Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL

Abstract

The ABC transporter ABCA1 regulates HDL levels and is considered to control the first step of reverse cholesterol transport from the periphery to the liver. To test this concept, we studied the effect of ABCA1 deficiency on hepatic metabolism and hepatobiliary flux of cholesterol in mice. Hepatic lipid contents and biliary secretion rates were determined in Abca1 -/-, Abca1 +/-, and Abca1 +/+ mice with a DBA background that were fed either standard chow or a high-fat, high-cholesterol diet. Hepatic cholesterol and phospholipid contents in Abca1 -/-mice were indistinguishable from those in Abca1 +/-and Abca1 +/+ mice on both diets. In spite of the absence of HDL, biliary secretion rates of cholesterol, bile salts, and phospholipid were unimpaired in Abca1 -/-mice. Neither the hepatic expression levels of genes controlling key steps in cholesterol metabolism nor the contribution of de novo synthesis to biliary cholesterol and bile salts were affected by Abca genotype. Finally, fecal excretion of neutral and acidic sterols was similar in all groups. We conclude that plasma HDL levels and ABCA1 activity do not control net cholesterol transport from the periphery via the liver into the bile, indicating that the importance of HDL in reverse cholesterol transport requires re-evaluation.

Beyond High-Density Lipoprotein Cholesterol Levels

“…Subsequently, blood is sampled at several time points, and feces and plasma are collected continuously over 48 h and assayed for technique used the murine J774 macrophage cell line to examine the effect of apoA-I overexpression achieved with a recombinant adenoviral vector. In contrast to prior studies measuring total centripetal flux (31,32), this macrophagespecific approach indicated increased macrophage RCT with apoA-I overexpression, consistent with the atheroprotective role of apoA-I (33). Compared with control subjects, mice overexpressing apoA-I demonstrated significantly higher levels of 3 H-tracer in plasma, liver, and feces after 48 h (Fig.…”

“…It is also possible that macrophage cholesterol represents a small compartment sensitive to factors that do not have major effects on the overall transport of cholesterol from the periphery to the liver. Unique attributes of the macrophage cholesterol pool may be the explanation for the failure of this method to detect a difference in centripetal cholesterol flux in mice with markedly different levels of HDL-C and apoA-I (31,32,40,41). Mass fecal steroid excretion.…”

Nuclear hormone receptors and cholesterol trafficking: the orphans find a new home

“…Drobnik et al [60], using a dual stable isotope method to measure intestinal cholesterol absorption, actually found that ABCA1 deficient mice had reductions in cholesterol absorption with enhanced fecal loss of neutral sterols. Groen and colleagues [61] found that ABCA1 deficiency had no effect on hepatic cholesterol and phospholipid content in mice fed low or high cholesterol diets, and that fecal excretion of neutral and acidic sterols were similar in the groups with and without functioning ABCA1 protein. Thus the role of ABCA1 in the gut remains uncertain, and the impact of the LXR activators on cholesterol absorption may eventually be ascribed to the regulation of other lipid transporters.…”

Experimental Models for the Investigation of High-Density Lipoprotein–Mediated Cholesterol Efflux

“…For instance, ABCA1 knockout mice show normal fecal steroid excretion in spite of being prone to atherosclerosis development [30]. Conversely, it may be possible that a drug increasing RCT and fecal steroid mass may induce adverse side effects that limit its potential anti-atherosclerotic effect.…”

“…The effect of pharmaceutical interventions or genetic manipulations in animal models can be reliably studied by this technique. For instance, reduction of atherosclerosis in animal models induced by apoA-I overexpression was postulated to be mediated by RCT; however, there were no actual proof for this hypothesis because the pre-existing methods assessed entire peripheral-tissue RCT and not macrophage-specific RCT [30]. This novel approach demonstrated an increased in vivo macrophage RCT [40] in apoA-I overexpression and the reduced RCT in apoA-I knockout mice [41].…”