ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo

Abstract

Cholesterol homeostasis is of emerging therapeutic importance for Alzheimer's disease (AD). Agonists of liver-X-receptors (LXRs) stimulate several genes that regulate cholesterol homeostasis, and synthetic LXR agonists decrease neuropathological and cognitive phenotypes in AD mouse models. The cholesterol transporter ABCG1 is LXRresponsive and highly expressed in brain. In vitro, conflicting reports exist as to whether ABCG1 promotes or impedes Ab production. To clarify the in vivo roles of ABCG1 in Ab metabolism and brain cholesterol homeostasis, we assessed neuropathological and cognitive outcome measures in PDAPP mice expressing excess transgenic ABCG1. A 6-fold increase in ABCG1 levels did not alter Ab, amyloid, apolipoprotein E levels, cholesterol efflux, or cognitive performance in PDAPP mice. Furthermore, endogenous murine Ab levels were unchanged in both ABCG1-overexpressing or ABCG1-deficient mice. These data argue against a direct role for ABCG1 in AD. However, excess ABCG1 is associated with decreased levels of sterol precursors and increased levels of SREBP-2 and HMG-CoA-reductase mRNA, whereas deficiency of ABCG1 leads to the opposite effects. Although functions for ABCG1 in cholesterol efflux and Ab metabolism have been proposed based on results with cellular model systems, the in vivo role of this enigmatic transporter may be largely one of regulating the sterol biosynthetic pathway.-Burgess,

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

“…The chromosome 21 lipid transporter ATP-binding cassette G1 (ABCG1) has been suggested to regulate cholesterol efflux and may alter cholesterol metabolism in people with DS 186 . Whether trisomy of this gene is related to the development of AD-DS remains unclear, as ABCG1 overexpression has been reported both to increase and to decrease Aβ generation in vitro 187,188 and does not change Aβ accumulation in vivo 189 , suggesting that this gene may not be associated with the development of AD-DS. Further study is required to understand the mechanisms that underlie the link between increased cholesterol levels and the onset of dementia in individuals with DS.…”

ABCG1 regulates mouse adipose tissue macrophage cholesterol levels and ratio of M1 to M2 cells in obesity and caloric restriction

“…Because background strain (C57BL/6), duration of diet, and dietary fat content (36% by weight) were comparable between our study and the study by Buchmann et al, these data suggest that cells other than myeloid based are critical for body weight regulation. For instance, Abcg1 is highly expressed in brain where it contributes greatly to cholesterol homeostasis in microglia ( 68 ). Thus, a possible explanation is that ABCG1 participates in food intake and peripheral…”

Differential regulation of ABCA1 and ABCG1 gene expressions in the remodeling mouse hippocampus after entorhinal cortex lesion and liver-X receptor agonist treatment

“…Cholesterol loading in vitro enhances ABCG1, but not ABCA1, expression and correlates best with cholesterol efflux from astrocytes (Karten et al, 2006). While difficult to reconcile, the in vivo and in vitro discrepancies still point to some common features: ABCG1 over-expression does not influence cognition, learning and memory, nor hippocampal synaptic plasticity (Parkinson et al, 2009), nor ABCA1 or apoE levels (Burgess et al, 2008a(Burgess et al, , 2008b in transgenic mice; suggesting a rather modest contribution of ABCG1, if any, in lipid mobilization and in the maintenance of synaptic integrity or plasticity in the adult brain.…”

“…While some studies failed to detect any effect of ABCG1 overexpression or deficiency on cholesterol efflux and brain lipid levels in apoE deficient (Burgess et al, 2008a) and PDAPP transgenic mice (Burgess et al, 2008b), others report positive correlations between ABCG1 expression and peripheral lipid tissue levels (Kennedy et al, 2005). ABCA1 has repeatedly been reported to act in concert with ABCG1, and both were shown to act sequentially in promoting phospholipids and cholesterol efflux from peripheral cell and to facilitate apoE-HDL lipidation (Gelissen et al, 2006;Karten et al, 2006;Kennedy et al, 2005;Vaughan and Oram, 2006).…”

“…ABCG1 has been associated with intracellular cholesterol trafficking and efflux (Abildayeva et al, 2006;Burgess et al, 2008aBurgess et al, , 2008bKarten et al, 2006;Klucken et al, 2000;Vaughan and Oram, 2005), whereas ABCA1 has been linked to secretion and lipidation of apoA1 with cholesterol and HDL production in the plasma, CSF and brain (Hirsch-Reinshagen et al, 2004;Koldamova et al, 2003;Wahrle et al, 2004). Furthermore, in vitro work demonstrated that the coordinated action of ABCA1 and G1 is required for optimal removal of cellular cholesterol (Gelissen et al, 2006;Vaughan and Oram, 2006).…”