Presence of individual enzymes of cholesterol biosynthesis in rat liver peroxisomes

Appelkvist, Eeva‐Liisa; Reinhart, Michael P.; Fischer, Reinhard; Billheimer, Jeffrey T.; Dallner, Gustav

doi:10.1016/0003-9861(90)90123-g

Cited by 63 publications

(28 citation statements)

References 21 publications

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“…The first indication for this came from immunoelectronmicroscopy studies of Keller and co-workers (1986) showing the presence of HMG-CoA reductase in the matrix of peroxisomes. Later, other enzymes were also found to be localized in peroxisomes, including mevalonate kinase (Stamellos et al 1992), FPP synthase (Krisans et al 1994), dihydrolanosterol oxidase, steroid 14-reductase, steroid 8-isomerase, and steroid 3-ketoreductase (Appelkvist et al 1990).…”

Section: * Correspondencementioning

confidence: 96%

Cholesterol biosynthesis in Zellweger syndrome: Normal activity of mevalonate kinase, mevalonate‐5′‐pyrophosphate decarboxylase and IPP‐isomerase in patients' fibroblasts but deficient mevalonate kinase activity in liver

Wanders

Romeijn

1996

J of Inher Metab Disea

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Section: * Correspondencementioning

confidence: 96%

Cholesterol biosynthesis in Zellweger syndrome: Normal activity of mevalonate kinase, mevalonate‐5′‐pyrophosphate decarboxylase and IPP‐isomerase in patients' fibroblasts but deficient mevalonate kinase activity in liver

Wanders

Romeijn

1996

J of Inher Metab Disea

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“…This observation suggests that reduced SCP-2 results in slower clearance of intracellular cholesterol and peroxisomal cholesterol accumulation. Peroxisomal cholesterol may arise from peroxisomal cholesterol biosynthesis (28,29) or it may come from adjacent lipid droplets or vesicles (26), derived from plasma membrane pinocytosis (47,72). Under these conditions, the branching reticular structure of peroxisomes may allow these organelles to function as a central collecting and processing site for intracellular cholesterol.…”

Section: Discussionmentioning

confidence: 99%

“…In peroxisome-deficient cells, derived from patients with Zellweger's syndrome, pre-SCP-2 is not processed to SCP-2 and is rapidly degraded (27). Furthermore, peroxisome-deficient cell lines have a reduced capacity for cholesterol biosynthesis (28,29) and alterations in cholesterol metabolism (30,31); however, it is currently unclear if any of these abnormalities can be attributed to SCP-2 deficiency. In this regard, Puglielli et al (32) recently demonstrated that Zellweger's fibroblasts have a delay in the rate of nascent cholesterol transfer to the plasma membrane and that this defect can be reproduced in normal fibroblasts by antisense SCP-2 oligonucleotide treatment.…”

mentioning

confidence: 99%

Sterol Carrier Protein-2 Overexpression Enhances Sterol Cycling and Inhibits Cholesterol Ester Synthesis and High Density Lipoprotein Cholesterol Secretion

