ATP‐binding cassette transporters G1 and G4 mediate cholesterol and desmosterol efflux to HDL and regulate sterol accumulation in the brain

Wang, Nan; Yvan‐Charvet, Laurent; Lütjohann, Dieter; Mulder, Monique; Vanmierlo, Tim; Kim, Tae‐Wan; Tall, Alan R.

doi:10.1096/fj.07-9944com

Cited by 161 publications

(162 citation statements)

References 45 publications

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“…The absence of either ABCG1 or ABCG4 in mice does not affect the cholesterol level in the brain. 96) Surprisingly, desmosterol and lathosterol levels in brain were increased in Abcg1-/-and Abcg4-/-mice respectively. 96) 97) However, the physiological significance of ABCG1 and ABCG4 in the brain is not fully understood.…”

Section: Functions Of Abcg1 and Abcg4 In Brainmentioning

confidence: 91%

ATP-Binding Cassette Proteins Involved in Glucose and Lipid Homeostasis

Matsuo¹

2010

Bioscience, Biotechnology, and Biochemistry

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Glucose and lipids are essential to the body, but excess glucose or lipids lead to metabolic syndrome. ATP-binding cassette (ABC) proteins are involved in the homeostasis of glucose and lipid in that they regulate insulin secretion and remove excess cholesterol from the body. Sulfonylurea receptor (SUR) is a subunit of the ATP-sensitive potassium channels, which regulate insulin secretion from pancreatic -cells by sensing cellular metabolic levels. ABCG1 removes excess cholesterol from peripheral tissues and functions in reverse cholesterol transport to the liver. ABCG5 and ABCG8 suppress the absorption of cholesterol in the intestine and exclude cholesterol from the liver to the bile duct. ABCG1 and ABCG4, expressed in the central nervous system, play roles in lipid metabolism in the brain. These ABC proteins are targets of drugs and functional foods to cure and prevent diabetes, hyperlipidemia, and neurodegenerative diseases. In this review, recent knowledge of the physiological function and regulation of ABC proteins in the homeostasis of glucose and lipids is discussed.

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Section: Functions Of Abcg1 and Abcg4 In Brainmentioning

confidence: 91%

ATP-Binding Cassette Proteins Involved in Glucose and Lipid Homeostasis

Matsuo¹

2010

Bioscience, Biotechnology, and Biochemistry

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“…in neurons and glia. 37,39,40) Experiments with Abca1 Ϫ/Ϫ mice demonstrated not only significant reduction of cholesterol in the CSF but also a reduction of apo E in the CSF and brain parenchyma. 41,42) It has recently been reported that neuronand glia-specific ABCA1 deficiency decreased levels of cholesterol and apo E in the brain and promoted the uptake of esterified cholesterol from plasma HDL into the brain.…”

