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Titolo:
Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA : cholesterol acyltransferase 1
Autore:
Accad, M; Smith, SJ; Newland, DL; Sanan, DA; King, LE; Linton, MF; Fazio, S; Farese, RV;
Indirizzi:
Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, San Francisco, CA94141 USA Univ Calif San Francisco San Francisco CA USA 94141 rancisco, CA94141 USA Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA Univ CalifSan Francisco San Francisco CA USA 94143 ancisco, CA 94143 USA Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USAUniv Calif San Francisco San Francisco CA USA 94143 ancisco, CA 94143 USA Vanderbilt Univ, Med Ctr, Dept Dermatol, Nashville, TN 37232 USA Vanderbilt Univ Nashville TN USA 37232 Dermatol, Nashville, TN 37232 USA Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA Vanderbilt Univ Nashville TN USA 37232 Dept Med, Nashville, TN 37232 USA
Titolo Testata:
JOURNAL OF CLINICAL INVESTIGATION
fascicolo: 6, volume: 105, anno: 2000,
pagine: 711 - 719
SICI:
0021-9738(200003)105:6<711:MXAACO>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
NORMOLIPEMIC PLANE XANTHOMA; ACAT INHIBITOR; COENZYME-A; ANTIATHEROSCLEROTIC AGENTS; ESTERIFICATION ENZYMES; EXPRESSION; GENE; ACCUMULATION; MACROPHAGES; DEFICIENCY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
34
Recensione:
Indirizzi per estratti:
Indirizzo: Farese, RV Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, POB 419100, San Francisco, CA 94141 USA Univ Calif San Francisco POB 419100 San Francisco CA USA 94141
Citazione:
M. Accad et al., "Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA : cholesterol acyltransferase 1", J CLIN INV, 105(6), 2000, pp. 711-719

Abstract

Inhibitors of acyl CoA:cholesterol acyltransferase (ACAT) have attracted considerable interest as a potential treatment for atherosclerosis. Currently available inhibitors probably act nonselectively against the two known ACATs. One of these enzymes, ACAT1, is highly expressed in macrophages in atherosclerotic lesions, where it contributes to foam-cell formation. In this study, we examined the effects of selective ACAT1 deficiency in two mouse models of atherosclerosis. In the setting of severe hypercholesterolemia caused by deficiency in apoE or the LDL receptor (LDLR), total ACAT1 deficiency led to marked alterations in cholesterol homeostasis and extensive deposition of unesterified cholesterol in the skin and brain. Bone marrow transplantation experiments demonstrated that ACAT1 deficiency in macrophages was sufficient to cause dermal xanthomas in hyperlipidemic LDLR-deficient mice. ACAT1 deficiency did not prevent the development of atherosclerotic lesions in either apoE-deficient or LDLR-deficient mice, despite causing relatively lower serum cholesterol levels. However, the lesions in ACAT1-deficient mice were atypical in composition, with reduced amounts of neutral lipids and a paucity of macrophages in advanced lesions. Although the latter findings may be associated with increased lesion stability, the marked alterations in cholesterol homeostasis indicate that selectively inhibiting ACAT1 in the setting of severe hyperlipidemia may have detrimental consequences.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/12/20 alle ore 06:50:48