Expression of the Apolipoprotein E Gene in the Skin is Controlled by a Unique Downstream Enhancer

Grehan, Sharon; Allan, Charles M.; Tse, Elizabeth; Walker, David W.; Taylor, John M.

doi:10.1046/j.1523-1747.2001.00213.x

Cited by 26 publications

(14 citation statements)

References 46 publications

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“…For hepatic expression, previous reports revealed that the human apoE gene expression in the liver is regulated by specific enhancers, HCR.1 and HCR.2 (41,46,47). In the skin, apoE gene expression is controlled by a unique 1.0-kb enhancer domain located 1.7 kb downstream of the apoE gene (48). Two distal downstream enhancers, ME.1 and ME.2, direct the expression of the apoE gene in macrophages, adipose tissue, and astrocytes (38,49,50).…”

Section: Discussionmentioning

confidence: 99%

Macrophage-specific Up-regulation of Apolipoprotein E Gene Expression by STAT1 Is Achieved via Long Range Genomic Interactions

Trusca

Fuior

Florea

et al. 2011

Journal of Biological Chemistry

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In atherogenesis, macrophage-derived apolipoprotein E (apoE) has an athero-protective role by a mechanism that is not fully understood. We investigated the regulatory mechanisms involved in the modulation of apoE expression in macrophages. The experiments showed that the promoters of all genes of the apoE/apoCI/apoCIV/apoCII gene cluster are enhanced by multienhancer 2 (ME.2), a regulatory region that is located 15.9 kb downstream of the apoE gene. ME.2 interacts with the apoE promoter in a macrophage-specific manner. Transient transfections in RAW 264.7 macrophages showed that the activity of ME.2 was strongly decreased by deletion of either 87 bp from the 5 end or 131 bp from the 3 end. We determined that the minimal fragment of this promoter that can be activated by ME.2 is the proximal ؊100/؉73 region. The analysis of the deletion mutants of ME.2 revealed the importance of the 5 end of ME.2 in apoE promoter transactivation. Chromatin conformational capture assays demonstrated that both ME.2 and ME.1 physically interacted with the apoE promoter in macrophages. Our data showed that phorbol 12-myristate 13-acetate-induced differentiation of macrophages is accompanied by a robust induction of apoE and STAT1 expression. In macrophages (but not in hepatocytes), STAT1 up-regulated apoE gene expression via ME.2. The STAT1 binding site was located in the 174 -182 region of ME.2. In conclusion, the specificity of the interactions between the two multienhancers (ME.1 and ME.2) and the apoE promoter indicates that these distal regulatory elements play an important role in the modulation of apoE gene expression in a cell-specific manner.Apolipoprotein E (apoE), a glycoprotein of 35 kDa, is associated with the chylomicron remnants, very low density lipoproteins, low density lipoproteins (LDL), and high density lipoproteins (HDL) and plays an important role in lipid metabolism (1-6). Deficiency in apoE results in atherosclerosis in humans and in animal models (7-12). ApoE knock-out mice are the best-characterized animal models of atherosclerosis (13). ApoE is a ligand for the LDL receptor found in the liver and other tissues and for the LDL receptor-related protein found in hepatocytes and as such it facilitates the clearance of lipoprotein remnants from the circulation (14 -16). Malfunction of the mechanisms of cholesterol clearance leads to the accumulation of remnants in the plasma, a process associated with premature atherosclerosis (8,11,12). ApoE regulates plasma cholesterol levels, also having an important role in cholesterol efflux, as documented by studies in patients and animal models with apoE deficiency or mutated apoE genes (17-24). Recently, antioxidant and anti-inflammatory functions within the atherosclerotic plaque were attributed to apoE (23,24).ApoE is mainly synthesized by the liver and also by various cells and peripheral tissues (25). At the site of atherosclerotic lesion, apoE is provided by macrophages. Transgenic mice expressing apoE only in macrophages are protected against atherosclerosis even th...

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Section: Discussionmentioning

confidence: 99%

Macrophage-specific Up-regulation of Apolipoprotein E Gene Expression by STAT1 Is Achieved via Long Range Genomic Interactions

Trusca

Fuior

Florea

et al. 2011

Journal of Biological Chemistry

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“…In fact, human epidermal skin grafts transplanted onto mice result in the appearance of human apolipoprotein E in the serum, demonstrating that the production of apolipoprotein E in the skin may result in the systemic delivery of apolipoprotein E (148). The expression of apolipoprotein E in the epidermis is specified by a unique 1.0 kb enhancer domain located 1.7 kb downstream of the apolipoprotein E gene (149). Deletion of this enhancer resulted in the lack of expression of apolipoprotein E in the epidermis.…”

Section: Jlr: Are the Apolipoproteins That Interact With Lipoprotein mentioning

confidence: 99%

Thematic review series: Skin Lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis

