Cholesterol homeostasis in the developing brain: a possible new target for ethanol

Abstract

Cholesterol is an essential component of cell membranes and plays an important role in signal transduction. This brief overview presents evidence from the literature that ethanol may affect cholesterol homeostasis and that, in the developing brain, this may be involved in its developmental neurotoxicity. The effects caused by inborn errors of cholesterol synthesis and by in utero ethanol exposure present several similarities in humans (eg, Smith-Lemli-Opitz syndrome and fetal alcohol syndrome), as well as in animal models. Ethanol has a cholesterol-reducing effect on the cardiovascular system, and a protective effect against Alzheimer's disease, whose pathogenesis has been linked to altered cholesterol homeostasis in the brain. In vitro, ethanol affects several functions that are mediated by cholesterol and important for brain development, such as glial cell proliferation, synaptogenesis, neuronal survival and neurite outgrowth. The brain contains high levels of cholesterol, mostly synthesized in situ. Astrocytes produce large amounts of cholesterol that can be released by these cells and utilized by neurons to form synapses. Ethanol up-regulates the cholesterol transporter ATP binding cassette A1 and cholesterol efflux from primary astrocyte cultures without affecting cholesterol synthesis. Human & Experimental Toxicology (2007) 26, 355-360

Keywords

astrocytes cholesterol ethanol fetal alcohol syndrome

References

Astley SJ , Clarren SK Diagnosing the full spectrum of fetal alcohol-exposed individuals: introducing the 4-digit diagnostic code. Alcohol Alcohol 2000; 35: 40010.

May PA , Gossage JP

Estimating the prevalence of fetal alcohol syndrome. A summary. Alcohol Res

Health 2001; 25: 159-67.

Streissguth AP et al. Fetal alcohol syndrome in adolescents and adults. JAMA 1991; 265: 1961-67.

Guizzetti M. , Costa LG Inhibition of muscarinic receptor-stimulated glial cell proliferation by ethanol. J Neurochem 1996; 67: 2236-45.

Kotter K. , Klein J. Ethanol inhibits astroglial cell proliferation by disruption of phospholipase D-mediated signaling. J Neurochem 1999; 73: 251723.

Inomata K. , Nasu F. , Tanaka H. Decreased density of synaptic formation in the frontal cortex of neonatal rats exposed to ethanol in utero. Int J Dev Neurosci 1987; 5: 455-60.

Kuge T. et al. Effect of ethanol on the development and maturation of synapses in the rat hippocampus: a quantitative electron-microscopic study. Environ Res 1993; 62: 99-105.

Ikonomidou C. et al. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000; 287: 1056-60.

Yanni PA , Lindsley TA Ethanol inhibits development of dendrites and synapses in rat hippocampal pyramidal neuron cultures. Brain Res Dev Brain Res 2000; 120: 233-43.

10.

Porter FD Human malformation syndromes due to inborn errors of cholesterol synthesis . Curr Opin Pediatr 2003; 15: 607-13.

11.

Nowaczyk MJ , Whelan DT , Heshka TW , Hill RE Smith-Lemli-Opitz syndrome: a treatable inherited error of metabolism causing mental retardation. Can Med Assoc J 1999; 161: 165-70.

12.

Woollett LA The origins and roles of cholesterol and fatty acids in the fetus. Curr Opin Lipidol 2001 ; 12: 305-12.

13.

Dietschy JM , Turley SD Cholesterol metabolism in the brain. Curr Opin Lipidol 2001; 12: 105-12.

14.

Dobbing J. , Sands J. Comparative aspects of the brain growth spurt. Early Hum Dev 1979; 3: 79-83.

15.

Bochelen D. et al. Effect of oxysterol treatment on cholesterol biosynthesis and reactive astrocyte proliferation in injured rat brain cortex . J Neurochem 1995; 65: 2194-200.

16.

Mauch DH et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science 2001; 294: 135457.

17.

Michikawa M. , Yanagisawa K. Inhibition of cholesterol production but not of nonsterol isoprenoid products induces neuronal cell death. J Neurochem 1999; 72: 2278-85.

