Search results for ABCA1

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Pathway (5 results from a total of 5)

Identifier: R-HSA-5682113
Species: Homo sapiens
In an ATP-dependent reaction, ATP-binding cassette sub-family A member 1 (ABCA1) mediates the movement of intracellular cholesterol to the extracellular face of the plasma membrane. Cholesterol associated with cytosolic vesicles is a substrate for this reaction. Under physiologocal conditions, the active form of ABCA1 is post-translationally modified (palmitoylated and phosphorylated), predominantly a tetramer and is associated with apolipoprotein A-I (APOA1). Defects in ABCA1 can cause Tangier disease (TGD; MIM:205400 aka high density lipoprotein deficiency type 1), an autosomal recessive disorder characterised by significantly reduced levels of plasma high density lipoproteins (HDL) resulting in tissue accumulation of cholesterol esters (Brooks-Wilson et al. 1999). Low HDL levels are among the most common biochemical abnormalities observed in coronary heart disease (CHD) patients (Kolovou et al. 2006, Iatan et al. 2008, Iatan et al. 2012).
Identifier: R-HSA-5682294
Species: Homo sapiens
ATP-binding cassette sub-family A member 12 (ABCA12) is thought to function as an epidermal keratinocyte lipid transporter. These lipids form extracellular lipid layers in the stratum corneum of the epidermis, essential for skin barrier function. Defects in ABCA12 results in the loss of the skin lipid barrier, leading to autosomal recessive congenital ichthyosis 4B (ARCI4B; MIM:242500, aka harlequin ichthyosis, HI). ARCI4B shows the most severe phenotype of the congenital ichthyoses, with newborns having a thick covering of armour-like scales. The skin dries out to form hard diamond-shaped plaques separated by fissures. Affected babies are often born prematurely and rarely survive the perinatal period (Akiyama et al. 2005, Akiyama 2010, 2014).
Identifier: R-HSA-9029569
Species: Homo sapiens
Compartment: nucleoplasm
The liver X receptors (LXRs), LXRα (NR1H3) and LXRβ (NR1H2), are nuclear receptors that are activated by endogenous oxysterols, oxidized derivatives of cholesterol (Janowski BA et al. 1996). When cellular oxysterols accumulate as a result of increasing concentrations of cholesterol, NR1H2,3 induce the transcription of genes that protect cells from cholesterol overload (Zhao C & Dahlman‑Wright K 2010; Ma Z et al. 2017). In peripheral cells such as macrophages, NR1H2 and NR1H3 increase cholesterol efflux by inducing expression of ATP-binding cassette subfamily A type 1 (ABCA1), ABCG1, and apolipoprotein APOE (Jakobsson T et al. 2009; Laffitte BA et al. 2001; Mak PA et al. 2002). In the intestine, LXR agonists decrease cholesterol absorption through induction of ABCA1, ABCG5, and ABCG8 (Repa JJ et al. 2000; Back SS et al. 2013). Cholesterol removal from non-hepatic peripheral cells, such as lipid-laden macrophages, and its delivery back to the liver for catabolism and excretion are processes collectively known as reverse cholesterol transport (RCT) (Francis GA 2010; Rosenson RS et al. 2012). This Reactome module describes the activation of several direct NR1H2,3 target genes that are closely associated with the RCT pathway, including genes encoding membrane lipid transporters, such ABCA1, ABCG1, ABCG5, ABCG8 and a cluster of apolipoprotein genes APOE, APOC1, APOC2 and APOC4 (Jakobsson T et al. 2009; Back SS et al. 2013; Mak PA et al. 2002).
Identifier: R-HSA-1989781
Species: Homo sapiens
Compartment: cytosol, endoplasmic reticulum membrane, extracellular region, lipid droplet, mitochondrial inner membrane, mitochondrial matrix, mitochondrial outer membrane, nucleoplasm, peroxisomal matrix, peroxisomal membrane, plasma membrane
The set of genes regulated by PPAR-alpha is not fully known in humans, however many examples have been found in mice. Genes directly activated by PPAR-alpha contain peroxisome proliferator receptor elements (PPREs) in their promoters and include:
1) genes involved in fatty acid oxidation and ketogenesis (Acox1, Cyp4a, Acadm, Hmgcs2);
2) genes involved in fatty acid transport (Cd36, , Slc27a1, Fabp1, Cpt1a, Cpt2);
3) genes involved in producing fatty acids and very low density lipoproteins (Me1, Scd1);
4) genes encoding apolipoproteins (Apoa1, Apoa2, Apoa5);
5) genes involved in triglyceride clearance ( Angptl4);
6) genes involved in glycerol metabolism (Gpd1 in mouse);
7) genes involved in glucose metabolism (Pdk4);
8) genes involved in peroxisome proliferation (Pex11a);
9) genes involved in lipid storage (Plin, Adfp).
Many other genes are known to be regulated by PPAR-alpha but whether their regulation is direct or indirect remains to be found. These genes include: ACACA, FAS, SREBP1, FADS1, DGAT1, ABCA1, PLTP, ABCB4, UGT2B4, SULT2A1, Pnpla2, Acsl1, Slc27a4, many Acot genes, and others (reviewed in Rakhshandehroo et al. 2010).
