Comparison of lipids in total brain tissue from five mouse genotypes

Sampugna, J.; Clements, Janice E.; Carter, T. P.; Campagnoni, Anthony T.

doi:10.1002/neu.480060302

Cited by 8 publications

(3 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The brain can also synthesize cholesterol. In average, the human brain contains 20 mg of cholesterol per gram of tissue, which is six times the amount present in the liver (64). Because cholesterol is synthesized de novo in the brain and its metabolism is very slow (a half-life of 1 year in human brains compared to a few hours in the blood), serum cholesterol fluctuations do not affect central nervous system cholesterol (65).…”

Section: Understanding the Role Of Acat In Cholesterol Metabolism Usimentioning

confidence: 99%

Potential Role of Acyl-Coenzyme A:Cholesterol Transferase (ACAT) Inhibitors as Hypolipidemic and Antiatherosclerosis Drugs

2005

View full text Add to dashboard Cite

Acyl-coenzyme A:cholesterol transferase (ACAT) is an integral membrane protein localized in the endoplasmic reticulum. ACAT catalyzes the formation of cholesteryl esters from cholesterol and fatty acyl coenzyme A. The cholesteryl esters are stored as cytoplasmic lipid droplets inside the cell. This process is very important to the organism as high cholesterol levels have been associated with cardiovascular disease. In mammals, two ACAT genes have been identified, ACAT1 and ACAT2. ACAT1 is ubiquitous and is responsible for cholesteryl ester formation in brain, adrenal glands, macrophages, and kidneys. ACAT2 is expressed in the liver and intestine. The inhibition of ACAT activity has been associated with decreased plasma cholesterol levels by suppressing cholesterol absorption and by diminishing the assembly and secretion of apolipoprotein B-containing lipoproteins such as very low density lipoprotein (VLDL). ACAT inhibition also prevents the conversion of macrophages into foam cells in the arterial walls, a critical event in the development of atherosclerosis. This review paper will focus on the role of ACAT in cholesterol metabolism, in particular as a target to develop novel therapeutic agents to control hypercholesterolemia, atherosclerosis, and Alzheimer's disease.

show abstract

Section: Understanding the Role Of Acat In Cholesterol Metabolism Usimentioning

confidence: 99%

Potential Role of Acyl-Coenzyme A:Cholesterol Transferase (ACAT) Inhibitors as Hypolipidemic and Antiatherosclerosis Drugs

2005

View full text Add to dashboard Cite

show abstract

“…OT-440 was formulated with cream cheese for feeding treatments or with water for gavage treatments by Othera Pharmaceuticals, Inc. Pharmacokinetic studies showed that 0.006% of a single oral OT-440 dose distributes to the brain by 30 minutes after administration (G. Patil, unpublished, 2010). Because adult mouse brain contains 80% water [28], [29] and adult C57BL/6 mouse (the background strain) brains weigh 0.41–0.45 grams [30], [31], this result suggests the concentration of OT-440 in the water of the brain following a 5 mg oral dose is 4 µM. This dose also resulted in OT-440 concentrations of 11 µM in retina/choroid and 20 µM in optic nerve tissue.…”

Section: Methodsmentioning

confidence: 97%

Protection by an Oral Disubstituted Hydroxylamine Derivative against Loss of Retinal Ganglion Cell Differentiation following Optic Nerve Crush

