Apoptosis: repulsive encounters.
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Apoptosis↗
Biomedical subjects
Giovanna Chimini
Publications and source records attributed to Giovanna Chimini.
Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1.
The ATP-binding cassette transporter ABCA1 is essential for high density lipoprotein (HDL) formation and considered rate-controlling for reverse cholesterol transport. Expression of the Abca1 gene is under control of the liver X receptor (LXR). We have evaluated effects of LXR activation by the synthetic agonist T0901317 on hepatic and intestinal cholesterol metabolism in C57BL/6J and DBA/1 wild-type mice and in ABCA1-deficient DBA/1 mice. In wild-type mice, T0901317 increased expression of Abca1 in liver and intestine, which was associated with an approximately 60% rise in HDL. Biliary cholesterol excretion rose 2.7-fold upon treatment, and fecal neutral sterol output was increased by 150-300%. Plasma cholesterol levels also increased in treated Abca1(-/-) mice (+120%), but exclusively in very low density lipoprotein-sized fractions. Despite the absence of HDL, hepatobiliary cholesterol output was stimulated upon LXR activation in Abca1(-/-) mice, leading to a 250% increase in the biliary cholesterol/phospholipid ratio. Most importantly, fecal neutral sterol loss was induced to a similar extent (+300%) by the LXR agonist in DBA/1 wild-type and Abca1(-/-) mice. Expression of Abcg5 and Abcg8, recently implicated in biliary excretion of cholesterol and its intestinal absorption, was induced in T0901317-treated mice. Thus, activation of LXR in mice leads to enhanced hepatobiliary cholesterol secretion and fecal neutral sterol loss independent of (ABCA1-mediated) elevation of HDL and the presence of ABCA1 in liver and intestine.
Animals↗
The ABCA1 transporter and ApoA-I: obligate or facultative partners?
Premature cardiovascular disease, the leading cause of death in the Western world, is frequently associated with disorders of lipid metabolism and, in particular, with low levels of circulating high-density lipoprotein (HDL) cholesterol. However, the relationship among HDL, centripetal cholesterol transport, and early atherogenesis has remained elusive until the characterization of the molecular defect leading to Tangier disease. In this disorder, the loss of function of the adenosine triphosphate-binding cassette transporter, ABCA1, leads to an impaired formation of nascent HDL particles by preventing the release of cellular lipids and cholesterol to the acceptor apolipoprotein (apo)A-I. Lipids bound to circulating apoA-I are derived from cell membranes via active effluxes experimentally elicited by the interaction of nascent lipid-free apoA-I with the membrane itself. The nature of this key interaction is still enigmatic, however, and a large number of controversial results (discussed in this article) have been reported. Indeed, although the active mechanism that assists the extraction of cellular lipids entails as a simplest option the existence of a dedicated receptor at the membrane, the unambiguous identification of this molecule has not been achieved. This lack of precise evidence makes it necessary to consider alternative models, taking into account the dynamic and functional constraints that regulate the interaction between apoA-I and the plasma membrane.
ATP-Binding Cassette Transporters↗
Identification and functional analysis of a naturally occurring E89K mutation in the ABCA1 gene of the WHAM chicken.
The Wisconsin hypoalpha mutant (WHAM) chicken has a >90% reduction in plasma HDL due to hypercatabolism by the kidney of lipid-poor apoA-I. The WHAM chickens have a recessive white skin phenotype caused by a single-gene mutation that maps to the chicken Z-chromosome. This corresponds to human 9q31.1, a chromosomal segment that contains the ATP-binding cassette protein-1 (ABCA1) gene, which is mutated in Tangier Disease and familial hypoalphalipoproteinemia. Complete sequencing of the WHAM ABCA1 cDNA identified a missense mutation near the N-terminus of the protein (E89K). The substitution of this evolutionary conserved glutamate residue for lysine in the mouse ABCA1 transporter leads to complete loss of function, resulting principally from defective intracellular trafficking and very little ABCA1 reaching the plasma membrane. The WHAM chicken is a naturally occurring animal model for Tangier Disease.
ATP Binding Cassette Transporter 1↗
Distinct sites on ABCA1 control distinct steps required for cellular release of phospholipids.
The loss of ABCA1 function leads to Tangier dyslipidemia in humans and to a Tangier-like phenotype in mice, by impairing the transformation of nascent apolipoproteins into mature HDL particles. Mechanistically this ensues from the inability of cells to release membrane lipids and cholesterol. Whereas the ability of ABCA1 to promote phospholipid effluxes, surface binding of apolipoproteins and outward flip of membrane lipids has been documented, the relationship between this series of ABCA1-dependent events is still elusive. Here we provide evidence that i) lipid effluxes require both flip of membrane lipids and binding of apolipoproteins to the cell surface, ii) apolipoprotein A-I binding depends on structural determinants on ABCA1, and iii) phospholipid effluxes can be modulated by engineered mutations on the structural determinants identified on ABCA1.
ATP Binding Cassette Transporter 1↗