Centripetal cholesterol flux from extrahepatic organs to the liver is independent of the concentration of high density lipoprotein-cholesterol in plasma.

Osono, Yasunori; Woollett, Laura A.; Marotti, Keith R.; Melchior, George W.; Dietschy, John M.

doi:10.1073/pnas.93.9.4114

Cited by 78 publications

(56 citation statements)

References 44 publications

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“…According to our results, ABCA1 does not significantly control total body cholesterol fluxes, even under highly stressed conditions. Assuming that the overall centripetal cholesterol flux in the mice used in these studies is of the same order of magnitude as that reported in several other mouse models (51,52,56), our results strongly suggest that ABCA1 is not involved in control of this flux. Since very low HDL levels resulting from the absence of apoA-I also do not influence centripetal cholesterol flux in mice (56-58), we hypothesize that HDL does not play a quantitatively important role in this pathway of cholesterol transport.…”

Section: Figuresupporting

confidence: 54%

“…Elucidation of the factors involved in regulation of this HDL-mediated pathway is therefore of prime importance. Detailed information about the magnitude of the different cholesterol fluxes in the bodies of rodents has been generated in a series of elegant studies from Dietschy's group (2,(47)(48)(49)(50)(51)(52)(53). An important conclusion from their work is that reverse cholesterol transport, which they call "centripetal cholesterol flux," is not determined by the plasma level of HDL, but by processes in peripheral tissues that make cholesterol available for uptake by nascent HDL particles.…”

Section: Discussionmentioning

confidence: 99%

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

Groen¹,

Bloks²,

Bandsma³

et al. 2001

J. Clin. Invest.

133

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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.

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Section: Figuresupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

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

Groen¹,

Bloks²,

Bandsma³

et al. 2001

J. Clin. Invest.

133

View full text Add to dashboard Cite

show abstract

“…Studies in transgenic mice have shown that arterial macrophages contribute little to HDL-cholesterol (8 ) and that the plasma HDL-cholesterol concentration is not a reliable indicator of the rate of flux of cholesterol from peripheral tissues to the liver (9,10 ). Plasma HDL-cholesterol is influenced by the lipolysis of TGRLs, by the transfer of CEs to apo B-containing lipoproteins via CETP (7 ), and by the activity of the ABCA1 transporter in liver cells (19 ).…”

Section: Discussionmentioning

confidence: 99%

Association of Coronary Heart Disease with Pre-β-HDL Concentrations in Japanese Men

Hashimoto¹,

Kujiraoka²,

Egashira³

et al. 2004

Clinical Chemistry

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Background:In individuals heterozygous for ABCA1 transporter mutations, defective reverse cholesterol transport (RCT) causes low HDL-cholesterol and premature coronary heart disease (CHD). However, the extent to which impaired RCT underlies premature CHD in others with low HDL-cholesterol is not known. The primary acceptors of cell cholesterol are a minor subclass of lipid-poor pre-␤-HDLs. These are generated during remodeling of ␣-HDLs, which account for almost all HDL-cholesterol. We studied the strength of the association of CHD with pre-␤-HDL concentrations in Japanese men. Methods: Blood was collected from 42 men with clinical CHD and 44 healthy controls 40 -70 years of age. Pre-␤-HDL was assayed by crossed immunoelectrophoresis. Results: Cases had lower HDL-cholesterol (؊23%), total apolipoprotein A-I (؊26%), and pre-␤-HDL (؊55%; all P <0.001) concentrations; lower pre-␤-HDL:␣-HDL ratios (؊45%; P <0.001); and higher plasma triglycerides (20%; P <0.03) than the controls. On stepwise logistic regression, CHD was associated most strongly with pre-␤-HDL concentrations. On ROC analysis, pre-␤-

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“…This challenges and dampens the traditional notion of reverse cholesterol transport from peripheral cells to the liver via HDL (84) The knowledge of the sites and control of ABCA1 expression has already prompted the discussion of the concept of reverse cholesterol transport (16). Intriguingly, the HDL level appears to have no relation to net flux of cholesterol through HDL (85).…”

Section: Effect Of Abca1 Deficiency On Distribution Of Hapoa-i and Chmentioning

confidence: 99%

ApoA-I Lipidation in Primary Mouse Hepatocytes

Kiss¹,

Franklin

Wang

et al. 2005

Journal of Biological Chemistry

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The liver is the major site of both apolipoprotein A-I (apoA-I) synthesis and ATP-binding cassette transporter A1 (ABCA1) expression. Here, we compare the lipidation with cholesterol and phospholipid of newly synthesized human apoA-I (hapoA-I) using adenoviral vector-mediated endogenous expression or exogenously added hapoA-I in wild type and ABCA1-null hepatocytes. 3 H]choline. ABCA1 deficiency decreased apoA-I phospholipidation by 80%, but acquisition of de novo synthesized and exogenous cholesterol only decreased by 40 -60%. The transfer of de novo synthesized cholesterol to apoA-I was decreased at all time points, but that of exogenously delivered cholesterol was independent of ABCA1 activity at the early time points. Progesterone does not affect apoA-I synthesis or its lipidation but inhibited the early phase of apoA-I cholesterol lipidation in both wild type and ABCA1-null hepatocytes. Fast protein liquid chromatography analysis of medium lipoproteins confirmed that with ABCA1 deficiency, the proportion of secreted high density lipoprotein-associated apoA-I and cholesterol decreased by about 50%. The very low density lipoprotein (VLDL)/ LDL size fraction also contained a significant level of cholesterol in ABCA1 deficiency, consistent with the result of immunoprecipitations showing the presence of lipoproteins with both apoA-I and murine apoB. ApoA-I lipidation with newly synthesized cholesterol in ABCA1-null hepatocytes was significantly decreased by brefeldin A and monensin. In conclusion, we demonstrate that: (i) whereas most hepatic phospholipidation of apoA-I is mediated by ABCA1, acquisition of cholesterol depends on active transfer from intracellular compartments by ABCA1-dependent and -independent pathways, both sensitive to progesterone and (ii) there is separate regulation of phospholipid and cholesterol lipidation of apoA-I in hepatocytes.The ATP-binding cassette transporter protein, ABCA1, 1 is the major determinant of the phospholipid and cholesterol lipidation of apolipoprotein A-I that enables formation of high density lipoprotein (HDL) (1). ABCA1 has been shown to regulate lipid efflux, and a deficiency in ABCA1, as in Tangier disease, results in nearly undetectable levels of HDL (2-6). Macrophages in various tissues are profoundly affected by this disease, first suggesting that ABCA1 function in macrophages was critical for the maintenance of HDL levels in the plasma, as part of the reverse cholesterol transport. However, Haghpassand et al. (7) demonstrated that macrophages account for only 20% of the generation of circulating HDL. ABCA1 (4, 8 -12) and apoA-I (13, 14) are both highly expressed in the liver and intestine, suggesting that ABCA1 contributes to the lipidation of newly secreted lipoproteins in those tissues. Basso et al. (15) used an ABCA1 adenovirus expression system to promote liver expression of ABCA1, thereby raising plasma HDLcholesterol and promoting cholesterol efflux from primary hepatocytes, supporting the role of the liver as a major source of HDL.As noted by Tall e...

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Centripetal cholesterol flux from extrahepatic organs to the liver is independent of the concentration of high density lipoprotein-cholesterol in plasma.

Cited by 78 publications

References 44 publications

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

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

Association of Coronary Heart Disease with Pre-β-HDL Concentrations in Japanese Men

ApoA-I Lipidation in Primary Mouse Hepatocytes

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