<b>A Novel Mode of Inhibition of Cholesterol Biosynthesis</b>

Dvornik, D.; Kraml, M.; Dubuc, Jean-Émile; Givner, Morris L.; Gaudry, Roger

doi:10.1021/ja00903a066

Cited by 129 publications

(50 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1). The identity of 7-dehydrocholesterol as the principal precursor accumulating during AY-9944 administration has been documented previously (14).…”

Section: Ay-9944mentioning

confidence: 85%

An Ultrastructural and Biochemical Study of the Effects of Three Inhibitors of Cholesterol Biosynthesis Upon Murine Adrenal Gland and Testis

Dietert

Scallen

1969

The Journal of Cell Biology

View full text Add to dashboard Cite

Triparanol and 20,25-diazacholesterol inhibit cholesterol biosynthesis and result in the accumulation of desmosterol. AY-9944, another inhibitor, produces an accumulation of 7-dehydrocholesterol. Adult male C3H mice receive one of these drugs intraperitoneally. Livers, adrenal glands, and testes from each drug group are excised, and portions of each are analyzed by a modified Liebermann-Burchard reaction for quantitation of sterols. Adrenals and testes are examined also by electron microscopy. Fine-structural localization of acid phosphatase has been studied in triparanol-treated adrenal glands. Biochemical analysis reveals that 14-64% of the sterols occurs as desmosterol or 7-dehydrocholesterol. Fine-structural alterations in the adrenal glands and testes from each drug group are essentially identical. The predominant cytological feature is the occurrence of increased numbers of pleomorphic, unit-membrane-limited, electron-opaque, cytoplasmic inclusions. Hence, the cellular modifications following triparanol administration are not unique, as has been suggested. They represent a generalized phenomenon, probably related to inhibition of cholesterol biosynthesis, which is an effect common to each drug. Lead phosphate reaction product (indicating acid phosphatase activity) is demonstrable within these membrane-limited cytoplasmic bodies, identifying them as morphological lysosomes. The utilization of a lysosomal mechanism in sterol-synthesizing cells, which are accumulating cholestercl intermediates, is discussed.

show abstract

“…1). The identity of 7-dehydrocholesterol as the principal precursor accumulating during AY-9944 administration has been documented previously (14).…”

Section: Ay-9944mentioning

confidence: 85%

An Ultrastructural and Biochemical Study of the Effects of Three Inhibitors of Cholesterol Biosynthesis Upon Murine Adrenal Gland and Testis

Dietert

Scallen

1969

The Journal of Cell Biology

View full text Add to dashboard Cite

show abstract

“…The SLOS rat model was produced as previously described (Fliesler et al, 2004), by treatment of Sprague Dawley (albino) rats with AY9944, a selective inhibitor of 3β-hydroxysterol-Δ 7 -reductase (Dvornik et al, 1963;Givner and Dvornik, 1965 Vaughan et al, 2003 Vaughan et al, , 2005. Rats (6-wk postnatal age, N=4 per group) were darkadapted overnight, and then exposed for 24 hr to intense green light (1700 lux, 490-580 nm) in a temperature-controlled, Plexiglass chamber (kindly provided by D.T.…”

Section: Introductionmentioning

confidence: 99%

“…More recently, we showed that intense light exposure markedly exacerbates that retinal degeneration, whereas treatment of rats with dimethylthiourea, a hydroxyl radical scavenger and anti-oxidant, prior to light exposure largely protects against the enhancement of degeneration (Vaughan et al, 2005), implicating a free radical mechanism in the degeneration. Herein, we provide evidence that correlates the severity of retinal degeneration in the SLOS rat model, relative to normal albino rats, with accumulated levels of lipid hydroxperoxides (LPOs) in the retina, particularly with intense light exposure.The SLOS rat model was produced as previously described (Fliesler et al, 2004), by treatment of Sprague Dawley (albino) rats with AY9944, a selective inhibitor of 3β-hydroxysterol-Δ 7 -reductase (Dvornik et al, 1963;Givner and Dvornik, 1965 Vaughan et al, 2003 Vaughan et al, , 2005. Rats (6-wk postnatal age, N=4 per group) were darkadapted overnight, and then exposed for 24 hr to intense green light (1700 lux, 490-580 nm) in a temperature-controlled, Plexiglass chamber (kindly provided by D.T.…”

