| 1. |
- Abdel-Khalik, Jonas, et al.
(författare)
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Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates.
- 2021
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Ingår i: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 206
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Tidskriftsartikel (refereegranskat)abstract
- Bile acids are the end products of cholesterol metabolism secreted into bile. They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have identified a series of unusual Δ5-unsaturated bile acids in plasma and urine of patients with Smith-Lemli-Opitz syndrome (SLOS), a defect in cholesterol biosynthesis resulting in elevated levels of 7-dehydrocholesterol (7-DHC), an immediate precursor of cholesterol. Using liquid chromatography - mass spectrometry (LC-MS) we have uncovered a pathway of bile acid biosynthesis in SLOS avoiding cholesterol starting with 7-DHC and proceeding through 7-oxo and 7β-hydroxy intermediates. This pathway also occurs to a minor extent in healthy humans, but elevated levels of pathway intermediates could be responsible for some of the features SLOS. The pathway is also active in SLOS affected pregnancies as revealed by analysis of amniotic fluid. Importantly, intermediates in the pathway, 25-hydroxy-7-oxocholesterol, (25R)26-hydroxy-7-oxocholesterol, 3β-hydroxy-7-oxocholest-5-en-(25R)26-oic acid and the analogous 7β-hydroxysterols are modulators of the activity of Smoothened (Smo), an oncoprotein that mediates Hedgehog (Hh) signalling across membranes during embryogenesis and in the regeneration of postembryonic tissue. Computational docking of the 7-oxo and 7β-hydroxy compounds to the extracellular cysteine rich domain of Smo reveals that they bind in the same groove as both 20S-hydroxycholesterol and cholesterol, known activators of the Hh pathway.
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| 2. |
- Besga, A., et al.
(författare)
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Differences in brain cholesterol metabolism and insulin in two subgroups of patients with different CSF biomarkers but similar white matter lesions suggest different pathogenic mechanisms
- 2012
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 510:2, s. 121-126
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Tidskriftsartikel (refereegranskat)abstract
- Investigate possible associations of white matter hyperintensities (WMHs) with the metabolism of cholesterol and insulin in two subgroups of patients with memory complaints and different CSF A beta 42 and CSF tau levels. 59 patients from the memory clinic at Karolinska Hospital were included. Degree of WMHs was rated using the ARWMC scale and the following biomarkers were measured in CSF and plasma: insulin, cholesterol, lanosterol, lathosterol, and oxidized cholesterol metabolites. The WMHs in CSF control-like group correlated with increased brain cholesterol synthesis and reduced efflux of oxysterols and insulin in CSF. In the CSF AD-like group, the WMHs correlated with increased peripheral cholesterol metabolism. Despite having similar appearance on FLAIR images, the pathogenic mechanisms of WMHS are likely to be different in the two groups investigated.
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| 3. |
- Bodin, Karl, et al.
(författare)
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Metabolism of 4 beta -hydroxycholesterol in humans
- 2002
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 277:35, s. 31534-31540
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Tidskriftsartikel (refereegranskat)abstract
- One of the major oxysterols in the human circulation is 4 beta-hydroxycholesterol formed from cholesterol by the drug-metabolizing enzyme cytochrome P450 3A4. Deuterium-labeled 4 beta-hydroxycholesterol was injected into two healthy volunteers, and the apparent half-life was found to be 64 and 60 h, respectively. We have determined earlier the half-lives for 7 alpha-, 27-, and 24-hydroxycholesterol to be approximately 0.5, 0.75, and 14 h, respectively. Patients treated with certain antiepileptic drugs have up to 20-fold increased plasma concentrations of 4 beta-hydroxycholesterol. The apparent half-life of deuterium-labeled 4 beta-hydroxycholesterol in such a patient was found to be 52 h, suggesting that the high plasma concentration was because of increased synthesis rather than impaired clearance. 4 beta-Hydroxycholesterol was converted into acidic products at a much slower rate than 7 alpha-hydroxycholesterol in primary human hepatocytes, and 4 beta-hydroxycholesterol was 7 alpha-hydroxylated at a slower rate than cholesterol by recombinant human CYP7A1. CYP7B1 and CYP39A1 had no activity toward 4 beta-hydroxycholesterol. These results suggest that the high plasma concentration of 4 beta-hydroxycholesterol is because of its exceptionally slow elimination, probably in part because of the low rate of 7 alpha-hydroxylation of the steroid. The findings are discussed in relation to a potential role of 4 beta-hydroxycholesterol as a ligand for the nuclear receptor LXR.
