Role of the hepatic ABCA1 transporter in modulating intrahepatic cholesterol and plasma HDL cholesterol concentrations
Autor: | Silvia Santamarina-Fojo, Marcelo Amar, Nicholas Duverger, Alan T. Remaley, Federica Basso, H. Bryan Brewer, Edward B. Neufeld, Catherine L. Knapper, John A. Stonik, Terese Tansey, Lita A. Freeman, Jamila Fruchart-Najib |
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Jazyk: | angličtina |
Rok vydání: | 2003 |
Předmět: |
Male
Apolipoprotein E Genetically modified mouse medicine.medical_specialty Lipoproteins Recombinant Fusion Proteins Tangier disease QD415-436 Biology Biochemistry Adenoviridae Mice chemistry.chemical_compound Endocrinology Internal medicine medicine Animals Liver X receptor Cells Cultured Cholesterol Cholesterol HDL Reverse cholesterol transport lipoprotein nutritional and metabolic diseases cholesterol Cell Biology medicine.disease Lipids reverse cholesterol transport Mice Inbred C57BL Liver chemistry ABCA1 Hepatocytes biology.protein ATP-Binding Cassette Transporters lipids (amino acids peptides and proteins) ATP Binding Cassette Transporter 1 Lipoprotein |
Zdroj: | Journal of Lipid Research, Vol 44, Iss 2, Pp 296-302 (2003) |
ISSN: | 0022-2275 |
Popis: | The current model for reverse cholesterol transport proposes that HDL transports excess cholesterol derived primarily from peripheral cells to the liver for removal. However, recent studies in ABCA1 transgenic mice suggest that the liver itself may be a major source of HDL cholesterol (HDL-C). To directly investigate the hepatic contribution to plasma HDL-C levels, we generated an adenovirus (rABCA1-GFP-AdV) that targets expression of mouse ABCA1-GFP in vivo to the liver. Compared with mice injected with control AdV, infusion of rABCA1-GFP-AdV into C57Bl/6 mice resulted in increased expression of mouse ABCA1 mRNA and protein in the liver. ApoA-I-dependent cholesterol efflux was increased 2.6-fold in primary hepatocytes isolated 1 day after rABCA1-GFP-AdV infusion. Hepatic ABCA1 expression in C57Bl/6 mice (n = 15) raised baseline levels of TC, PL, FC, HDL-C, apoE, and apoA-I by 150–300% (P < 0.05 all). ABCA1 expression led to significant compensatory changes in expression of genes that increase hepatic cholesterol, including HMG-CoA reductase (3.5-fold), LDLr (2.1-fold), and LRP (5-fold) in the liver.These combined results demonstrate that ABCA1 plays a key role in hepatic cholesterol efflux, inducing pathways that modulate cholesterol homeostasis in the liver, and establish the liver as a major source of plasma HDL-C. |
Databáze: | OpenAIRE |
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