterol content ( ‫ف‬ 14 mg/g wet weight) of all organs in the body compared with only ‫ف‬ 2-3 mg/g in most tissues ( 7,8 ), including the neural retina and RPE ( 9 ). When compared with the major cholesterogenic tissues (i.e., liver and intestine), the rate of cholesterol synthesis in the mature brain and retina is relatively slow ( 10,11 ).…”

Side effects of oxysterols: cytotoxicity, oxidation, inflammation, and phospholipidosis

“…The microsomal cytochrome P450 system is largely responsible for the enzymatic generation of endogenous oxysterols (Table 1), including hepatic 7α-hydroxycholesterol (catalyzed by CYP7A1), 24S-hydroxycholesterol in brain and retina (catalyzed by CYP46) (6), and 27-hydroxycholesterol in most tissues (catalyzed by CYP27), whereas the minor oxysterol, 25-hydroxycholesterol, is generated by the non-heme iron protein enzyme, cholesterol 25-hydroxylase (7). In the hepatocytes, 27-hydroxylase (CYP27A1) and 7α-hydroxylase (CYP7A1) are two key enzymes of bile acid biosynthesis, and the enzyme CYP7A1 is the enzyme limiting the conversion of cholesterol into bile acids (1,2,7).…”