et al. 2013

View full text Add to dashboard Cite

Thy-1 is a cell surface protein that is expressed during the differentiation of retinal ganglion cells (RGCs). Optic nerve injury induces progressive loss in the number of RGCs expressing Thy-1. The rate of this loss is fastest during the first week after optic nerve injury and slower in subsequent weeks. This study was undertaken to determine whether oral treatment with a water-soluble N-hydroxy-2,2,6,6-tetramethylpiperidine derivative (OT-440) protects against loss of Thy-1 promoter activation following optic nerve crush and whether this effect targets the earlier quick phase or the later slow phase. The retina of mice expressing cyan fluorescent protein under control of the Thy-1 promoter (Thy1-CFP mice) was imaged using a blue-light confocal scanning laser ophthalmoscope (bCSLO). These mice then received oral OT-440 prepared in cream cheese or dissolved in water, or plain vehicle, for two weeks and were imaged again prior to unilateral optic nerve crush. Treatments and weekly imaging continued for four more weeks. Fluorescent neurons were counted in the same defined retinal areas imaged at each time point in a masked fashion. When the counts at each time point were directly compared, the numbers of fluorescent cells at each time point were greater in the animals that received OT-440 in cream cheese by 8%, 27%, 52% and 60% than in corresponding control animals at 1, 2, 3 and 4 weeks after optic nerve crush. Similar results were obtained when the vehicle was water. Rate analysis indicated the protective effect of OT-440 was greatest during the first two weeks and was maintained in the second two weeks after crush for both the cream cheese vehicle study and water vehicle study. Because most of the fluorescent cells detected by bCSLO are RGCs, these findings suggest that oral OT-440 can either protect against or delay early degenerative responses occurring in RGCs following optic nerve injury.

show abstract

“…This is surprising because the brain contains more cholesterol than any other organ in the human body. An average human brain contains 20 mg of cholesterol per gram of tissue, which is far more than the 3.2 mg of cholesterol per gram of tissue present in the liver (99). One reason for the relative insensitivity of CNS disorders to serum cholesterol levels might be because cholesterol metabolism in the CNS is regulated independently from that in the periphery.…”

Section: Overviewmentioning

confidence: 99%

The Cellular Biochemistry of Cholesterol and Statins: Insights into the Pathophysiology and Therapy of Alzheimer's Disease

et al. 2004

View full text Add to dashboard Cite

The causes of late onset Alzheimer disease (AD) are poorly understood. Although beta-amyloid (Abeta) is thought to play a critical role in the pathophysiology of AD, no genetic evidence directly ties Abeta to late onset AD. This suggests that the accumulation of Abeta and neurodegeneration associated with AD might result from an abnormality that indirectly affects Abeta production or accumulation. Increasing evidence suggests that abnormalities in the metabolism of cholesterol and related molecules, such as cholseterol esters and 24(S) hydroxycholesterol might contribute to the pathophysiology of late onset AD by increasing production of Abeta. 24(S) Hydroxycholesterol is a member of a family of oxidized cholesterol catabolites, termed oxysterols, which function to regulate export of cholesterol from the cell and transcription of genes related to cholesterol metabolism. Cholesterol esters are cholesterol derivatives used for cholesterol storage. Levels of 24(S) hydroxycholesterol increase with AD. Polymorphisms in several different genes important for cholesterol physiology are associated with an increased load or level of Abeta in AD. These genes include apolipoprotein E, cholesterol 24 hydroxylase (Cyp46), acyl-CoA:cholesterol acetyltransferase (ACAT), and the cholesterol transporter ABCA1. Other studies show that levels of cholesterol, or its precursors, are elevated in subjects early in the course of AD. Finally, studies of the processing of amyloid precursor protein show that cholesterol and its catabolites modulate amyloid precursor protein processing and Abeta production. These lines of evidence raise the possibility that genetic abnormalities in cholesterol metabolism might contribute to the pathophysiology of AD.

show abstract

Comparison of lipids in total brain tissue from five mouse genotypes

Cited by 8 publications

References 24 publications

Potential Role of Acyl-Coenzyme A:Cholesterol Transferase (ACAT) Inhibitors as Hypolipidemic and Antiatherosclerosis Drugs

Potential Role of Acyl-Coenzyme A:Cholesterol Transferase (ACAT) Inhibitors as Hypolipidemic and Antiatherosclerosis Drugs

Protection by an Oral Disubstituted Hydroxylamine Derivative against Loss of Retinal Ganglion Cell Differentiation following Optic Nerve Crush

The Cellular Biochemistry of Cholesterol and Statins: Insights into the Pathophysiology and Therapy of Alzheimer's Disease

Contact Info

Product

Resources

About