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Biomedical subjects

Bart Staels

Publications and source records attributed to Bart Staels.

At least 109 records · Page 6Linked to original sources
PubMed2003

Regulation of the scavenger receptor BI and the LDL receptor by activators of aldosterone production, angiotensin II and PMA, in the human NCI-H295R adrenocortical cell line.

In human adrenal cells, cholesterol for steroidogenesis is derived from both high-density lipoproteins (HDL) via the Scavenger Receptor Class B Type I (SR-BI) and low-density lipoproteins (LDL) via the LDL receptor pathway. We have previously shown that, in the human adrenocortical carcinoma cell line, NCI-H295R, SR-BI and LDL receptor expression and steroidogenesis are coordinately regulated by activators of protein kinase A (PKA) leading to glucocorticoid synthesis. In the present study, we studied whether SR-BI and LDL receptor expression are regulated by activators of the protein kinase C (PKC) signaling pathway, such as angiotensin II, which stimulate mineralocorticoid synthesis. First, it is shown that, in NCI-H295R cells, aldosterone synthesis is stimulated by a phorbol ester (phorbol-12-myristate-13 acetate, PMA), a potent PKC activator. Northern blot analysis indicated that both angiotensin II and PMA stimulated SR-BI expression in a time-dependent manner. LDL receptor expression is slightly stimulated by PMA. The induction of SR-BI gene expression occurs at the transcriptional level, via an activation of the human SR-BI promoter, as shown by transient transfection experiments. Finally, SR-BI protein level was increased in angiotensin II- and PMA-stimulated cells, resulting in higher lipoprotein binding and specific cholesteryl ester (CE) uptake from HDL, as well from LDL after angiotensin II and PMA stimulation.

Adrenal Cortex↗
PubMed2003

Liver X receptors and the control of cholesterol homeostasis: potential therapeutic targets for the treatment of atherosclerosis.

The liver X receptors (LXRalpha and LXRbeta) are nuclear receptor transcription factors that are activated by certain oxysterol derivatives of cholesterol. As such, LXR activity may be up-regulated by cellular lipid loading or dietary cholesterol intake. Intensive research interest in the LXRs has led to the identification of an expanding list of LXR target genes. The identity of these genes, and their response to LXR activation, indicates that the LXRs play an important role in the response to excess cholesterol, and that their activation may protect against tissue cholesterol overload. In this review, we highlight the multiple roles of the LXRs in controlling cholesterol homeostasis via their coordinated effects on cholesterol synthesis, dietary cholesterol absorption, reverse cholesterol transport, and bile acid synthesis and excretion. We discuss the therapeutic interest of developing LXR agonists, in view of their apparent protective effects against atherosclerosis. However, we also draw attention to the possible undesirable side-effects of LXR activation, and thus the potential interest of developing target gene-specific LXR agonists, or agonists that are specific for only one LXR isoform.

Animals↗
PubMed2003

Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor alpha activators.

The recently discovered APOA5 gene has been shown in humans and mice to be important in determining plasma triglyceride levels, a major cardiovascular disease risk factor. apoAV represents the first described apolipoprotein where overexpression lowers triglyceride levels. Since fibrates represent a commonly used therapy for lowering plasma triglycerides in humans, we investigated their ability to modulate APOA5 gene expression and consequently influence plasma triglyceride levels. Human primary hepatocytes treated with Wy 14,643 or fenofibrate displayed a strong induction of APOA5 mRNA. Deletion and mutagenesis analyses of the proximal APOA5 promoter firmly demonstrate the presence of a functional peroxisome proliferator-activated receptor response element. These findings demonstrate that APOA5 is a highly responsive peroxisome proliferator-activated receptor alpha target gene and support its role as a major mediator for how fibrates reduce plasma triglycerides in humans.

Apolipoprotein A-V↗
PubMed2003

The UDP-glucuronosyltransferase 1A9 enzyme is a peroxisome proliferator-activated receptor alpha and gamma target gene.