18.

Bellosta S. et al. Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth. J Biol Chem 1995; 270: 27063-71.

19.

Fagan AM et al. Apolipoprotein E-containing high density lipoprotein promotes neurite outgrowth and is a ligand for the low density lipoprotein receptor-related protein. J Biol Chem 1996; 271: 30121-125.

20.

Dietschy JM , Turley SD Thematic review series: brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 2004; 45: 1375-97.

21.

Puglielli L. , Tanzi RE , Kovacs DM Alzheimer's disease: the cholesterol connection . Nat Neurosci 2003; 6: 345-51.

22.

Jurevics HA , Kidwai FZ , Morell P. Sources of cholesterol during development of the rat fetus and fetal organs. J Lipid Res 1997; 38: 723-33.

23.

Poirier J. , Baccichet A. , Dea D. , Gauthier S. Cholesterol synthesis and lipoprotein reuptake during synaptic remodelling in hippocampus in adult rats. Neuroscience 1993; 55: 81-90.

24.

Nakai M. et al. Expression of apolipoprotein E mRNA in rat microglia. Neurosci Lett 1996; 211: 41-44.

25.

Panzenboeck U. et al. ABCA1 and scavenger receptor class B, type I, are modulators of reverse sterol transport at an in vitro blood-brain barrier constituted of porcine brain capillary endothelial cells. J Biol Chem 2002; 277: 42781-789.

26.

Lund EG , Guileyardo JM , Russell DW cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci USA 1999; 96: 7238-43.

27.

Raffai RL , Weisgraber KH Cholesterol: from heart attacks to Alzheimer's disease. J Lipid Res 2003; 44: 1423-30.

28.

Lutjohann D. , von Bergmann K. 24S-hydroxycholesterol: a marker of brain cholesterol metabolism. Pharmacopsychiatry 2003; 36 Suppl 2: S102-106.

29.

Bjorkhem I. , Meaney S. Brain cholesterol: long secret life behind a barrier. Arterioscler Thromb Vasc Biol 2004 ; 24: 806-15.

30.

LaDu MJ et al. Nascent astrocyte particles differ from lipoproteins in CSF . J Neurochem 1998; 70: 2070-81.

31.

Pitas RE et al. Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim Biophys Acta 1987; 917: 148-61.

32.

Wahrle SE et al. ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem 2004; 279: 40987-993.

33.

Oram JF , Heinecke JW ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease. Physiol Rev 2005; 85: 134372.

34.

Ullian EM , Sapperstein SK , Christopherson KS , Barres BA Control of synapse number by glia. Science 2001; 291: 657-61.

35.

Herz J. The LDL receptor gene family: (un)expected signal transducers in the brain . Neuron 2001; 29: 57181.

36.

Jones KL , Smith DW , Ulleland CN , Streissguth P. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1973; 1: 1267-71.

37.

Astley SJ , Magnuson SI , Omnell LM , Clarren SK Fetal alcohol syndrome: changes in craniofacial form with age, cognition, and timing of ethanol exposure in the macaque. Teratology 1999; 59: 163-72.

38.

Blader P. , Strahle U. Ethanol impairs migration of the prechordal plate in the zebrafish embryo . Dev Biol 1998; 201: 185-201.

39.

Sulik KK Genesis of alcohol-induced craniofacial dysmorphism. Exp Biol Med (Maywood) 2005; 230: 366-75.

40.

Sulik KK , Johnston MC , Webb MA Fetal alcohol syndrome: embryogenesis in a mouse model. Science 1981; 214: 936-38.

41.

Dehart DB , Lanoue L. , Tint GS , Sulik KK Pathogenesis of malformations in a rodent model for Smith-LemliOpitz syndrome . Am J Med Genet 1997; 68: 328-37.

42.

Lanoue L. et al. Limb, genital, CNS, and facial malformations result from gene/environment-induced cholesterol deficiency: further evidence for a link to sonic hedgehog. Am J Med Genet 1997; 73: 24-31.