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| 4. |
- Bountouvi, Evangelia, et al.
(författare)
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Longitudinal Data in Patients with Niemann-Pick Type C Disease Under Combined High Intrathecal and Low Intravenous Dose of 2-hydroxylpropyl-β-cyclodextrin.
- 2021
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Ingår i: Innovations in clinical neuroscience. - 2158-8333. ; 18:1-3, s. 11-16
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Tidskriftsartikel (refereegranskat)abstract
- Niemann-Pick Type C disease (NPC) is a rare, incurable, autosomal-recessive, lysosomal storage disorder with protean and progressive neurovisceral manifestations characterized by accumulation of intracellular unesterified cholesterol. The investigational use of 2-hydroxypropyl-beta-cyclodextrin (HP-β-CD) in the treatment of NPC has shown promising results in improving life expectancy and reducing neurological damage in this patient population. This case report describes two children with the neurological form of NPC: a 5-year-old male patient in advanced stage of the disease and an 11-year-old female patient in moderately advanced stage. Despite treatment with the enzyme inhibitor, miglustat, both patients continued to exhibit severe neurodegeneration. High intrathecal (900mg) and low intravenous (350-500mg/kg) doses of HP-β-CD (Trappsol®Cyclo™) were administrated twice monthly to the patients in addition to miglustat therapy. The patients were monitored clinically as well as by imaging, laboratory, and biomarker (e.g., total tau protein [T-tau]; phosphorylated tau [P-tau]; neurofilament light [NFL], oxysterols) studies over a period of 16 to 22 months. The combination therapy of miglustat and HP-β-CD resulted in disease stabilization in both patients. The combination therapy demonstrated a good safety profile, and no adverse effects on hearing were observed. Additionally, CSF biomarkers appeared useful in monitoring neuronal damage. Large, randomized studies are needed to confirm these findings.
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| 5. |
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| 6. |
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| 7. |
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| 8. |
- Heverin, Maura, et al.
(författare)
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On the regulatory importance of 27-hydroxycholesterol in mouse liver
- 2017
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier. - 0960-0760 .- 1879-1220. ; 169, s. 10-21
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Forskningsöversikt (refereegranskat)abstract
- 27-Hydroxycholesterol (27OH) is a strong suppressor of cholesterol synthesis and a weak activator of LXR in vitro. The regulatory importance of 27OH in vivo is controversial. Here we utilized male mice with increased levels of 27OH either due to increased production (CYP27A1 transgenic mice) or reduced metabolism (Cyp7b1-/- mice). We also used mice lacking 27OH due to a knockout of Cyp27a1. The latter mice were treated with cholic acid to compensate for reduced bile acid synthesis. The effects of the different levels of 27OH on Srebp- and other LXR-regulated genes in the liver were investigated. In the liver of CYP27tg mice we found a modest increase of the mRNA levels corresponding to the LXR target genes Cyp7b1 and Abca1. A number of other LXR-regulated genes were not affected. The effect on Abca1 mRNA was not seen in the liver of Cyp7b1-/- mice. There were little or no effects on cholesterol synthesis. In the liver of the Cyp27-/- mice treated with 0.025% cholic acid there was no significant effect of the knockout on the LXR target genes. In a previous work triple-knockout mice deficient in the biosynthesis of 24S-hydroxycholesterol, 25-hydroxycholesterol and 27OH were shown to have impaired response to dietary cholesterol, suggesting side-chain oxidized oxysterols to be mediators in cholesterol-induced effects on LXR target genes at a transcriptional level (Chen W. et al., Cell Metab. 5 (2007) 73-79). The hydroxylated oxysterol responsible for the effect was not defined. We show here that treatment of wildtype mice with dietary cholesterol under the same conditions as in the above study induced the LXR target genes Lpl, Abcg8 and Srebp1c in wild type mice but failed to activate the same genes in mice lacking 27-hydroxycholesterol due to a knockout of Cyp27. We failed to demonstrate the above effects at the protein level (Abcg8) or at the activity level (Lpl). The results suggest that 27OH is not an important regulator of Srebp- or LXR regulated genes under basal conditions in mouse liver. On the other hand 27OH appears to mediate cholesterol-induced effects on some LXR target genes at a transcriptional level under some in vivo conditions.