Peroxisome proliferator-activated receptor (PPAR) alpha and gamma are ligand-activated transcription factors belonging to the nuclear receptor family. PPAR alpha mediates the hypolipidemic action of the fibrates, whereas PPAR gamma is a receptor for the antidiabetic glitazones. In the present study, the UDP-glucuronosyltransferase (UGT) 1A9 enzyme is identified as a PPAR alpha and PPAR gamma target gene. UGTs catalyze the glucuronidation reaction, which is a major pathway in the catabolism and elimination of numerous endo- and xenobiotics. Among the UGT1A family enzymes, UGT1A9 metabolizes endogenous compounds, including catecholestrogens, and xenobiotics, such as fibrates and to a lesser extent troglitazone. Treatment of human hepatocytes and macrophages and murine adipocytes with activators of PPAR alpha or PPAR gamma resulted in an enhanced UGT1A9 expression and activity. In addition, disruption of the PPAR alpha gene in mice completely abolished the PPAR alpha agonist-induced UGT1A9 mRNA and activity levels. A PPAR response element was identified in the promoter of UGT1A9 at positions -719 to -706 bp by transient transfection and electromobility shift assays. Considering the role of UGT1A9 in catecholestrogen metabolism, PPAR alpha and PPAR gamma activation may contribute to the protection against genotoxic catecholestrogens by stimulating their inactivation in glucuronide derivatives. Furthermore, since UGT1A9 is involved in the catabolism of fibrates, these results suggest that PPAR alpha and PPAR gamma may control the intracellular level of active fibrates.

3T3 Cells↗
PubMed2003

Rupture of the atherosclerotic plaque: does a good animal model exist?

By its very nature, rupture of the atherosclerotic plaque is difficult to study directly in humans. A good animal model would help us not only to understand how rupture occurs but also to design and test treatments to prevent it from happening. However, several difficulties surround existing models of plaque rupture, including the need for radical interventions to produce the rupture, lack of direct evidence of rupture per se, and absence of convincing evidence of platelet- and fibrin-rich thrombus at the rupture site. At the present time, attention should therefore focus on the processes of plaque breakdown and thrombus formation in humans, whereas the use of animal models should probably be reserved for studying the function of particular genes and for investigating isolated features of plaques, such as the relationship between cap thickness and plaque stability.

Aged↗
PubMed2003

Peroxisome proliferator-activated receptor (PPAR) alpha and PPARbeta/delta, but not PPARgamma, modulate the expression of genes involved in cardiac lipid metabolism.

Long-chain fatty acids (FA) coordinately induce the expression of a panel of genes involved in cellular FA metabolism in cardiac muscle cells, thereby promoting their own metabolism. These effects are likely to be mediated by peroxisome proliferator-activated receptors (PPARs). Whereas the significance of PPARalpha in FA-mediated expression has been demonstrated, the role of the PPARbeta/delta and PPARgamma isoforms in cardiac lipid metabolism is unknown. To explore the involvement of each of the PPAR isoforms, neonatal rat cardiomyocytes were exposed to FA or to ligands specific for either PPARalpha (Wy-14,643), PPARbeta/delta (L-165041, GW501516), or PPARgamma (ciglitazone and rosiglitazone). Their effect on FA oxidation rate, expression of metabolic genes, and muscle-type carnitine palmitoyltransferase-1 (MCPT-1) promoter activity was determined. Consistent with the PPAR isoform expression pattern, the FA oxidation rate increased in cardiomyocytes exposed to PPARalpha and PPARbeta/delta ligands, but not to PPARgamma ligands. Likewise, the FA-mediated expression of FA-handling proteins was mimicked by PPARalpha and PPARbeta/delta, but not by PPARgamma ligands. As expected, in embryonic rat heart-derived H9c2 cells, which only express PPARbeta/delta, the FA-induced expression of genes was mimicked by the PPARbeta/delta ligand only, indicating that FA also act as ligands for the PPARbeta/delta isoform. In cardiomyocytes, MCPT-1 promoter activity was unresponsive to PPARgamma ligands. However, addition of PPARalpha and PPARbeta/delta ligands dose-dependently induced promoter activity. Collectively, the present findings demonstrate that, next to PPARalpha, PPARbeta/delta, but not PPARgamma, plays a prominent role in the regulation of cardiac lipid metabolism, thereby warranting further research into the role of PPARbeta/delta in cardiac disease.

Animals↗
PubMed2003

Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice.