Feingold

2007

Journal of Lipid Research

366

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The permeability barrier is required for terrestrial life and is localized to the stratum corneum, where extracellular lipid membranes inhibit water movement. The lipids that constitute the extracellular matrix have a unique composition and are 50% ceramides, 25% cholesterol, and 15% free fatty acids. Essential fatty acid deficiency results in abnormalities in stratum corneum structure function. The lipids are delivered to the extracellular space by the secretion of lamellar bodies, which contain phospholipids, glucosylceramides, sphingomyelin, cholesterol, and enzymes. In the extracellular space, the lamellar body lipids are metabolized by enzymes to the lipids that form the lamellar membranes. The lipids contained in the lamellar bodies are derived from both epidermal lipid synthesis and extracutaneous sources. Inhibition of cholesterol, fatty acid, ceramide, or glucosylceramide synthesis adversely affects lamellar body formation, thereby impairing barrier homeostasis. Studies have further shown that the elongation and desaturation of fatty acids is also required for barrier homeostasis. The mechanisms that mediate the uptake of extracutaneous lipids by the epidermis are unknown, but keratinocytes express LDL and scavenger receptor class B type 1, fatty acid transport proteins, and CD36. Topical application of physiologic lipids can improve permeability barrier homeostasis and has been useful in the treatment of cutaneous disorders.-Feingold, K. R. The role of epidermal lipids in cutaneous permeability barrier homeostasis. J. Lipid Res.

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“…Thus, polymorphisms within the proximal promoter of APOE may cause increased apoE levels in the brain, thereby increasing the risk for AD, especially for those carrying the ⑀4 allele (122). Transcription of APOE is regulated by an array of tissue-specific cis-acting regulatory elements distributed over a 20-kilobase region spanning the APOE locus (110,(123)(124)(125)(126)(127)(128)(129)(130)(131)). Although our current study does not directly address the mechanisms by which the astrocyte-derived factor or factors regulate the transcription of APOE, we speculate that the factor or factors may trigger a signal pathway, such as the Erk pathway, that leads to activation of certain tissue-specific cis-acting regulatory elements of APOE that might be modified by APOE promoter polymorphisms.…”

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confidence: 99%

Astroglial Regulation of Apolipoprotein E Expression in Neuronal Cells

Harris

Tesseur

Brecht

et al. 2004

Journal of Biological Chemistry

122

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Although apolipoprotein (apo) E is synthesized in the brain primarily by astrocytes, neurons in the central nervous system express apoE, albeit at lower levels than astrocytes, in response to various physiological and pathological conditions, including excitotoxic stress. To investigate how apoE expression is regulated in neurons, we transfected Neuro-2a cells with a 17-kilobase human apoE genomic DNA construct encoding apoE3 or apoE4 along with upstream and downstream regulatory elements. The baseline expression of apoE was low. However, conditioned medium from an astrocytic cell line (C6) or from apoE-null mouse primary astrocytes increased the expression of both isoforms by 3-4-fold at the mRNA level and by 4 -10-fold at the protein level. These findings suggest that astrocytes secrete a factor or factors that regulate apoE expression in neuronal cells. The increased expression of apoE was almost completely abolished by incubating neurons with U0126, an inhibitor of extracellular signal-regulated kinase (Erk), suggesting that the Erk pathway controls astroglial regulation of apoE expression in neuronal cells. Human neuronal precursor NT2/D1 cells expressed apoE constitutively; however, after treatment of these cells with retinoic acid to induce differentiation, apoE expression diminished. Cultured mouse primary cortical and hippocampal neurons also expressed low levels of apoE. Astrocyte-conditioned medium rapidly up-regulated apoE expression in fully differentiated NT2 neurons and in cultured mouse primary cortical and hippocampal neurons. Thus, neuronal expression of apoE is regulated by a diffusible factor or factors released from astrocytes, and this regulation depends on the activity of the Erk kinase pathway in neurons.The ⑀4 allele of the gene encoding apolipoprotein (apo) 1 E has been genetically linked to late-onset familial and sporadic Alzheimer's disease (AD) and has a gene-dose effect on the risk and age of onset of the disease (1-5). Individuals with two copies of the ⑀4 allele have a 50 -90% chance of developing AD by the age of 85, and those with one copy have about a 45% chance (1,6). Only about 20% of the general population develops AD by the age of 85 (1).ApoE is found in amyloid plaques and neurofibrillary tangles, two neuropathological hallmarks of AD (7-13), but its role in their pathogenesis is unclear. ApoE4 has several adverse effects that might explain the association between AD and the ⑀4 allele. It modulates the deposition and clearance of amyloid ␤ peptides and plaque formation (14 -21), impairs the antioxidative defense system (22), dysregulates neuronal signaling pathways (23), disrupts cytoskeletal structure and function (24,25), and alters the phosphorylation of tau and the formation of neurofibrillary tangles (26 -30). However, the mechanisms of these effects are still largely unknown, and it is not known which are the primary effects and which are subsequent or downstream effects.Initially, apoE was thought to be synthesized in the brain only by astrocytes, oligodendrocyte...

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Expression of the Apolipoprotein E Gene in the Skin is Controlled by a Unique Downstream Enhancer

Cited by 26 publications

References 46 publications

Macrophage-specific Up-regulation of Apolipoprotein E Gene Expression by STAT1 Is Achieved via Long Range Genomic Interactions

Macrophage-specific Up-regulation of Apolipoprotein E Gene Expression by STAT1 Is Achieved via Long Range Genomic Interactions

Thematic review series: Skin Lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis

Astroglial Regulation of Apolipoprotein E Expression in Neuronal Cells

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