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

Abstract

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...

Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

“…We next examined if astrocytes contribute cholesterol to promote APP presence in neuronal lipid rafts in vivo. Astrocyte cholesterol synthesis was disrupted in mice by crossing SREBP2 floxed mice to GFAP-Cre mice resulting in a homyzgous deletion in SREBP2 in astrocyte cells 46 . At four weeks of age, brains were collected and APP-GM1 pair correlation was determined in neurons by dSTORM imaging.…”

Neuroprotective potential of astroglia

“…In addition to thrombospondins, cholesterol has also been shown to be an important astrocytic factor for synapse maturation. CNS neurons produce enough cholesterol to survive and grow, but the formation of numerous mature synapses demands additional amounts, which are provided by astrocytes (Mauch et al, ; Ferris et al, ; Van Deijk et al, ). Astrocytes also participate in formation of the inhibitory synapses (Elmariah et al, ).…”

Cholesterol regulates polymodal sensory transduction in Müller glia

“…Because cholesterol‐carrying lipoproteins are largely incapable of crossing the blood‐brain barrier, neurons derive it mainly from in situ biosynthesis, particularly from glia which transport cholesterol via specialized carriers such as the ATP‐binding cassette (ABC) transporters ABCA1 and ABCG1, lecithin‐cholesterol acyltransferase (LCAT) and the sterol regulatory element‐binding protein 2 (SREBP2) (van Deijk et al, ). Suppression of glioneuronal shuttling of cholesterol through astrocyte‐specific deletion of SREBP2 causes metabolic defects, altered brain development and abnormal cognition, social and motor behaviors (Ferris et al, ).…”

“…Suppression of glioneuronal shuttling of cholesterol through astrocytespecific deletion of SREBP2 causes metabolic defects, altered brain development and abnormal cognition, social and motor behaviors (Ferris et al, 2017).…”