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| 9. |
- Keller, Lina, et al.
(författare)
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A Functional Polymorphism In The Hmgcr Promoter Affects Transcriptional Activity But Not The Risk For Alzheimer Disease In Swedish Populations
- 2010
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Ingår i: Brain Research. - Amsterdam : Elsevier. - 0006-8993 .- 1872-6240. ; 1344, s. 185-91
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Tidskriftsartikel (refereegranskat)abstract
- Variations in genes associated with cholesterol homeostasis have been reported to modify the risk of developing Alzheimer disease (AD). To date there have been few investigations into variations in genes directly involved in cholesterol biosynthesis and AD. We investigated the influence of the -911C>A polymorphism (rs3761740) in the hydroxy-methyl-glutaryl CoA reductase (HMGCR) gene promoter on basal and regulated transcription, plasma cholesterol levels and the association with AD. Under in vitro conditions the A allele was found to be significantly more responsive to SREBP-2 mediated regulation than the C allele. In an age and sex matched case-control study, the genotype distribution and allele frequency of this polymorphism were not associated with AD (OR=1.03; 95% CI=0.72-1.48). However, we did find evidence supporting an interaction between the HMGCR A allele, the APOE E4 allele and an altered risk of AD (OR=2.41; 95% CI=0.93-6.22).
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| 10. |
- Kober, Alexandra Carmen, et al.
(författare)
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Implications of cerebrovascular ATP-binding cassette transporter G1 (ABCG1) and apolipoprotein M in cholesterol transport at the blood-brain barrier
- 2017
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981. ; 1862:6, s. 573-588
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Tidskriftsartikel (refereegranskat)abstract
- Impaired cholesterol/lipoprotein metabolism is linked to neurodegenerative diseases such as Alzheimer's disease (AD). Cerebral cholesterol homeostasis is maintained by the highly efficient blood-brain barrier (BBB) and flux of the oxysterols 24(S)-hydroxycholesterol and 27-hydroxycholesterol, potent liver-X-receptor (LXR) activators. HDL and their apolipoproteins are crucial for cerebral lipid transfer, and loss of ATP binding cassette transporters (ABC)G1 and G4 results in toxic accumulation of oxysterols in the brain. The HDL-associated apolipoprotein (apo)M is positively correlated with pre-β HDL formation in plasma; its presence and function in the brain was thus far unknown. Using an in vitro model of the BBB, we examined expression, regulation, and functions of ABCG1, ABCG4, and apoM in primary porcine brain capillary endothelial cells (pBCEC). RT Q-PCR analyses and immunoblotting revealed that in addition to ABCA1 and scavenger receptor, class B, type I (SR-BI), pBCEC express high levels of ABCG1, which was up-regulated by LXR activation. Immunofluorescent staining, site-specific biotinylation and immunoprecipitation revealed that ABCG1 is localized both to early and late endosomes and on apical and basolateral plasma membranes. Using siRNA interference to silence ABCG1 (by 50%) reduced HDL-mediated [3H]-cholesterol efflux (by 50%) but did not reduce [3H]-24(S)-hydroxycholesterol efflux. In addition to apoA-I, pBCEC express and secrete apoM mainly to the basolateral (brain) compartment. HDL enhanced expression and secretion of apoM by pBCEC, apoM-enriched HDL promoted cellular cholesterol efflux more efficiently than apoM-free HDL, while apoM-silencing diminished cellular cholesterol release. We suggest that ABCG1 and apoM are centrally involved in regulation of cholesterol metabolism/turnover at the BBB.
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