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor that controls expression of genes involved in lipid metabolism and is activated by fatty acids and hypolipidaemic fibrates. Fibrates induce the hepatic expression of murine multidrug resistance 2 ( Mdr2 ), encoding the canalicular phospholipid translocator. The physiological role of PPARalpha in regulation of Mdr2 and other genes involved in bile formation is unknown. We found no differences in hepatic expression of the ATP binding cassette transporter genes Mdr2, Bsep (bile salt export pump), Mdr1a / 1b, Abca1 and Abcg5 / Abcg8 (implicated in cholesterol transport), the bile salt-uptake systems Ntcp (Na(+)-taurocholate co-transporting polypeptide gene) and Oatp1 (organic anion-transporting polypeptide 1 gene) or in bile formation between wild-type and Ppar alpha((-/-)) mice. Upon treatment of wild-type mice with ciprofibrate (0.05%, w/w, in diet for 2 weeks), the expression of Mdr2 (+3-fold), Mdr1a (+6-fold) and Mdr1b (+11-fold) mRNAs was clearly induced, while that of Oatp1 (-5-fold) was reduced. Mdr2 protein levels were increased, whereas Bsep, Ntcp and Oatp1 were drastically decreased. Exposure of cultured wild-type mouse hepatocytes to PPARalpha agonists specifically induced Mdr2 mRNA levels and did not affect expression of Mdr1a / 1b. Altered transporter expression in fibrate-treated wild-type mice was associated with a approximately 400% increase in bile flow: secretion of phospholipids and cholesterol was increased only during high-bile-salt infusions. No fibrate effects were observed in Ppar alpha((-/-)) mice. In conclusion, our results show that basal bile formation is not affected by PPARalpha deficiency in mice. The induction of Mdr2 mRNA and Mdr2 protein levels by fibrates is mediated by PPARalpha, while the induction of Mdr1a / 1b in vivo probably reflects a secondary phenomenon related to chronic PPARalpha activation.

ATP Binding Cassette Transporter 1↗
PubMed2003

Inhibition of cytokine production by the herbicide atrazine. Search for nuclear receptor targets.

The hematological toxicity of the commonly used triazine herbicides is a cause for concern. In a search for molecular targets of these compounds, as their effects paralleled those seen with dexamethasone (DEX), we first looked for interaction with the glucocorticoid receptor. In contrast to the effects on proliferation and cytokine production of DEX, those induced by atrazine were not prevented by the glucocorticoid antagonist RU486. Also, whereas DEX was able to inhibit the promoter activity of genes regulated by NF-kappaB, atrazine failed to do so. We next looked for interaction with members of the peroxisome proliferator-activated receptor (PPAR) family. No peroxisome proliferation was observed in the liver or kidneys of mice treated with atrazine. Moreover, no PPAR-mediated induction of promoter activity was seen on targets of PPARalpha, PPARgamma, or PPARdelta. Similarly, neither atrazine nor simazine were able to stimulate RORalpha-mediated promoter activity. Finally, no binding of atrazine to the AR was observed. In conclusion, the effects of atrazine-type herbicides most probably do not result from interaction with the above-mentioned nuclear receptors.

Animals↗
PubMed2003

Fibrates down-regulate hepatic scavenger receptor class B type I protein expression in mice.

Fibrates are normolipidemic drugs used in atherogenic dyslipidemia because of their ability to raise high density lipoprotein (HDL) and decrease triglyceride levels. They exert multiple effects on lipid metabolism by activating the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), which controls the transcriptional regulation of genes involved in hepatic fatty acid, cholesterol, and lipoprotein metabolism. The hepatic expression of the scavenger receptor class B type I (SR-BI) plays a critical role in lipoprotein metabolism, mainly due to its ability to mediate selective cholesterol uptake. Because fibrates and PPAR-alpha agonists up-regulate SR-BI expression in human and murine macrophages, we tested whether fibrates raised a similar regulatory response on hepatic SR-BI expression in mice. Surprisingly, fibrate treatment suppressed SR-BI protein expression in the liver without changing steady state SR-BI mRNA levels. Decreased hepatic SR-BI protein expression correlated with enlarged HDL particle size. This effect was concomitant with down-regulation of CLAMP, a putative SR-BI-stabilizing protein found in the hepatic plasma membrane, which was also not associated to changes in CLAMP mRNA levels. The post-transcriptional regulatory effect of fibrates over hepatic SR-BI protein levels was dependent on PPAR-alpha expression, because it was absent in PPAR-alpha-deficient mice. Restoring hepatic SR-BI expression in fibrate-treated mice by recombinant adenoviral gene transfer abolished fibrate-mediated HDL particle size enlargement. This study describes a novel effect of fibrates on hepatic SR-BI expression providing an alternative mechanism by which this drug family modulates HDL metabolism in vivo.