Section: Lipoprotein Formation In the Cnsmentioning

confidence: 99%

Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

Hayashi

2011

Biological & Pharmaceutical Bulletin

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INTRODUCTIONFunctions of the central nervous system (CNS) are performed mainly by neurons and glia-primarily astrocytes, microglia and oligodendrocytes. It has been thought for a long time that glia only passively support neurons, but we now know that glia actively attend to assist in neuronal functions like synaptogenesis and neurotransmission. 1) Although it was believed that ca. 90% of the cells in the brain are glia and the rest of cells are neurons, Azevedo et al. recently reported that the numbers of neurons and non-neuronal cells (glia) are close to equal in human adult brain.2) Brain is the most cholesterol-rich organ in the body, and cholesterol metabolism in the CNS is tightly regulated between neurons and glia. [3][4][5][6][7] Imbalances in the metabolism of lipids, especially cholesterol, are closely linked to the development of several neurodegenerative disorders such as Alzheimer's disease, 8,9) Niemann-Pick type C disease 10) and Smith-Lemli Opitz syndrome. 11,12) In this review the regulation of lipid metabolism and the roles of glial lipoproteins in the CNS will be discussed. LIPID HOMEOSTASIS IN THE CNSThe system of lipid metabolism and transport in the CNS is different from that in peripheral tissues because the CNS is segregated from the peripheral circulation by the blood-brain barrier (BBB).13) Although lipoprotein particles can cross the BBB in vivo in Drosophila, which has a functional BBB like that in vertebrates, 14) lipoproteins in the mouse, rat and human do not cross the BBB. Consequently, since labeled cholesterol peripherally administrated was not found in the CNS of mammals, 15,16) cholesterol in the CNS is derived from de novo synthesis inside of the CNS. Furthermore, in the plasma of subjects who had liver transplantation the genotype of apolipoprotein (apo) E was that of the donor, whereas the subjects retained the own apo E genotype in the cerebrospinal fluid (CSF).17) Moreover, lipoproteins in the CNS consist of only high density lipoprotein (HDL)-like particles in contrast to the circulation which contains very low density lipoproteins (VLDL), low density lipoproteins (LDL) and HDL. It is known that the HDL-like particles in the CNS are secreted from glia (glial lipoproteins), mainly astrocytes and microglia, under normal conditions, [18][19][20] however lipoproteins can be secreted from neurons in vitro 21,22) and in vivo 23) under some specific conditions. Unesterified cholesterol is the major sterol in the adult brain, and small amounts of desmosterol and cholesteryl ester are also present. The majority (70-80%) of cholesterol in the adult brain is in myelin formed by oligodendrocytes. 24)Thus, the activity of cholesterol synthesis in the CNS is the highest during the myelinogenesis. After myelination, cholesterol synthesis continues at very low level in the CNS, and occurs mainly in astrocytes. 5,13,24) Neurons do not efficiently synthesize cholesterol and rely on external source of cholesterol from astrocytes, 25) so that neurons take up cholesterol as lipoproteins via ...

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“…The transcription factor SREBP2 controls the expression of enzymes involved in cholesterol biosynthesis, including the rate-limiting enzyme HMG-CoA reductase (HMGR) (8). In addition, the nuclear receptors LXRs control the gene expression of proteins involved in cholesterol transport (9,10), including apoE, ABCA1, ABCG1, and ABCG4 (11,12). Cholesterol can be enzymatically converted by a brain-specific enzyme, 24-hydroxylase (CYP46A1) (13), to the oxysterol 24(S)-hydroxycholesterol (24SOH); the concentration of 24SOH far exceeds those of other oxysterols in the brain (14).…”

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confidence: 99%

ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD

Bryleva

Rogers

Chang

et al. 2010

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

175

186

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Cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative diseases, including the abnormal accumulation of amyloid-β, one of the pathological hallmarks of Alzheimer disease (AD). Acyl-CoA:cholesterol acyltransferases (ACAT1 and ACAT2) are two enzymes that convert free cholesterol to cholesteryl esters. ACAT inhibitors have recently emerged as promising drug candidates for AD therapy. However, how ACAT inhibitors act in the brain has so far remained unclear. Here we show that ACAT1 is the major functional isoenzyme in the mouse brain. ACAT1 gene ablation (A1−) in triple transgenic (i.e., 3XTg-AD) mice leads to more than 60% reduction in full-length human APPswe as well as its proteolytic fragments, and ameliorates cognitive deficits. At 4 months of age, A1− causes a 32% content increase in 24-hydroxycholesterol (24SOH), the major oxysterol in the brain. It also causes a 65% protein content decrease in HMG-CoA reductase (HMGR) and a 28% decrease in sterol synthesis rate in AD mouse brains. In hippocampal neurons, A1− causes an increase in the 24SOH synthesis rate; treating hippocampal neuronal cells with 24SOH causes rapid declines in hAPP and in HMGR protein levels. A model is provided to explain our findings: in neurons, A1− causes increases in cholesterol and 24SOH contents in the endoplasmic reticulum, which cause reductions in hAPP and HMGR protein contents and lead to amelioration of amyloid pathology. Our study supports the potential of ACAT1 as a therapeutic target for treating certain forms of AD.Alzheimer disease | cholesterol esterification | lipid metabolism | oxysterols

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ATP‐binding cassette transporters G1 and G4 mediate cholesterol and desmosterol efflux to HDL and regulate sterol accumulation in the brain

Cited by 161 publications

References 45 publications

ATP-Binding Cassette Proteins Involved in Glucose and Lipid Homeostasis

ATP-Binding Cassette Proteins Involved in Glucose and Lipid Homeostasis

Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD

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