Cholesterol efflux is differentially regulated in neurons and astrocytes: Implications for brain cholesterol homeostasis

Abstract

Disruption of cholesterol homeostasis in the central nervous system (CNS) has been associated with neurological, neurodegenerative, and neurodevelopmental disorders. The CNS is a closed system with regard to cholesterol homeostasis, as cholesterol-delivering lipoproteins from the periphery cannot pass the blood-brain-barrier and enter the brain. Different cell types in the brain have different functions in the regulation of cholesterol homeostasis, with astrocytes producing and releasing apolipoprotein E and lipoproteins, and neurons metabolizing cholesterol to 24(S)-hydroxycholesterol. We present evidence that astrocytes and neurons adopt different mechanisms also in regulating cholesterol efflux. We found that in astrocytes cholesterol efflux is induced by both lipid-free apolipoproteins and lipoproteins, while cholesterol removal from neurons is triggered only by lipoproteins. The main pathway by which apolipoproteins induce cholesterol efflux is through ABCA1. By upregulating ABCA1 levels and by inhibiting its activity and silencing its expression, we show that ABCA1 is involved in cholesterol efflux from astrocytes but not from neurons. Furthermore, our results suggest that ABCG1 is involved in cholesterol efflux to apolipoproteins and lipoproteins from astrocytes but not from neurons, while ABCG4, whose expression is much higher in neurons than astrocytes, is involved in cholesterol efflux from neurons but not astrocytes. These results indicate that different mechanisms regulate cholesterol efflux from neurons and astrocytes, reflecting the different roles that these cell types play in brain cholesterol homeostasis. These results are important in understanding cellular targets of therapeutic drugs under development for the treatments of conditions associated with altered cholesterol homeostasis in the CNS.

Direct intracerebral delivery of a miR-33 antisense oligonucelotide into mouse brain increases brain ABCA1 expression

“…ABCA1 expression in astrocytes is responsive to LXR stimulation which results in net increase in cholesterol efflux [4]. Our data show that, in addition to ABCA1 expression, miR-33 ASO treatment significantly increased ABCA1 cholesterol efflux activity in astrocytes, and in a concentration dependent manner, but not in neurons ( Fig.…”

What are lipoproteins doing in the brain?

“…Cholesterol efflux from astrocytes is facilitated by apolipoproteins alone or lipoprotein particles, while cholesterol removal from neurons is triggered only by lipoprotein particles. ABCA1- and ABCG1-regulated cholesterol efflux occurs only in astrocytes while ABCG4-mediated cholesterol efflux happens only in neurons 11 . Furthermore, the newly synthesized cholesterol is rarely converted to CE, and is quickly re-distributed among various cell types within the brain (reviewed in 10 ).…”

An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers

“…Astrocytes synthesize the majority of brain cholesterol from glucose, glutamine or acetate-derived acetyl-CoA and supply cholesterol to neighboring cells, including neurons, in the form of ApoE-containing HDL-like lipoprotein particles (Hayashi et al, 2004; Karten et al, 2006; Wahrle et al, 2004). Neurons and astrocytes both produce oxysterols as products of cholesterol metabolism, which act as endogenous ligands for the liver X receptors (LXRs) to decrease excess cellular cholesterol levels by promoting efflux through sterol transporters such as ABCA1 and suppressing uptake through IDOL-dependent degradation of LDLR (Chen et al, 2013; Repa et al, 2000; Venkateswaran et al, 2000; Zelcer et al, 2009). This negative feedback system complements suppression of HMG-CoA reductase (HMGCR), the rate-limiting enzyme for sterol synthesis, when cholesterol levels rise (Björkhem, 2006; Brown and Goldstein, 1980) to maintain cholesterol homeostasis within distinct cell types in the brain.…”