Baum

Reschly

Gayen

et al. 1997

Journal of Biological Chemistry

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Recent data indicate that sterol carrier protein-2 (SCP-2) functions in the rapid movement of newly synthesized cholesterol to the plasma membrane (Puglielli, L., Rigotti, A., Greco, A. V., Santos, M. J., and Nervi, F. (1995) J. Biol. Chem. 270, 18723-18726). In order to further characterize the cellular function of SCP-2, we transfected McA-RH7777 rat hepatoma cells with a pre-SCP-2 cDNA expression construct. In stable transfectants, pre-SCP-2 processing resulted in an 8-fold increase in peroxisomal levels of SCP-2. SCP-2 overexpression increased the rates of newly synthesized cholesterol transfer to the plasma membrane and plasma membrane cholesterol internalization by 4-fold. There was no effect of SCP-2 overexpression on the microsomal levels of acyl-CoA:cholesterol acyltransferase and neutral cholesterol ester (CE) hydrolase; however, in the intact cell, CE synthesis and mass were reduced by 50%. SCP-2 overexpression also reduced high density lipoprotein-cholesterol secretion and apoA-I gene expression by 70% and doubled the rate of plasma membrane desmosterol conversion to cholesterol. We conclude that SCP-2 overexpression enhances the rate of cholesterol cycling, which reduces the availability of cholesterol for CE synthesis and alters the activity of a cellular cholesterol pool involved in regulating apoA-Imediated high density lipoprotein cholesterol secretion. The net result of these changes in cholesterol metabolism is a 46% increase in plasma membrane cholesterol content, the implications of which are discussed. Cellular free cholesterol is predominantly located in the plasma membrane (reviewed in Ref. 1). Cellular cholesterol content, however, is determined by the concerted action of intracellular enzymes and regulatory proteins as follows: ACAT 1 which catalyzes the synthesis of CE, sterol regulatory element binding proteins, which regulate the transcription of a number of genes involved in cholesterol metabolism (2, 3), and various cell type-specific metabolic reactions, e.g. lipoprotein secretion, steroidogenesis, and bile acid synthesis. Since cholesterol is highly insoluble in an aqueous environment, it has been postulated that sterol carrier protein-2 (SCP-2) regulates the movement and thus the availability of cholesterol for different cellular processes (4 -6). The evidence supporting this contention was initially derived in large part from studies demonstrating that the addition of purified SCP-2 stimulated the in vitro conversion of sterol intermediates to cholesterol (7) and cholesterol to 7␣-hydroxycholesterol (8) steroid hormones (9 -13) and cholesterol ester (14). More recent studies indicate that SCP-2 gene expression is regulated by changes in cellular cholesterol content (15-17); however, in these studies, a direct role in cholesterol trafficking and esterification was not demonstrated. The strongest support for a role in cellular cholesterol metabolism comes from studies on the role of SCP-2 in steroidogenesis. SCP-2 gene expression is coordinately regulated with steroid hormone syn...

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“…Mevinolin treated rats were fed chow mixed with mevinolin (500 mg/kg food) for 21 days. The livers were homogenized in a medium containing sucrose, EDTA and ethanol, and used for subfractionation as described earlier [7]. Peroxisomes were isolated from the light mitochondrial fraction by centrifugation on a preformed linear Nycodenz gradient.…”

Section: Methodsmentioning

confidence: 99%

“…Peroxisomal squalene synthase exhibits regulation by mevinolin and by various inducers distinct from that of the microsomal enzyme [3,6]. Several other enzymes involved in cholesterol synthesis could also be detected in peroxisomes [7]. *Corresponding author.…”

Section: Introductionmentioning

confidence: 99%

Estimation of dolichol and cholesterol synthesis in microsomes and peroxisomes isolated from rat liver

1995

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The participation of peroxisomal and microsomal fractions from rat liver in dolichol and cholesterol synthesis was investigated using marker enzymes. Recovery was 8% for peroxisomes and 33% for microsomes, with virtually no cross-contamination between these fractions. Using these data, it was calculated that the peroxisomal branch-point enzyme activities for dolichol and cholesterol biosynthesis, i.e. cis-prenyltransferase and squalene synthase, were 25% and 12%, respectively, of the total homogenate activity. Treatment with mevinolin increased the peroxisomal contribution in the case of both enzymes, to levels almost equal to that of their microsomal counterparts. These results indicate that peroxisomes play a role in the biosynthesis of isoprenoid lipids and that the extent of this participation is increased extensively when peroxisomes are induced by various treatments.

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Presence of individual enzymes of cholesterol biosynthesis in rat liver peroxisomes

Cited by 63 publications

References 21 publications

Cholesterol biosynthesis in Zellweger syndrome: Normal activity of mevalonate kinase, mevalonate‐5′‐pyrophosphate decarboxylase and IPP‐isomerase in patients' fibroblasts but deficient mevalonate kinase activity in liver

Cholesterol biosynthesis in Zellweger syndrome: Normal activity of mevalonate kinase, mevalonate‐5′‐pyrophosphate decarboxylase and IPP‐isomerase in patients' fibroblasts but deficient mevalonate kinase activity in liver

Sterol Carrier Protein-2 Overexpression Enhances Sterol Cycling and Inhibits Cholesterol Ester Synthesis and High Density Lipoprotein Cholesterol Secretion

Estimation of dolichol and cholesterol synthesis in microsomes and peroxisomes isolated from rat liver

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