43.

Cohen MM Jr , Shiota K. Teratogenesis of holoprosencephaly. Am J Med Genet 2002; 109: 1-15.

44.

Incardona JP , Roelink H. The role of cholesterol in Shh signaling and teratogen-induced holoprosencephaly. Cell Mol Life Sci 2000; 57: 1709-19.

45.

Ahlgren SC , Thakur V. , Bronner-Fraser M. Sonic hedgehog rescues cranial neural crest from cell death induced by ethanol exposure. Proc Natl Acad Sci USA 2002; 99: 10476-481.

46.

Chrisman K. et al. Gestational ethanol exposure disrupts the expression of FGF8 and sonic hedgehog during limb patterning. Birth Defects Res A Clin Mol Teratol 2004; 70: 163-71.

47.

Hannuksela ML , Liisanantt MK , Savolainen MJ Effect of alcohol on lipids and lipoproteins in relation to atherosclerosis. Crit Rev Clin Lab Sci 2002; 39: 22583.

48.

van Tol A. , Hendriks HF Moderate alcohol consumption: effects on lipids and cardiovascular disease risk. Curr Opin Lipidol 2001; 12: 19-23.

49.

Beulens JW et al. Moderate alcohol consumption increases cholesterol efflux mediated by ABCA1. J Lipid Res 2004; 45: 1716-23.

50.

van der Gaag MS et al. Alcohol consumption stimulates early steps in reverse cholesterol transport. J Lipid Res 2001; 42: 2077-83.

51.

Wolozin B. Cholesterol and the biology of Alzheimer's disease. Neuron 2004; 41: 7-10.

52.

Kivipelto M. et al. Apolipoprotein E ℝ4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer's disease. Ann Intern Med 2002; 137: 149-55.

53.

Poirier J. Apolipoprotein E and cholesterol metabolism in the pathogenesis and treatment of Alzheimer's disease. Trends Mol Med 2003 ; 9: 94-101.

54.

Cordy JM et al. Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein . Proc Natl Acad Sci USA 2003; 100: 11735-740.

55.

Koldamova RP et al. 22R-hydroxycholesterol and 9cis-retinoic acid induce ATP-binding cassette transporter A1 expression and cholesterol efflux in brain cells and decrease amyloid beta secretion. J Biol Chem 2003; 278: 13244-256.

56.

Fukumoto H. et al. Induction of the cholesterol transporter ABCA1 in central nervous system cells by liver X receptor agonists increases secreted Abeta levels. J Biol Chem 2002; 277: 48508-513.

57.

Wellington CL Cholesterol at the crossroads: Alzheimer's disease and lipid metabolism. Clin Genet 2004 ; 66: 1-16.

58.

Bond GE et al. Alcohol, aging, and cognitive performance: a cross-cultural comparison. J Aging Health 2003; 15: 371-90.

59.

Ruitenberg A. et al. Alcohol consumption and risk of dementia: the Rotterdam Study. Lancet 2002; 359: 281-86.

60.

Stampfer MJ et al. Effects of moderate alcohol consumption on cognitive function in women. N Engl J Med 2005; 352: 245-53.

61.

Huang W. , Qiu C. , Winblad B. , Fratiglioni L. Alcohol consumption and incidence of dementia in a community sample aged 75 years and older. J Clin Epidemiol 2002; 55: 959-64.

62.

Mukamal KJ et al. Prospective study of alcohol consumption and risk of dementia in older adults. JAMA 2003; 289: 1405-13.

63.

Luchsinger JA et al. Alcohol intake and risk of dementia . J Am Geriatr Soc 2004; 52: 540-46.

64.

Hebert R. et al. Vascular dementia: incidence and risk factors in the Canadian study of health and aging. Stroke 2000; 31: 1487-93.

65.

Rimm EB et al. Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ 1999; 319: 152328.

66.

Reynolds K. et al. Alcohol consumption and risk of stroke: a meta-analysis. JAMA 2003; 289: 579-88.