Identifier: R-HSA-9024446
Species: Homo sapiens
Compartment: nucleoplasm
The liver X receptors LXRα (NR1H3) and LXRβ (NR1H2) are members of the nuclear receptor superfamily and function as ligand-activated transcription factors. The natural ligands of NR1H2 and NR1H3 are oxysterols (e.g., 24(S),25-epoxycholesterol, 24(S)-hydroxycholesterol (OH), 25-OH, and 27-OH) that are produced endogenously by enzymatic reactions, by reactive oxygen species (ROS)-dependent oxidation of cholesterol and by the alimentary processes (reviewed in:Jakobsson T et al. 2012; Huang C 2014; Komati R et al. 2017). It has been shown that these oxysterols bind directly to the ligand-binding domain of LXRs with Kd values ranging from 0.1 to 0.4 microM. 24(S), 25-epoxycholesterol was found to be the most potent endogenous agonist (Janowski BA et al. 1999). NR1H3 (LXRα) and NR1H2 (LXRβ) showed similar affinities for these compounds (Janowski BA et al. 1999). In physiological conditions, oxysterols are formed in amounts proportional to cholesterol content in the cell and therefore the LXRs operate as cholesterol sensors to alter gene expression and protect the cells from cholesterol overload via: (1) inhibiting intestinal cholesterol absorption; (2) stimulating cholesterol efflux from cells to high-density lipoproteins through the ATP-binding cassette transporters ABCA1 and ABCG1: (3) activating the conversion of cholesterol to bile acids in the liver; and (4) activating biliary cholesterol and bile acid excretion (reviewed in: Wójcicka G et al. 2007; Baranowski M 2008; Laurencikiene J & Rydén M 2012; Edwards PA et al. 2002; Zelcer N & Tontonoz P 2006; Zhao C & Dahlman-Wright K 2010). In addition, LXR agonists enhance de novo fatty acid synthesis by stimulating the expression of a lipogenic transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c), leading to the elevation of plasma triglycerides and hepatic steatosis (Wójcicka G et al. 2007; Baranowski M 2008; Laurencikiene J & Rydén M 2012). In addition to their function in lipid metabolism, NR1H2,3 have also been found to modulate immune and inflammatory responses in macrophages (Zelcer N & Tontonoz P 2006). The NR1H2 and NR1H3 molecules can be viewed as having four functional domains: (1) an amino-terminal ligand-independent activation function domain (AF-1), which may stimulate transcription in the absence of ligand; (2) a DNA-binding domain (DBD) containing two zinc fingers; (3) a hydrophobic ligand-binding domain (LBD) required for ligand binding and receptor dimerization; and, (4) a carboxy-terminal ligand-dependent transactivation sequence (also referred to as the activation function-2 (AF-2) domain) that stimulates transcription in response to ligand binding (Robinson-Rechavi M et al. 2003; Jakobsson T et al. 2012; Färnegardh M et al. 2003; Lin CY & Gustafsson JA 2015). Although both NR1H3 and NR1H2 are activated by the same ligands and are structurally similar, their tissue expression profiles are very different. NR1H3 is selectively expressed in specific tissues and cell types, such as the liver, intestine, adrenal gland, adipose tissue and macrophages, whereas NR1H2 is ubiquitously expressed (Nishimura M et al. 2004; Bookout AL et al. 2006). Upon activation NR1H2 or NR1H3 heterodimerizes with retinoid X receptors (RXR) and binds to LXR-response elements (LXREs) consisting of a direct repeat of the core sequence 5'-AGGTCA-3' separated by 4 nucleotides (DR4) in the DNA of target genes (Wiebel FF & Gustafsson JA 1997). An inverted repeat of the same consensus sequence with no spacer region(IR-0) and an inverted repeat of the same consensus sequence separated by a 1 bp spacer (IR-1) have also been shown to mediate LXR transactivation (Mak PA et al. 2002, Landrier JF et al. 2003). NR1H3 and NR1H2 have been shown to regulate gene expression via LXREs in the promoter regions of their target genes such as UDP glucuronosyltransferase 1 family, polypeptide A3 (UGT1A3) (Verreault M et al. 2006), fatty acid synthase (FAS) (Joseph SB et al. 2002a), carbohydrate response element binding protein (ChREBP, also known as MLX-interacting protein-like or MLXIPL) (Cha JY & Repa JJ 2007) and phospholipid transfer protein (PLTP) (Mak PA et al. 2002). LXREs have also been reported to be present in introns of target genes such as the ATP-binding cassette transporter G1 (ABCG1) (Sabol SL et al. 2005). NR1H3 has been shown to activate gene expression via the FXR-responsive element found in the proximal promoter of the human ileal bile acid-binding protein (FABP6) (Landrier JF et al. 2003). The NR1H2,3:RXR heterodimers are permissive, in that they can be activated by ligands for either NR1H2,3 (LXR) or RXR (Willy PJ et al. 1995).
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