mentioning

confidence: 99%

“…Herein, we provide evidence that correlates the severity of retinal degeneration in the SLOS rat model, relative to normal albino rats, with accumulated levels of lipid hydroxperoxides (LPOs) in the retina, particularly with intense light exposure. The SLOS rat model was produced as previously described (Fliesler et al, 2004), by treatment of Sprague Dawley (albino) rats with AY9944, a selective inhibitor of 3β-hydroxysterol-Δ 7 -reductase (Dvornik et al, 1963;Givner and Dvornik, 1965 Inc.) upon weaning; rats were provided water, ad lib, and were maintained in dim cyclic light (20-40 lux, 12 hr light-12 hr dark) at 22-25 °C, unless otherwise stated. The retinal light damage paradigm was performed essentially as previously described (Organisciak et al, 1996(Organisciak et al, , 1999Vaughan et al, 2003Vaughan et al, , 2005.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Lipid hydroperoxide formation in the retina: correlation with retinal degeneration and light damage in a rat model of Smith–Lemli–Opitz syndrome

Richards

Nagel

Fliesler

2006

Experimental Eye Research

View full text Add to dashboard Cite

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disease presenting with multiple congenital anomalies, caused by a defect in cholesterol biosynthesis that results in abnormally elevated levels of 7-dehydrocholesterol (7DHC). Progressive retinal degeneration has been demonstrated in a rat model of SLOS, which is markedly exacerbated by intense light, far more so than occurs in normal albino rats under the same conditions. Herein, we demonstrate that, by six postnatal weeks, retinas in the SLOS rat model contain levels of lipid hydroperoxides (LPOs) comparable to those found in light-damaged albino rats (twice the normal steady-state levels), and that intense light exposure results in a three-fold elevation of LPOs with concomitant severe retinal degeneration. These results suggest a correlation between retinal degeneration and LPO levels. We propose that the presence of 7DHC in the SLOS rat retina potentiates LPO formation, and promotes the observed hypersensitivity to light-induced retinal degeneration. KeywordsAY9944; Smith-Lemli-Opitz syndrome; retina; degeneration; light damage; lipid hydroperoxide; rat Retinal degenerations resulting either from hereditary or exogenous causes are thought to entail molecular events that, in part, involve oxidative damage to lipids, proteins, and/or nucleic acids, resulting in cellular dysfunction and, ultimately, cell death. Such events are known to be potentiated by exposure to intense light (Organisciak and Winkler, 1994;Boulton et al., 2001;Glickman, 2002;Wenzel et al., 2005). Certain metabolic conditions result in the formation of pro-oxidant molecules, the presence of which can promote cellular degeneration and death. The Smith-Lemli-Opitz syndrome (SLOS) likely represents such a condition. SLOS, the first described 'multiple congenital anomalies syndrome ' (Smith et al., 1964; cf. Porter, 2000;Jira et al., 2003), is also the first member of a growing family of inborn errors of anabolic metabolism involving defective cholesterol biosynthesis (Kelley, 2000;Porter, 2003). SLOS specifically is due to a defect in 3β-hydroxysterol-Δ 7 -reductase (Waterham and Wanders, 2000;Correa-Cerro and Porter, 2005), resulting in abnormal and excessive accumulation of the cholesterol precursor, 7-dehydrocholesterol (7DHC) (Tint et al., 1994 cf. Fliesler, 2002).We have previously demonstrated a progressive retinal degeneration in a pharmacologically induced rat model of SLOS (Fliesler et al., 2004). More recently, we showed that intense light exposure markedly exacerbates that retinal degeneration, whereas treatment of rats with dimethylthiourea, a hydroxyl radical scavenger and anti-oxidant, prior to light exposure largely protects against the enhancement of degeneration (Vaughan et al., 2005), implicating a free radical mechanism in the degeneration. Herein, we provide evidence that correlates the severity of retinal degeneration in the SLOS rat model, relative to normal albino rats, with accumulated levels of lipid hydroxperoxides (LPOs) in the retina, particu...