Adenoviridae↗
PubMed2003

A paradigm for gene regulation: inflammation, NF-kappaB and PPAR.

The onset of inflammatory gene expression is driven by the transcription factor NF-kappaB, whose transcriptional activity is regulated at multiple levels. First, NF-kappaB activity is regulated by cytoplasmic degradation of the IkappaB inhibitor and nuclear translocation. Second, the nuclear p65 transactivation potential can be further influenced by posttranslational modifications, such as phosphorylation and/or acetylation. The p65 phosphorylation is a process highly regulated by both cell- and stimulus-dependent activating kinases. Ser276 phosphorylation seems to be highly important considering its crucial role in the interaction with and the engagement of the cofactor CBP/p300. We have identified MSK1 as an acting kinase in the TNF-signalling pathway, where it is responsible for p65 phosphorylation at Ser276, as well as for H3 phosphorylation of Ser10 in IL-6 promoter-associated chromatin (Fig. 1) (Saccani et al., 2002; Vermeulen et al., 2002, 2003). To our knowledge, this was the first report that identifies one particular kinase involved in transcription factor phosphorylation and histone modification at the level of a single promoter in order to establish gene activation. The question of which element takes the initial step to recruit and to assemble the activated transcription complex still remains unanswered (Vanden Berghe et al., 2002). PPAR alpha negatively interferes with inflammatory gene expression by up-regulation of the cytoplasmic inhibitor molecule IkappaB alpha, thus establishing an autoregulatory loop (Fig. 1). This induction takes place in the absence of a PPRE, but requires the presence of NF-kappaB and Sp1 elements in the IkappaB alpha promoter sequence as well as DRIP250 cofactors. The detailed mechanism how PPAR can activate genes in a non-DNA-binding way needs further investigation; moreover, it is at present not clear whether this upregulation, unlike the inhibitory effect of glucocorticoids, is a cell type- or a PPAR-specific phenomenon.

Animals↗
PubMed2003

FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity.

BACKGROUND & AIMS: Bile acids are essential for bile formation and intestinal absorption of lipids and fat-soluble vitamins. However, the intrinsic toxicity of hydrophobic bile acids demands a tight control of their intracellular concentrations. Bile acids are ligands for the farnesoid X receptor (FXR) that regulates the expression of genes controlling bile acid synthesis and transport. The human uridine 5'-diphosphate-glucuronosyltransferase 2B4 (UGT2B4) converts hydrophobic bile acids into more hydrophilic glucuronide derivatives. In this study, we identify UGT2B4 as an FXR target gene. METHODS: Human hepatocytes or hepatoblastoma HepG2 cells were treated with chenodeoxycholic acid or the synthetic FXR agonist GW4064, and the levels of UGT2B4 messenger RNA, protein, and activity were determined by using real-time polymerase chain reaction, Western blot, and glucuronidation assays. RESULTS: Treatment of hepatocytes and HepG2 cells with FXR agonists resulted in an increase of UGT2B4 messenger RNA, protein, and activity. A bile acid response element in the UGT2B4 promoter (B4-BARE) to which FXR, but not retinoid X receptor, binds, was identified by site-directed mutagenesis, electromobility shift, and chromatin immunoprecipitation assays. Retinoid X receptor activation abolished the induction of UGT2B4 expression and inhibited binding of FXR to the B4-BARE, suggesting that retinoid X receptor modulates FXR target gene activation. Overexpression of UGT2B4 in HepG2 cells resulted in the attenuation of bile acid induction of the FXR target gene small heterodimeric partner. CONCLUSIONS: These data suggest that UGT2B4 gene induction by bile acids contributes to a feed-forward reduction of bile acid toxicity and a decrease of the activity of these biological FXR activators.

Bile Acids and Salts↗
PubMed2003

Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression.

