Cholesterol 24S-Hydroxylase Overexpression Inhibits the Liver X Receptor (LXR) Pathway by Activating Small Guanosine Triphosphate-Binding Proteins (sGTPases) in Neuronal Cells

Abstract

The neuronal-specific cholesterol 24S-hydroxylase (CYP46A1) is important for brain cholesterol elimination. Cyp46a1 null mice exhibit severe deficiencies in learning and hippocampal long-term potentiation, suggested to be caused by a decrease in isoprenoid intermediates of the mevalonate pathway. Conversely, transgenic mice overexpressing CYP46A1 show an improved cognitive function. These results raised the question of whether CYP46A1 expression can modulate the activity of proteins that are crucial for neuronal function, namely of isoprenylated small guanosine triphosphate-binding proteins (sGTPases). Our results show that CYP46A1 overexpression in SH-SY5Y neuroblastoma cells and in primary cultures of rat cortical neurons leads to an increase in 3-hydroxy-3-methyl-glutaryl-CoA reductase activity and to an overall increase in membrane levels of RhoA, Rac1, Cdc42 and Rab8. This increase is accompanied by a specific increase in RhoA activation. Interestingly, treatment with lovastatin or a geranylgeranyltransferase-I inhibitor abolished the CYP46A1 effect. The CYP46A1-mediated increase in sGTPases membrane abundance was confirmed in vivo, in membrane fractions obtained from transgenic mice overexpressing this enzyme. Moreover, CYP46A1 overexpression leads to a decrease in the liver X receptor (LXR) transcriptional activity and in the mRNA levels of ATPbinding cassette transporter 1, sub-family A, member 1 and apolipoprotein E. This effect was abolished by inhibition of prenylation or by co-transfection of a RhoA dominantnegative mutant. Our results suggest a novel regulatory axis in neurons; under conditions of membrane cholesterol reduction by increased CYP46A1 expression, neurons increase isoprenoid synthesis and sGTPase prenylation. This leads to a reduction in LXR activity, and consequently to a decrease in the expression of LXR target genes.

Role of Liver X Receptor in AD Pathophysiology

“…Second, we observed increased expression levels of ApoE and ABCA1 proteins, which are direct target genes regulated by LXRs, and recently reported to be expressed in vitro in primary culture of cortical neurons [ 48 ]. A previous study reported a 4-fold increase of ABCA1 levels in cerebral cortex and a 6-fold increase in hippocampus in APP/PS1 mice treated for 8 weeks as compared to untreated APP/PS1.…”

LXR Regulation of Brain Cholesterol: From Development to Disease

“…24-OHC also acts as either a pro-survival or pro-death factor in neurons. At physiological concentrations 24-OHC induces LXR signaling in neurons and generates a neuroprotective response [9,10], while at high concentrations 24-OHC inhibits LXR transcriptional activity [10], promoting a “necroptosis-like” death pathway in neurons [11,12]. Recently it has been proposed that the neuroprotective action of 24-OHC involves allosteric modulation of N-methyl-D-aspartate receptor (NMDAR) function, but this activity is the result of direct binding to NMDA receptors and not LXR activation [13,14], adding further complexity to the mechanisms by which LXR-activating oxysterols act on neurons.…”

The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment

“…Liver X receptors are important transcription factors (10)(11)(12), whereas NMDA receptors mediate excitatory transmission throughout the CNS and are involved in memory and learning (13). In addition, CYP46A1 activity or expression levels could affect protein prenylation and protein phosphorylation (14)(15)(16). Protein prenylation is linked to CYP46A1 via cholesterol biosynthesis and availability of the nonsterol intermediates used for prenylation (14,16).…”