Lipid efflux mechanisms, relation to disease and potential therapeutic aspects

Age-related macular degeneration (AMD) is a progressive disease of the retinal pigment epithelium (RPE) and the retina leading to loss of central vision. Polymorphisms in genes involved in lipid metabolism, including the ATP-binding cassette transporter A1 (ABCA1), have been associated with AMD risk. However, the significance of retinal lipid handling for AMD pathogenesis remains elusive. Here, we study the contribution of lipid efflux in the RPE by generating a mouse model lacking ABCA1 and its partner ABCG1 specifically in this layer. Mutant mice show lipid accumulation in the RPE, reduced RPE and retinal function, retinal inflammation and RPE/photoreceptor degeneration. Data from human cell lines indicate that the ABCA1 AMD risk-conferring allele decreases ABCA1 expression, identifying the potential molecular cause that underlies the genetic risk for AMD. Our results highlight the essential homeostatic role for lipid efflux in the RPE and suggest a pathogenic contribution of reduced ABCA1 function to AMD.

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Phosphatidylcholine Transfer Protein Promotes Apolipoprotein A-I-mediated Lipid Efflux in Chinese Hamster Ovary Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m106799200 ◽

2001 ◽

Vol 277 (8) ◽

pp. 6198-6206 ◽

Cited By ~ 17

Author(s):

Juan M. Baez ◽

Suzanne E. Barbour ◽

David E. Cohen

Keyword(s):

Chinese Hamster Ovary ◽

Chinese Hamster Ovary Cells ◽

Chinese Hamster ◽

Ovary Cells ◽

Transfer Protein ◽

Lipid Efflux ◽

Apolipoprotein A ◽

Phosphatidylcholine Transfer Protein

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Modification of HDL3 by mild oxidative stress increases ATP-binding cassette transporter-1-mediated lipid efflux: role of pre-β-migrating particles

Nutrition Metabolism and Cardiovascular Diseases ◽

10.1016/s0939-4753(04)80112-1 ◽

2004 ◽

Vol 14 (5) ◽

pp. 296

Keyword(s):

Oxidative Stress ◽

Atp Binding ◽

Atp Binding Cassette Transporter ◽

Lipid Efflux ◽

Atp Binding Cassette

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Lipid Droplet Accumulation and Impaired Fat Efflux in Polarized Hepatic Cells: Consequences of Ethanol Metabolism

International Journal of Hepatology ◽

10.1155/2012/978136 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 21

Author(s):

Benita L. McVicker ◽

Karuna Rasineni ◽

Dean J. Tuma ◽

Mark A. McNiven ◽

Carol A. Casey

Keyword(s):

Lipid Droplets ◽

Human Fibroblasts ◽

Ethanol Metabolism ◽

Ethanol Treatment ◽

Alcohol Metabolism ◽

Hepatic Cells ◽

Lipid Efflux ◽

Associated Proteins ◽

Dose Dependent Increase ◽

Dose Dependent

Steatosis, an early manifestation in alcoholic liver disease, is associated with the accumulation of hepatocellular lipid droplets (LDs). However, the role ethanol metabolism has in LD formation and turnover remains undefined. Here, we assessed LD dynamics following ethanol and oleic acid treatment to ethanol-metabolizing WIF-B cells (a hybrid of human fibroblasts (WI 38) and Fao rat hepatoma cells). An OA dose-dependent increase in triglyceride and stained lipids was identified which doubled (P<0.05) in the presence of ethanol. This effect was blunted with the inclusion of an alcohol metabolism inhibitor. The ethanol/ OA combination also induced adipophilin, LD coat protein involved in the attenuation of lipolysis. Additionally, ethanol treatment resulted in a significant reduction in lipid efflux. These data demonstrate that the metabolism of ethanol in hepatic cells is related to LD accumulation, impaired fat efflux, and enhancements in LD-associated proteins. These alterations in LD dynamics may contribute to ethanol-mediated defects in hepatocellular LD regulation and the formation of steatosis.

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