Identification of the abnormal cholestatic lipoprotein (LP‐X) in familial lecithin:Cholesterol acyltransferase deficiency

Torsvik, Harald; Berg, Kåre; Magnani, H.N.; McConathy, Walter J.; Alaupovic, P.; Gjone, E

doi:10.1016/0014-5793(72)80758-0

Cited by 69 publications

(21 citation statements)

References 14 publications

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“…lipoprotein X-like particles of vesicular structure (24). Subsequently, SR-BI Tg mice were found to have functional LCAT deficiency (see below) in which lipoprotein X accumulates especially on a high fat diet (25,26).…”

Section: Sr-bi Expression In Sr-bi Tgmentioning

confidence: 99%

“…On the Western type diet the particles accumulating in VLDL were found to contain free cholesterol and phospholipids and to be almost devoid of cholesteryl esters and apoB. Thus they are likely to represent lipoprotein X-like particles that are non-apoB-containing vesicular lipoproteins that accumulate in animals with LCAT deficiency, especially in response to high fat diets, where they probably represent surface remnants of triglyceride-rich lipoproteins (25,26). It is not clear why these particles were more prominent on the Western type diet than the very high cholesterol diet, although it could be related to a more pronounced rise in plasma Tg levels on the Western type diet 5.…”

Section: Fig 4 Plasma Decay Curves and Fcrs Formentioning

confidence: 99%

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Liver-specific Overexpression of Scavenger Receptor BI Decreases Levels of Very Low Density Lipoprotein ApoB, Low Density Lipoprotein ApoB, and High Density Lipoprotein in Transgenic Mice

Wang

Arai

et al. 1998

Journal of Biological Chemistry

270

234

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Scavenger receptor BI (SR-BI) is known to mediate the selective uptake of high density lipoprotein (HDL) cholesteryl ester (CE) in liver and steroidogenic tissues. To evaluate the role of SR-BI in plasma lipoprotein metabolism, we have generated transgenic mice with liverspecific overexpression of murine SR-BI. On a chow diet SR-BI transgenic (SR-BI Tg) mice have decreased HDL-CE, apoA-I, and apoA-II levels; plasma triglycerides, low density lipoprotein (LDL) cholesterol, and very low density lipoprotein (VLDL) and LDL apoB were also decreased, compared with control mice. Turnover studies using non-degradable CE and protein labels showed markedly increased total and selective uptake of HDL-CE in the liver and increased HDL protein catabolism in both liver and kidney. To evaluate the changes in apoB further, mice were challenged with high fat, high cholesterol diets. In SR-BI Tg mice plasma apoB levels were only 3-15% of control levels, and the dietary increase in VLDL and LDL apoB was virtually abolished. These studies show that steady state overexpression of hepatic SR-BI reduces HDL levels and increases reverse cholesterol transport. They also indicate that SR-BI can play a role in the metabolism of apoB-containing lipoproteins. The dual effects of increased reverse cholesterol transport and lowering of apoB-containing lipoproteins that result from hepatic SR-BI overexpression could have anti-atherogenic consequences.The risk of coronary heart disease is inversely correlated with the levels of plasma high density lipoproteins (HDL) 1 (1, 2). HDL appears to transport cholesterol from peripheral tissues to the liver for catabolism and secretion (reverse cholesterol transport) (3, 4). A putative cell-surface receptor for this process has been identified (5). This receptor, scavenger receptor BI (SR-BI), mediates high affinity binding of HDL and the selective uptake of HDL cholesteryl ester (CE) (5), a process for delivery of cholesteryl ester into cells without degradation of HDL proteins (6). Furthermore, SR-BI mRNA and protein levels are highest in adrenal gland, ovary, testis, and liver, tissues that display greatest selective cholesteryl ester uptake from HDL (7-9). SR-BI expression in steroidogenic cells is regulated by hormones and mutations that alter cholesterol supply or metabolism in those tissues in vivo (8 -11). More recently, strong support for the role of SR-BI in HDL metabolism has been provided by studies of mice with a targeted mutation resulting in decreased SR-BI gene expression (12, 13). These mice demonstrate increased plasma HDL cholesterol, decreased adrenal cholesterol content (12, 13), and decreased hepatic fractional clearance rate (FCR) for HDL-CE (13), suggesting that SR-BI is the major molecule mediating HDL-CEselective uptake in the liver. By contrast, adenovirus-mediated, hepatic overexpression of SR-BI in mice results in depletion of plasma HDL and an increase in biliary cholesterol concentration (14). Although these studies nicely demonstrate the effect of acute overexpression of ...

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Section: Sr-bi Expression In Sr-bi Tgmentioning

confidence: 99%

Section: Fig 4 Plasma Decay Curves and Fcrs Formentioning

confidence: 99%

Liver-specific Overexpression of Scavenger Receptor BI Decreases Levels of Very Low Density Lipoprotein ApoB, Low Density Lipoprotein ApoB, and High Density Lipoprotein in Transgenic Mice

Wang

Arai

et al. 1998

Journal of Biological Chemistry

270

234

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“…This provided the basis for a simple analytical technique (10) to demonstrate LP-X in plasma samples; its appearance has been used as a new diagnostic test in the differential diagnosis of cholestatic liver disease. Several studies in adults and children (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) have demonstrated that the presence of this lipoprotein is an extremely specific sign of cholestasis, with the sole exception of the rare familial disease lecithin: cholesterol acyltransferase deficiency (23)(24)(25). Although many data have accumulated in the past regarding the protein-lipid composition of LP-X, its immunological and physicochemical characteristics, its electrophoretic behavior in various media, and its structural properties (1)(2)(3)(4)(5)(6)(7)(8)(9), little or no information is available regarding the source of LP-X, its metabolism, or its fluctuations in the course of cholestatic liver disease.…”

Section: Introductionmentioning

confidence: 99%

Formation of lipoprotein-X. Its relationship to bile compounds.

Manzato¹,

Fellin²,

Baggio³

et al. 1976

J. Clin. Invest.

140

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A B S T R A C T In this study we have demonstrated that in native bile, lipids are organized in the form of a lipoprotein (bile LP) carrying albumin as apoprotein. The lipid composition of bile LP is almost identical to lipoprotein-X (LP-X, the characteristic lipoprotein of cholestasis). However, it differs from LP-X in its protein/lipid ratio and immunological and electrophoretic characteristics. Bile lipoprotein can be converted into "LP-X-like" material in vitro by adding albumin or serum to native bile. The LP-X-like material formed in vitro has physicochemical and chemical characteristics similar or identical to LP-X isolated from serum. As bile lipoprotein can be converted into LP-X-like material by the addition of albumin to bile, LP-X can be converted into bile-LP-like particles by adding bile salts to a LP-X-positive serum. Furthermore, experimental connection of the common bile duct to the vena cava is followed after a few hours by the appearance of LP-Xlike material in the plasma. These facts taken together strongly suggest that bile LP is a precursor lipoprotein for LP-X and that it refluxes into the plasma pool under cholestatic conditions.

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“…However, serum albumin has never been shown to associate with bulk phospholipid, although the protein is known to be important in lipoprotein metabolism and is an integral component of lipoprotein particles under certain conditions. 18 If serum albumin does associate with bulk phospholipid, it probably does so with the following restrictions: (1) cooperative interactions with another protein (or possibly lipid) are required for bulk binding and (2) the association is easily reversible, i.e., associated serum albumin can be displaced by another apolipoprotein such as C-111.…”

Section: Discussionmentioning

confidence: 99%