Hepatic uptake and metabolism of free cholesterol from different lipoprotein classes. An in vivo study in the rat

The clearance of free cholesterol from plasma lipoproteins by tissues is of major quantitative importance, but it is not known whether this is passive or receptormediated. Based Plasma high density lipoprotein (HDL)1 plays a key role in maintaining cholesterol homeostasis. Epidemiological studies demonstrated a strong inverse correlation between HDL levels and the risk of coronary artery disease (1). Although detailed mechanisms remain uncertain, it has been proposed that HDL promotes reverse cholesterol transport by facilitating transfer of cholesterol from peripheral tissues to the liver for secretion into bile (Ref. 2; see Ref. 3 for a recent review). Early studies using HDL and low density lipoprotein (LDL) with radiolabeled free cholesterol (FC) showed that FC in HDL is the preferred source for biliary cholesterol (4 -8). Recent work with plant sterols provided further evidence that HDL is the preferred carrier for the transport of cholesterol into bile (9). Based on the observations that HDL FC is preferentially utilized for biliary secretion and that, in tissue culture studies, HDL, but not LDL, selectively binds FC (10), Schwartz et al. (5) predicted that a cell-surface HDL receptor might be involved in the hepatic uptake of HDL FC. As a counterpoint to this idea, free cholesterol exchanges readily between lipoproteins and cells, suggesting that passive FC uptake by the liver might be possible.Scavenger receptor BI (SR-BI) has recently been identified as an authentic HDL receptor that mediates the selective uptake of HDL cholesteryl ester (CE) (11) and bi-directional transfer of FC between HDL and cells (12, 13). Its tissue distribution (11,14) and regulatable expression in the adrenal gland, testis, and ovary (14, 15) indicate that the receptor plays an important physiological role in cholesterol metabolism (16,17). Hepatic overexpression of SR-BI leads to decreased HDL levels in mice (18 -20) due to accelerated hepatic uptake of HDL CE and subsequently increased HDL CE and protein catabolism (19). On the other hand, decreased expression of SR-BI in gene-targeted mice results in increased HDL levels (21, 22). Furthermore, SR-BI mRNA is expressed in thickened intima of atheromatous aorta (12), and the receptor suppresses the development of atherosclerosis in SR-BI transgenic (SR-BI Tg)/LDL receptor-deficient compound mice fed the Paigen diet (23).In our previous work, we found that, in transfected Chinese hamster ovary cells, SR-BI mediates the cellular uptake of HDL FC as well as CE (12). Moreover, SR-BI promotes cholesterol efflux from cells to HDL (12, 13) or protein-free phospholipid (PL) vesicles (13), and the efflux rates correlate with the expression level of SR-BI in different cell lines (Refs. 12 and 13; see Ref. 24 for review). In mice with hepatic overexpression of SR-BI, the biliary concentration of cholesterol is increased (18,25). These results led us to hypothesize that SR-BI plays a physiological role in vivo in promoting the hepatic uptake of HDL FC and facilitating the secretion of...

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“…Similar results were obtained in squirrel monkeys (7) and rats (8,35). However, the molecular basis for this preference of HDL FC was not clear.…”

Section: Discussionsupporting

confidence: 74%

Hepatic Scavenger Receptor BI Promotes Rapid Clearance of High Density Lipoprotein Free Cholesterol and Its Transport into Bile

Ji¹,

Wang²,

Ramakrishnan³

et al. 1999

Journal of Biological Chemistry

253

203

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“…5,7 When different lipoproteins have been compared, there is general agreement that the cholesterol that is derived from HDL is preferentially delivered to bile, and that HDL-UC rather than HDL-CE is the principal precursor of bile UC. [28][29][30][31] Moreover, these findings pertain not only to laboratory animals, but also to humans, in which, by elaborate compartmental analysis, the metabolic fate and transport of cholesterol between different pools has been mapped. 32 Our present studies with SIT support the general conclusions obtained in studies using isotopic cholesterol.…”

Section: Discussionmentioning

confidence: 99%

Delineation of A Novel Hepatic Route for the Selective Transfer of Unesterified Sterols From High–Density Lipoproteins to Bile: Studies Using the Perfused Rat Liver

Robins

Fasulo

1999

Hepatology

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Cholesterol is principally excreted from the body in bile as unesterified cholesterol (UC). Using the unesterified plant sterol, sitostanol (SIT), as a nonexchangeable analog for UC, we have found that high-density lipoproteins (HDL), but not low-density lipoproteins, provide a vehicle for the direct delivery of cholesterol to bile. To determine the mechanism for preferential cholesterol transport from HDL to bile, isolated rat livers were perfused with a reconstituted HDL, made with radiolabeled unesterified SIT, UC, and cholesteryl esters (CE). Total biliary sterol secretion was independent of the concentration of HDL added to perfusions, but with increasing HDL-SIT perfused, the proportion of SIT to cholesterol in bile was linearly increased. Biliary SIT secretion was rapid (detected within 2 to 4 minutes after reconstituted HDL was added to perfusions) and was dependent on the immediate presence of SIT in the perfusate, but independent of the amount of SIT that had accumulated in the liver. The ratio of SIT to UC was seven-to ninefold greater in bile than in the liver, consistent with preferential mobilization of membrane sterols delivered from HDL. Although radiolabeled UC as well as SIT was taken up from HDL by the liver and secreted in bile, net UC uptake could not be quantitated because of both UC exchange and a sizable enrichment of HDL with UC mass that approximated the SIT removed during the passage of HDL through the liver. These results are consistent with sterol transport to bile from HDL by a direct plasma membrane pathway and by a mechanism that appears to involve substitution of unesterified (exogenous) sterol from HDL for plasma membrane UC during transport. By this process, HDL can promote reverse cholesterol transport from peripheral tissues to bile, even without an increase in biliary cholesterol secretion. (HEPATOLOGY 1999; 29:1541-1548.)

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“…'~' ,~~~ This finding is the more remarkable given the relatively minor contribution of plasma-derived to biliary lipid secretion. The application of liposomes to target-specific (phospho-)lipids to hepatocytes may phospho~ipids173.174 and cholestero167,1"7.1.58, 160,168,[175][176][177][178][179][180] be of valuable help to further dissect these proIn summary, the precise intracellular origins of the lipids, which are secreted into the bile, have not yet been identified indisputably. However, various novel experimental models offer promising opportunities t o approach these obscurities in the next few particularly when data were obtained to suggest that crystallization of cholesterol occurs from supersaturated vesicles.81~1ti3~210~214~217~21g~…”

Section: Obscurities In the Process Of Biliarymentioning

confidence: 99%

New insights into the mechanism of bile acid—induced biliary lipid secretion

1995

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Hepatic uptake and metabolism of free cholesterol from different lipoprotein classes. An in vivo study in the rat

Cited by 34 publications

References 19 publications

Hepatic Scavenger Receptor BI Promotes Rapid Clearance of High Density Lipoprotein Free Cholesterol and Its Transport into Bile

Hepatic Scavenger Receptor BI Promotes Rapid Clearance of High Density Lipoprotein Free Cholesterol and Its Transport into Bile

Delineation of A Novel Hepatic Route for the Selective Transfer of Unesterified Sterols From High–Density Lipoproteins to Bile: Studies Using the Perfused Rat Liver

New insights into the mechanism of bile acid—induced biliary lipid secretion

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