BACKGROUND & AIMS: Increased serum triglyceride levels constitute a risk factor for coronary heart disease. Apolipoprotein CIII (Apo CIII) is a determinant of serum triglyceride metabolism. In this study, we investigated whether activators of the nuclear farnesoid X receptor (FXR) modulate Apo CIII gene expression. METHODS: The influence of bile acids and synthetic FXR activators on Apo CIII and triglyceride metabolism was studied in vivo by using FXR wild-type and FXR-deficient mice and in vitro by using human primary hepatocytes and HepG2 cells. RESULTS: In mice, treatment with the FXR agonist taurocholic acid strongly decreased serum triglyceride levels, an effect associated with reduced Apo CIII serum and liver messenger RNA levels. By contrast, no change was observed in FXR-deficient mice. Incubation of human primary hepatocytes and HepG2 cells with bile acids or the nonsteroidal synthetic FXR agonist GW4064 resulted in a dose-dependent down-regulation of Apo CIII gene expression. Promoter transfection experiments and mutation analysis showed that bile acid-activated FXR decrease human Apo CIII promoter activity via a negative FXR response element located in the I(4) footprint between nucleotides -739 and -704. Chromatin immunoprecipitation experiments showed that bile acid treatment led to binding of FXR/retinoid X receptor heterodimers to and displacement of HNF4alpha from this site. Bile acid treatment still repressed liver Apo CIII gene expression in hepatic HNF4alpha-deficient mice, suggesting an active rather than a competitive mechanism of Apo CIII repression by the FXR. CONCLUSIONS: We identified bile acid and synthetic activators of the nuclear FXR as negative regulators of Apo CIII expression, an effect that may contribute to the triglyceride-decreasing action of FXR agonists.

Animals↗
PubMed2003

Peroxisome proliferator-activated receptors: regulation of transcriptional activities and roles in inflammation.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. Three PPARs isoforms have been characterized: PPARalpha, beta/delta and gamma. As other nuclear receptors, the PPARs are organized in distinct functional domains: A/B, C or DNA binding domain (DBD), D, E or ligand binding domain (LBD) and F. The A/B domain contains the activation function 1 (AF-1) which is transcriptionally active in absence of ligands. The DBD and the LBD of the PPARs determine the specificity of promoter DNA sequence recognition and ligand recognition, respectively. An activation function 2 (AF-2) is contained in the E domain, which mediates the ligand-dependent activation of the receptor. The transcriptional activity of the PPARs is regulated by post-translational modifications, such as phosphorylation and ubiquitination. Phosphorylation of PPARs is controlled by environmental factors activating different kinase pathways leading to the modulation of their activities. PPARs degradation by the ubiquitin-proteasome system modulates the intensity of the ligand response by controlling the level of PPAR proteins in the cells. PPARs also control the expression of genes implicated in the inflammatory response via negative interference with different inflammatory pathways, such as NFkappaB, AP-1, C/EBP beta, STAT-1 and NFAT. As such, PPARs influence inflammatory cytokine production and cell recruitment to the inflammatory sites. A better understanding of the mechanism of action of PPARs could improve the design of more specific and more efficient novel drugs. Molecules with dissociated effects could be useful for the treatment of lipid disorders or inflammation.

Animals↗
PubMed2003

Expression and localization of peroxisome proliferator-activated receptors and nuclear factor kappaB in normal and lesional psoriatic skin.

Abnormal epidermal proliferation and differentiation characterize the inflammatory skin disease psoriasis. Here we demonstrate that expression of PPARdelta mRNA and protein is markedly upregulated in psoriatic lesions and that lipoxygenase products accumulating in psoriatic lesions are potent activators of PPARdelta. The expression levels of NF-kappaB p50 and p65 were not significantly altered in lesional compared with nonlesional psoriatic skin. In the basal layer of normal epidermis both p50 and p65 were sequestered in the cytoplasm, whereas p50, but not p65, localized to nuclei in the suprabasal layers, and this distribution was maintained in lesional psoriatic skin. In normal human keratinocytes PPAR agonists neither impaired IL-1beta-induced translocation of p65 nor IL-1beta-induced NF-kappaB DNA binding. We show that PPARdelta physically interacts with the N-terminal Rel homology domain of p65. Irrespective of the presence of agonists none of the PPAR subtypes decreased p65-mediated transactivation in keratinocytes. In contrast p65, but not p50, was a potent repressor of PPAR-mediated transactivation. The p65-dependent repression of PPARdelta- but not PPARalpha- or PPARgamma-mediated transactivation was partially relieved by forced expression of the coactivators p300 or CBP. We suggest that deficient NF-kappaB activation in chronic psoriatic plaques permitting unabated PPARdelta-mediated transactivation contributes to the pathologic phenotype of psoriasis.

