Side Chain-oxidized Oxysterols Regulate the Brain Renin-Angiotensin System through a Liver X Receptor-dependent Mechanism

Abstract

Disturbances in cholesterol metabolism have been associated with hypertension and neurodegenerative disorders. Because cholesterol metabolism in the brain is efficiently separated from plasma cholesterol by the blood-brain barrier (BBB), it is an unsolved paradox how high blood cholesterol can cause an effect in the brain. Here, we discuss the possibility that cholesterol metabolites permeable to the BBB might account for these effects. We show that 27-hydroxycholesterol (27-OH) and 24S-hydroxycholesterol (24S-OH) up-regulate the renin-angiotensin system (RAS) in the brain. Brains of mice on a cholesterol-enriched diet showed up-regulated angiotensin converting enzyme (ACE), angiotensinogen (AGT), and increased JAK/STAT activity. These effects were confirmed in in vitro studies with primary neurons and astrocytes exposed to 27-OH or 24S-OH, and were partially mediated by liver X receptors. In contrast, brain RAS activity was decreased in Cyp27a1-deficient mice, a model exhibiting reduced 27-OH production from cholesterol. Moreover, in humans, normocholesterolemic patients with elevated 27-OH levels, due to a CYP7B1 mutation, had markers of activated RAS in their cerebrospinal fluid. Our results demonstrate that side chain-oxidized oxysterols are modulators of brain RAS. Considering that levels of cholesterol and 27-OH correlate in the circulation and 27-OH can pass the BBB into the brain, we suggest that this cholesterol metabolite could be a link between high plasma cholesterol levels, hypertension, and neurodegeneration.

27-Hydroxycholesterol mediates negative effects of dietary cholesterol on cognition in mice

“…The brain of patients who had died with AD contained markedly increased levels of 27OH [8]. Under in vitro [9][10][11] as well as under some in vivo conditions [11], 27OH seems to accelerate neurodegenerative processes.…”

LXR Regulation of Brain Cholesterol: From Development to Disease

“…Decreased levels of 27-OHC have been observed in several neurodegenerative disorders including AD, HD, and PD [15]. 27-OHC may link high peripheral cholesterol with many CNS diseases through its ability to upregulate the brain renin-angiotensin system in an LXR-dependent manner [16]. Additionally, Zhang et al recently showed that peripheral injection of 27-OHC into rats upregulates LXRα and ATP-binding cassette transporter ABCA1 in the brain, downregulates HMG Co-A Reductase and LDLR, and produces dose-dependent impairments of spatial memory performance in the Morris Water Maze (MWM) task [17].…”

Side-Chain-Oxidized Oxysterols Upregulate ACE2 and Mas Receptor in Rat Primary Neurons

“…Furthermore, in an extensive study, we demonstrated that both 24S-OH and 27-OH upregulate several members of the brain RAS including AGT, ACE and AT1 receptor (AT1R). This modulation of the brain RAS by oxysterols was through a liver X receptor-dependent mechanism [7] . In AD, increased 27-OH levels in plasma and CSF correlated with enhanced CSF-ACE activity [11] , although CSF-ACE levels were reported to be decreased [12] .…”

“…Given that 24S-OH and 27-OH were described as important modulators of AGT, renin, ACE and AT1R [7] , the purpose of the present study was to investigate the effects of these oxysterols on ACE2 and MasR, in order to gain insight into how they affect this brain RAS axis. As shown in figure 1 b, significant increases in both ACE2 and MasR expressions were found in rat primary neurons treated with a physiological concentration (1 M ) of 27-OH or 24S-OH for 24 h.…”

“…In another recent study, we demonstrated that high levels of blood cholesterol enhanced the activity of the renin-angiotensin system (RAS) in the brain. Mice fed with cholesterol-enriched diet showed increased levels of the precursor angiotensinogen (AGT) and also of the main enzyme of this pathway, angiotensin-converting enzyme (ACE) [7] .…”