show abstract

“…The SLOS rat model (11)(12)(13) is induced by treatment of pregnant rats and their progeny with AY9944, a selective inhibitor of 3␤-hydroxysterol-⌬ 7 -reductase (14,15), the enzyme defective in SLOS. The clinical relevance of the SLOS rat model is highlighted by the fact that pediatric SLOS patients exhibit markedly abnormal darkadapted (rod) ERG (16), similar to those observed in the SLOS rat model.…”

mentioning

confidence: 99%

Partial Rescue of Retinal Function and Sterol Steady-State in a Rat Model of Smith-Lemli-Opitz Syndrome

Fliesler¹,

Vaughan

Jenewein

et al. 2007

Pediatr Res

View full text Add to dashboard Cite

ABSTRACT:The Smith-Lemli-Opitz syndrome (SLOS) is the firstdescribed in a growing family of hereditary defects in cholesterol biosynthesis, and presents with a spectrum of serious abnormalities, including multiple dysmorphologies, failure to thrive, cognitive and behavioral impairments, and retinopathy. Using a pharmacologically induced rat model of SLOS that exhibits key hallmarks of the disease, including progressive retinal degeneration and dysfunction, we show that a high-cholesterol diet can substantially correct abnormalities in retinal sterol composition, with concomitant improvement of visual function, particularly within the cone pathway. Although histologic degeneration still occurred, a high-cholesterol diet reduced the number of pyknotic photoreceptor nuclei, relative to animals on a cholesterol-free diet. These findings demonstrate that cholesterol readily crosses the blood-retina barrier (unlike the blood-brain barrier) and suggest that cholesterol supplementation may be efficacious in treating SLOS-associated retinopathy. H ereditary abnormalities in cholesterol biosynthesis underlie a family of human birth defects associated with specific enzyme defects and phenotypes (1-3). The first described and most common of these is SLOS (4), a multiple congenital anomalies syndrome involving the inability to efficiently convert 7DHC to Chol (5,6). The enzyme responsible for catalyzing this biosynthetic step (3␤-hydroxysterol-⌬ 7 -reductase; DHCR7; EC 1.3.1.21) is encoded by the DHCR7 gene localized to human chromosome 11q12-q13 (7-9). More than 100 mutations in DHCR7 have been identified in association with SLOS; many result in abnormally low levels of cholesterol and abnormally high levels of 7DHC in bodily tissues (8,9). With an estimated global incidence of 1 in 20,000 to 1 in 60,000 live births, SLOS is likely the fourth most common human recessive disease, after cystic fibrosis, phenylketonuria, and hemochromatosis (8,9). However, a recent study (10) estimates the SLOS carrier frequency to be 1 in 30, suggesting a much higher actual disease frequency, e.g. approximately 1 in 1,590 to 1 in 13,500. The SLOS phenotype displays a spectrum of clinical manifestations, from mild to lethal, and may include such findings as moderate to severe mental retardation, autism, dysmorphic craniofacial and skeletal malformations, and failure to thrive (1-3).We previously reported progressive retinal degeneration in a pharmacological rat model of SLOS (11) characterized by shortening and eventual loss of retinal ROS, pyknosis and thinning of the ONL, accumulation of membranous inclusions and lipid droplets in the retinal pigment epithelium (RPE), defects in rod and cone photoresponses, together with SLOSlike accumulation of 7DHC and diminished cholesterol levels in retina, brain, liver, and serum. The SLOS rat model (11-13) is induced by treatment of pregnant rats and their progeny with AY9944, a selective inhibitor of 3␤-hydroxysterol-⌬ 7 -reductase (14,15), the enzyme defective in SLOS. The clinical relevance of the S...

show abstract

A Novel Mode of Inhibition of Cholesterol Biosynthesis

Cited by 129 publications

References 8 publications

An Ultrastructural and Biochemical Study of the Effects of Three Inhibitors of Cholesterol Biosynthesis Upon Murine Adrenal Gland and Testis

An Ultrastructural and Biochemical Study of the Effects of Three Inhibitors of Cholesterol Biosynthesis Upon Murine Adrenal Gland and Testis

Lipid hydroperoxide formation in the retina: correlation with retinal degeneration and light damage in a rat model of Smith–Lemli–Opitz syndrome

Partial Rescue of Retinal Function and Sterol Steady-State in a Rat Model of Smith-Lemli-Opitz Syndrome

Contact Info

Product

Resources

About