CD36 Antigens↗
PubMed2003

Induction of hepatic ABC transporter expression is part of the PPARalpha-mediated fasting response in the mouse.

BACKGROUND & AIMS: Fatty acids are natural ligands of the peroxisome proliferator-activated receptor alpha (PPARalpha). Synthetic ligands of this nuclear receptor, i.e., fibrates, induce the hepatic expression of the multidrug resistance 2 gene (Mdr2), encoding the canalicular phospholipid translocator, and affect hepatobiliary lipid transport. We tested whether fasting-associated fatty acid release from adipose tissues alters hepatic transporter expression and bile formation in a PPARalpha-dependent manner. METHODS: A 24-hour fasting/48-hour refeeding schedule was used in wild-type and Pparalpha((-/-)) mice. Expression of genes involved in the control of bile formation was determined and related to secretion rates of biliary components. RESULTS: Expression of Pparalpha, farnesoid X receptor, and liver X receptor alpha genes encoding nuclear receptors that control hepatic bile salt and sterol metabolism was induced on fasting in wild-type mice only. The expression of Mdr2 was 5-fold increased in fasted wild-type mice and increased only marginally in Pparalpha((-/-)) mice, and it normalized on refeeding. Mdr2 protein levels and maximal biliary phospholipid secretion rates were clearly increased in fasted wild-type mice. Hepatic expression of the liver X receptor target genes ATP binding cassette transporter a1 (Abca1), Abcg5, and Abcg8, implicated in hepatobiliary cholesterol transport, was induced in fasted wild-type mice only. However, the maximal biliary cholesterol secretion rate was reduced by approximately 50%. CONCLUSIONS: Induction of Mdr2 expression and function is part of the PPARalpha-mediated fasting response in mice. Fasting also induces expression of the putative hepatobiliary cholesterol transport genes Abca1, Abcg5, and Abcg8, but, nonetheless, maximal biliary cholesterol excretion is decreased after fasting.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2003

The two variants of oxysterol binding protein-related protein-1 display different tissue expression patterns, have different intracellular localization, and are functionally distinct.

Oxysterol binding protein (OSBP) homologs comprise a family of 12 proteins in humans (Jaworski et al., 2001; Lehto et al., 2001). Two variants of OSBP-related protein (ORP) 1 have been identified: a short one that consists of the carboxy-terminal ligand binding domain only (ORP1S, 437 aa) and a longer N-terminally extended form (ORP1L, 950 aa) encompassing three ankyrin repeats and a pleckstrin homology domain (PHD). We now report that the two mRNAs show marked differences in tissue expression. ORP1S predominates in skeletal muscle and heart, whereas ORP1L is the most abundant form in brain and lung. On differentiation of primary human monocytes into macrophages, both ORP1S and ORP1L mRNAs were induced, the up-regulation of ORP1L being >100-fold. The intracellular localization of the two ORP1 variants was found to be different. Whereas ORP1S is largely cytosolic, the ORP1L variant localizes to late endosomes. A significant amount of ORP1S but only little ORP1L was found in the nucleus. The ORP1L ankyrin repeat region (aa 1-237) was found to localize to late endosomes such as the full-length protein. This localization was even more pronounced for a fragment that additionally includes the PHD (aa 1-408). The amino-terminal region of ORP1L consisting of the ankyrin repeat and PHDs is therefore likely to be responsible for the targeting of ORP1L to late endosomes. Interestingly, overexpression of ORP1L was found to enhance the LXRalpha-mediated transactivation of a reporter gene, whereas ORP1S failed to influence this process. The results suggest that the two forms of ORP1 are functionally distinct and that ORP1L is involved in control of cellular lipid metabolism.

Animals↗