Effect of cholesterol reduction on receptor signaling in neurons.

Fukui, Kenji; Ferris, Heather A.; Kahn, C.Ronald

doi:10.1074/jbc.a115.664367

Cited by 15 publications

(12 citation statements)

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“…Given the many roles of cholesterol in the CNS, it is clear that any disruption in the cholesterol supply to neurons can likely contribute to neurodysfunction. In agreement with human and animal studies, in vitro studies demonstrate that depletion of cholesterol has deleterious effects on neuronal function (Frank et al 2008; Fukui et al 2016; Thiele et al 2000; Valenza et al 2015). Taken together, this reveals a potential convergence point for cocaine use and HIV-1 Tat to accelerate neurocognitive impairment.…”

Section: Discussionsupporting

confidence: 74%

Cocaine and HIV‐1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV‐associated neurocognitive disorders in cocaine user patients

Cotto

Natarajaseenivasan

Ferrero

et al. 2018

Glia

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Cholesterol synthesis and clearance by astrocytes are tightly regulated to maintain constant levels within the brain. In this context, liver X receptors (LXRs) are the master regulators of cholesterol homeostasis in the central nervous system (CNS). Increasing levels of cholesterol in astrocytes trigger LXR activation leading to the transcription of target genes involved in cholesterol trafficking and efflux, including apolipoprotein E, cytochrome P450 enzymes, sterol regulatory binding protein, and several ATP-binding cassette transporter proteins. The disturbance of LXR signaling in the brain can lead to significant dysfunctions in cholesterol homeostasis, and disruptions in this pathway have been implicated in numerous neurological diseases including Alzheimer's disease and Huntington's disease. HIV infection of the CNS in combination with cocaine use is associated with astrocyte and neuronal energy deficit and damage. We propose that dysregulation in CNS cholesterol metabolism may be involved in the progression of HIV-associated neurocognitive disorders (HAND) and in cocaine-mediated neurocognitive impairments. We hypothesize that exposure of astrocytes to cocaine and the HIV protein Tat will disrupt LXR signaling. Alterations in these pathways will in turn, affect cholesterol bioavailability for neurons. Our data show that exposure of astrocytes to cocaine and HIV-Tat significantly decreases LXRβ levels, downstream signaling and bioavailability of cholesterol. Taken together, these data uncover novel alterations in a bioenergetic pathway in astrocytes exposed to cocaine and the HIV protein Tat. Results from these studies point to a new pathway in the CNS that may contribute to HAND in HIV+ cocaine user individuals.

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Section: Discussionsupporting

confidence: 74%

Cocaine and HIV‐1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV‐associated neurocognitive disorders in cocaine user patients

Cotto

Natarajaseenivasan

Ferrero

et al. 2018

Glia

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“…Subgroup analysis suggests that ApoE e4 carrier status increases the response to intranasal insulin, implying an insulin-cholesterol relationship in this patient population (32). Furthermore, we and others have shown that knockdown or inhibition of cholesterol synthesis from neurons creates insulin resistance in those cells (33,34), suggesting a feed-forward connection between diabetes and AD.…”

Section: Discussionmentioning

confidence: 55%

Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism

Ferris

Perry

Moreira

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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160

