Peroxisome Deficiency Does Not Result in Deficiency of Enzymes involved in Cholesterol Biosynthesis

Hogenboom, Sietske; Romeijn, G. J.; Houten, Sander M.; Baes, Myriam; Wanders, Ronald J. A.; Waterham, Hans R.

doi:10.1007/978-1-4419-9072-3_42

Cited by 23 publications

(37 citation statements)

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“…10) Hogenboom et al reported that the activities and protein levels of selected enzymes involved in cholesterol biosynthesis were at least as high in the peroxisome-deficient Zellweger mice as in control mice, indicating that mislocalization of enzymes to the cytosol does not lead to decreased activity or degradation of these enzymes. 13) They also reported that the previously reported deficiencies of MVK and PMVK activity in livers from human Zellweger patients reflect the bad condition of the livers, rather than mislocalization to the cytosol. 13) From these data, the relationship between peroxisome proliferation and the enzyme involved in cholesterol biosynthesis remains unclear.…”

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confidence: 89%

“…13) They also reported that the previously reported deficiencies of MVK and PMVK activity in livers from human Zellweger patients reflect the bad condition of the livers, rather than mislocalization to the cytosol. 13) From these data, the relationship between peroxisome proliferation and the enzyme involved in cholesterol biosynthesis remains unclear.…”

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confidence: 89%

“…16) Hogenboom et al reported that the activities and protein levels of MPD were at least as high in peroxisome-deficient Zellweger mice as in control mice. 13) Based on these facts, we consider that the expression of MPD is independent of the proliferation or deficiency of peroxisomes and may be maintained by a specific regulatory mechanism different from the regulation of expression by PPARa. In this study, the level of MPD was decreased by DHEA administration.…”

Section: Increase Of Peroxisomes By Peroxisome Proliferative Drugsmentioning

confidence: 99%

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Peroxisome Proliferative Drugs Do not Induce an Increase of Rat Mevalonate Pyrophosphate Decarboxylase.

Michihara

Sawamura

Yamori

et al. 2003

Biological & Pharmaceutical Bulletin

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confidence: 89%

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Section: Increase Of Peroxisomes By Peroxisome Proliferative Drugsmentioning

confidence: 99%

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Peroxisome Proliferative Drugs Do not Induce an Increase of Rat Mevalonate Pyrophosphate Decarboxylase.

Michihara

Sawamura

Yamori

et al. 2003

Biological & Pharmaceutical Bulletin

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“…The highly specific affinitypurified antibody directed against human MK (Hogenboom et al, 2002) was used at a 1:1000 dilution.…”

Section: Immunoblot Analysismentioning

confidence: 99%

“…Second, we measured normal MK activity and MK protein levels in fibroblasts and liver homogenates of patients with a peroxisome biogenesis defect and in liver homogenates of PEX5 knockout mice (Hogenboom et al, 2002) (Hogenboom et al, 2003). Moreover, we showed that the deficient MK activities found in some livers of diseased Zellweger patients are a result of the bad preservation of the livers, rather than a result of the presumed mislocalisation of the protein (Hogenboom et al, 2002). Finally, in conventional subcellular fractionation studies performed with rat tissue and cultured human fibroblasts, and digitonin permeabilisation experiments with cultured human fibroblasts, we have never been able to demonstrate a peroxisomal localisation of MK activity (S.H.…”

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Mevalonate kinase is a cytosolic enzyme in humans

Hogenboom

Tuyp

Espeel

et al. 2004

Journal of Cell Science

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In the past decade several reports have appeared which suggest that peroxisomes play a central role in isoprenoid/cholesterol biosynthesis. These suggestions were based primarily on the reported finding of several of the enzymes of the presqualene segment of the biosynthetic pathway in peroxisomes. More recently, however, conflicting results have been reported raising doubt about the postulated role of peroxisomes in isoprenoid biosynthesis, at least in humans. In this study we have studied the subcellular localisation of human mevalonate kinase (MK) using a variety of biochemical and microscopical techniques. These include conventional subcellular fractionation studies, digitonin permeabilisation studies, immunofluorescence microscopy and immunocytochemistry. We exclusively found a cytosolic localisation of both endogenous human MK (human fibroblasts, liver and HEK293 cells) and overexpressed human MK (human fibroblasts, HEK293 cells and CV1 cells). No indication of a peroxisomal localisation was obtained. Our results do not support a central role for peroxisomes in isoprenoid biosynthesis.

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Manipulation of isoprenoid biosynthesis as a possible therapeutic option in mevalonate kinase deficiency

Schneiders

Turkenburg

Wanders

et al. 2006

Arthritis & Rheumatism

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Objective. In cells from patients with the autoinflammatory disorder mevalonate kinase (MK) deficiency, which includes the hyperimmunoglobulin D with periodic fever syndrome, MK becomes the rate-limiting enzyme in the isoprenoid biosynthesis pathway. This suggests that up-regulation of residual MK activity in these patients could be a way in which to prevent or alleviate the associated symptoms. We studied the effect of 2 specific inhibitors of isoprenoid biosynthetic enzymes on the residual activity of MK in cells from patients with MK deficiency.Methods. Skin fibroblasts from MK-deficient patients and from controls were cultured for 7 days with either simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, or zaragozic acid A, an inhibitor of squalene synthase. Following culture, MK activity, MK protein levels, MVK messenger RNA levels, and the effect on the pathway flux toward nonsterol isoprenoid biosynthesis were determined.Results. Treatment of the fibroblasts with either of the inhibitors led to a marked increase in residual MK enzyme activity, which was largely attributable to increased MVK gene transcription. This effect was even more pronounced when the cells were cultured in lipoprotein-depleted medium. The flux toward nonsterol isoprenoid end-product synthesis was reduced when cells were treated with simvastatin but was partly restored by concomitant treatment with zaragozic acid A.Conclusion. Our results indicate that manipulations of the isoprenoid biosynthesis pathway that promote the synthesis of nonsterol isoprenoids may provide an interesting therapeutic option for the treatment of MK deficiency.

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Peroxisome Deficiency Does Not Result in Deficiency of Enzymes involved in Cholesterol Biosynthesis

Cited by 23 publications

References 1 publication

Peroxisome Proliferative Drugs Do not Induce an Increase of Rat Mevalonate Pyrophosphate Decarboxylase.

Peroxisome Proliferative Drugs Do not Induce an Increase of Rat Mevalonate Pyrophosphate Decarboxylase.

Mevalonate kinase is a cytosolic enzyme in humans

Manipulation of isoprenoid biosynthesis as a possible therapeutic option in mevalonate kinase deficiency

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