Lipoproteins and Lipolytic Plasma Enzymes in a Case of Tangier Disease

Greten, H.; Hannemann, Thomas; Gusek, W; Vivell, O

doi:10.1056/nejm197409122911103

Cited by 29 publications

(9 citation statements)

References 25 publications

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“…This finding was further supported by delayed in-vivo clearance of postprandial triglyceride after an oral fat load. The molecular explanation for this decreased lipolytic activity is unknown; however, these observations in HSKO mice agree with similar data demonstrating decreased lipoprotein lipase activity [19] and delayed clearance of postprandial lipid in Tangier disease patients [3]. …”

Section: Hepatic Atp-binding Cassette Transporter A1 and Triglyceridesupporting

confidence: 88%

Hepatic ABC transporters and triglyceride metabolism

Parks

Chung

Shelness³

2012

Current Opinion in Lipidology

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Purpose of review Elevated plasma triglyceride and reduced HDL concentrations are prominent features of metabolic syndrome and type 2 diabetes. Individuals with Tangier disease also have elevated plasma triglyceride concentrations and very low HDL, resulting from mutations in ATP-binding cassette transporter A1 (ABCA1), an integral membrane protein that facilitates nascent HDL particle assembly. Past studies attributed the inverse relationship between plasma HDL and triglyceride to intravascular lipid exchange and catabolic events. However, recent studies also suggest that hepatic signaling and lipid mobilization and secretion may explain how HDL affects plasma triglyceride concentrations. Recent findings Hepatocyte-specific ABCA1 knockout mice have markedly reduced plasma HDL and a two-fold increase in triglyceride due to failure to assemble nascent HDL particles by hepatocytes, causing increased catabolism of HDL apolipoprotein A-I and increased hepatic production of triglyceride-enriched VLDL. In-vitro studies suggest that nascent HDL particles may induce signaling to decrease triglyceride secretion. Inhibition of microRNA 33 expression in nonhuman primates augments hepatic ABCA1, genes involved in fatty acid oxidation, and decreases expression of lipogenic genes, causing increased plasma HDL and decreased triglyceride levels. Summary New evidence suggests potential mechanisms by which hepatic ABCA1-mediated nascent HDL formation regulates VLDL–triglyceride production and contributes to the inverse relationship between plasma HDL and triglyceride.

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Section: Hepatic Atp-binding Cassette Transporter A1 and Triglyceridesupporting

confidence: 88%

Hepatic ABC transporters and triglyceride metabolism

Parks

Chung

Shelness³

2012

Current Opinion in Lipidology

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“…The molecular explanation for this decrease is unknown at this time. However, our observations in HSKO mice agree with similar data demonstrating decreased LPL activity [122] and delayed clearance of postprandial lipid in Tangier disease subjects [123]. …”

Section: Hepatic Abca1: Another Link Between Hdl and Vldl Metabolismsupporting

confidence: 92%

Hepatic ABCA1 and VLDL triglyceride production

Liu

Chung

Shelness

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Elevated plasma triglyceride (TG) and reduced high density lipoprotein (HDL) concentrations are prominent features of metabolic syndrome (MS) and type 2 diabetes (T2D). Individuals with Tangier disease also have elevated plasma TG concentrations and a near absence of HDL, resulting from mutations in ATP binding cassette transporter A1 (ABCA1), which facilitates the efflux of cellular phospholipid and free cholesterol to assemble with apolipoprotein A-I (apoA-I), forming nascent HDL particles. In this review, we summarize studies focused on the regulation of hepatic very low density lipoprotein (VLDL) TG production, with particular attention on recent evidence connecting hepatic ABCA1 expression to VLDL, LDL, and HDL metabolism. Silencing ABCA1 in McArdle rat hepatoma cells results in diminished assembly of large (>10nm) nascent HDL particles, diminished PI3 kinase activation, and increased secretion of large, TG-enriched VLDL1 particles. Hepatocyte-specific ABCA1 knockout (HSKO) mice have a similar plasma lipid phenotype as Tangier disease subjects, with a twofold elevation of plasma VLDL TG, 50% lower LDL, and 80% reduction in HDL concentrations. This lipid phenotype arises from increased hepatic secretion of VLDL1 particles, increased hepatic uptake of plasma LDL by the LDL receptor, elimination of nascent HDL particle assembly by the liver, and hypercatabolism of apoA-I by the kidney. These studies highlight a novel role for hepatic ABCA1 in the metabolism of all three major classes of plasma lipoproteins and provide a metabolic link between elevated TG and reduced HDL levels that are a common feature of Tangier disease, MS, and T2D.

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“…Kocen and coworkers (22), moreover, found a low cholesterol: triglyceride ratio in their patient's LDL, an observation confirmed by Greten et al. (23) in another subject with Tangier disease. In the studies reported here, the lipid and apoprotein compositions of Tangier VLDL and LDL are compared with those of control subjects and striking deviations from the normal are defined.…”

supporting

confidence: 53%