117

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Cholesterol is important for normal brain function. The brain synthesizes its own cholesterol, presumably in astrocytes. We have previously shown that diabetes results in decreased brain cholesterol synthesis by a reduction in sterol regulatory elementbinding protein 2 (SREBP2)-regulated transcription. Here we show that coculture of control astrocytes with neurons enhances neurite outgrowth, and this is reduced with SREBP2 knockdown astrocytes. In vivo, mice with knockout of SREBP2 in astrocytes have impaired brain development and behavioral and motor defects. These mice also have altered energy balance, altered body composition, and a shift in metabolism toward carbohydrate oxidation driven by increased glucose oxidation by the brain. Thus, SREBP2-mediated cholesterol synthesis in astrocytes plays an important role in brain and neuronal development and function, and altered brain cholesterol synthesis may contribute to the interaction between metabolic diseases, such as diabetes and altered brain function.T he brain is one of the most cholesterol-rich organs in the body, with cholesterol playing an important role in membrane fluidity, vesicle formation, and synaptogenesis (1). Cholesterol levels are tightly controlled by sterol regulatory element-binding protein 2 (SREBP2), the major transcription factor regulating cholesterol synthetic genes (2). In contrast to fatty acids, which are in equilibrium with the rest of the body, nearly all brain cholesterol is synthesized in the brain because cholesterol-carrying lipoproteins, with the exception of some very dense HDL, cannot readily cross the blood-brain barrier (3-5).When cholesterol is abundant, SREBP2 precursor remains sequestered in the endoplasmic reticulum by SREBP cleavage activating protein (SCAP). As cholesterol is needed, SCAP shuttles SREBP2 to the Golgi for cleavage into a transcriptionally active form that translocates to the nucleus, binds to sterol regulatory elements in DNA, and activates transcription of enzymes of cholesterol synthesis (2). Insulin can regulate SREBP2 expression and activity, in part via two insulin-induced regulatory proteins, Insig1 and Insig2 (6, 7). Furthermore, in insulindeficient diabetes, there is a decrease in SREBP2 and SCAP in the brain leading to decreased brain cholesterol synthesis (8). We have previously shown that both neurons and glial cells express SREBP2 and the enzymes of cholesterol synthesis, and in both cell types expression of the cholesterol synthesis pathway is stimulated by insulin (7).Among the subtypes of glia, astrocytes serve the most diverse roles, providing both structural support to neurons and playing a major role in maintaining the blood-brain barrier. In addition, astrocytes provide a variety of metabolic functions, including storage of glycogen and uptake of ions and neurotransmitters from the synaptic cleft (9, 10).Astrocytes/glial cells have also been suggested to play an important role in brain cholesterol metabolism. When neuronallike retinal ganglion cells are grown in culture and expose...

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“…In many cases, recruitment of the receptor into lipid rafts following activation or receptor activation within the raft itself is critical for the type and duration of downstream signaling and can lead to dramatically different cellular outcomes if the receptor is activated elsewhere. Additionally, disruption of lipid rafts through cholesterol depletion or other destabilizing agents has inhibitory effects, especially on RTK‐mediated signals, most notably the PI3K/Akt and ERK pathways in neurons (Fukui et al, ). These observations highlight the importance of plasma membrane compartmentalization and lipid raft integrity in maintaining signaling pathways important for cellular growth and survival.…”

Section: Influence Of Membrane Architecture On Neuronal Signalingmentioning

confidence: 99%

How membrane dysfunction influences neuronal survival pathways in sphingolipid storage disorders

Sural-Fehr

Bongarzone

2016

J of Neuroscience Research

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Sphingolipidoses are a class of inherited diseases that result from the toxic accumulation of undigested sphingolipids in lysosomes and other cellular membranes. Sphingolipids are particularly enriched in cells of the nervous system, and their excessive accumulation during disease has a significant impact on the nervous system. Neuronal dysfunction followed by neurological compromise is a common feature in many of these diseases, however the underlying mechanisms that cause vulnerability of neurons are not fully understood. The plasma membrane plays a critical role in regulating cellular survival pathways, and its dysfunction has been implicated in neuronal failure in various adult onset neuropathies. In the context of sphingolipidoses, we hypothesized that the gradual accumulation of undigested lipids in plasma membranes would cause local disruptions in lipid raft domains, leading to deregulation of multiple signaling pathways important for neuronal survival and function. We propose that defects in downstream signaling as a result of membrane dysfunction is a common mechanism underlying neuronal vulnerability in sphingolipid storage disorders with neurological compromise.

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Effect of cholesterol reduction on receptor signaling in neurons.

Cited by 15 publications

References 0 publications

Cocaine and HIV‐1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV‐associated neurocognitive disorders in cocaine user patients

Cocaine and HIV‐1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV‐associated neurocognitive disorders in cocaine user patients

Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism

How membrane dysfunction influences neuronal survival pathways in sphingolipid storage disorders

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