Increased nonsterol isoprenoids, dolichol and ubiquinone, in the Smith-Lemli-Opitz syndrome: effects of dietary cholesterol

Pappu, Anuradha S.; Connor, William E.; Merkens, Louise S.; Jordan, John; Penfield, Jennifer A.; Illingworth, D. Roger; Steiner, Robert D.

doi:10.1194/jlr.m600295-jlr200

Cited by 10 publications

(17 citation statements)

References 52 publications

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“…Studies by our group suggest that enzyme deficiency results in cholesterol precursor accumulation and their metabolic diversion toward other branches of the cholesterol pathway In particular, we have demonstrated that urinary excretion of dolichol and ubiquinone) is increased in SLOS (Pappu et al 2006). Although some studies suggest that plasma and urinary dolichols are independently regulated (Humaloja, 1991; Roine, 1992), our urinary findings suggest that in SLOS there is diversion of sterol precursor farnesyl-PP toward long-chain isoprenoids (Fig.…”

Section: Introductionmentioning

confidence: 86%

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No evidence for mevalonate shunting in moderately affected children with Smith‐Lemli‐Opitz syndrome

Roullet

Merkens

Pappu

et al. 2012

J of Inher Metab Disea

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Summary Smith-Lemli-Opitz syndrome (SLOS) is caused by a genetic deficiency in 7-dehydrocholesterol (7-DHC) reductase (EC 1.3.1.21), the last enzyme of the cholesterol synthetic pathway. In SLOS, plasma cholesterol concentration is reduced and immediate precursor concentration (7-DHC) is elevated. Surprisingly, total sterol synthesis is reduced but HMG-CoA reductase activity, a rate-limiting enzyme in cholesterol synthesis is unaltered as judged by normal urinary excretion of mevalonic acid (MVA) (Pappu, 2002). These findings raise the possibility of increased diversion of MVA into the MVA shunt pathway away from sterol synthesis, by activation of the shunt pathway enzymes. To test this hypothesis, we measured the urinary excretion of 3-methylglutaconic acid (U-3MGC), a by-product of the shunt pathway, in 19 mild-to-moderately severely affected SLOS subjects (10 males, 9 females) receiving either a cholesterol-free or a high cholesterol diet, and in 20 age- and sex-matched controls. U-3MGC was similar in SLOS and controls, and was unaffected by dietary cholesterol intake. Further, no change in U-3MGC was observed in a subset of SLOS subjects (n=9) receiving simvastatin. In contrast, U-MVA was reduced by cholesterol supplementation (~54%, p<0.05) and by simvastatin (~50%, p<0.04). There was no correlation between U-3MGC and either plasma sterol concentrations, urinary isoprenoids, or the subjects’ clinical severity score. However U-3MGC was inversely correlated with age (p<0.04) and body weight (p<0.02), and higher in females than in males (~65%, p<0.025). The data show that DHCR7 deficiency does not result in 3MGC accumulation in SLOS and suggest that the MVA shunt pathway is not activated in patients with the condition.

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Section: Introductionmentioning

confidence: 86%

“…Dolichol and CoQ measurements were performed by reverse-phase high performance liquid chromatography (Pappu et al 2006). Intra- and interassay variations for dolichol were <8%, and <5% for CoQ.…”

Section: Methodsmentioning

confidence: 99%

No evidence for mevalonate shunting in moderately affected children with Smith‐Lemli‐Opitz syndrome

Roullet

Merkens

Pappu

et al. 2012

J of Inher Metab Disea

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“…This observation may explain abnormal pancreatic secretory granule formation ( 142 ). In addition to altered sterol composition, Pappu et al ( 143 ) demonstrated increased levels of dolichol and ubiquinone synthesis in SLOS and postulated that these nonsterol isoprenoids could alter membrane fl uidity, permeability, and function.…”

Section: Slos Animal Modelsmentioning

confidence: 99%

Malformation syndromes caused by disorders of cholesterol synthesis

Porter

Herman

2011

Journal of Lipid Research

398

440

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“…It is unlikely that a single pathogenic mechanism can explain the pleiotropic phenotypic findings and symptoms observed in SLOS and lathosterolosis (1,46). To identify biological pathways that potentially contribute to the SLOS and lathosterolosis phenotypes, we performed comparative proteomics analysis of control, Dhcr7 ⌬3-5/⌬3-5 , and Sc5d Ϫ/Ϫ embryonic mouse brains.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence for both processes is provided by prior clinical studies. Kelley and Kratz (72) reported increased mevalonate shunt activity in SLOS children, and Pappu et al (46) reported increased urinary excretion of ubiquinone and dolichol. Previous work by Dallner and co-workers (31,73,74) has shown that the first committed enzymes of dolichol and ubiquinone biosynthesis have higher affinities for the branch point intermediate farnesyl pyrophosphate than the first committed enzyme of sterol biosynthesis, thus favoring nonsterol isoprenoid synthesis.…”

Section: Sc5dmentioning

confidence: 99%

Quantitative Proteomics Analysis of Inborn Errors of Cholesterol Synthesis

Jiang

Backlund

Wassif

et al. 2010

Molecular & Cellular Proteomics

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Smith-Lemli-Opitz syndrome (SLOS) and lathosterolosis are malformation syndromes with cognitive deficits caused by mutations of 7-dehydrocholesterol reductase (DHCR7) and lathosterol 5-desaturase (SC5D), respectively. DHCR7 encodes the last enzyme in the Kandutsch-Russel cholesterol biosynthetic pathway, and impaired DHCR7 activity leads to a deficiency of cholesterol and an accumulation of 7-dehydrocholesterol. SC5D catalyzes the synthesis of 7-dehydrocholesterol from lathosterol. Impaired SC5D activity leads to a similar deficiency of cholesterol but an accumulation of lathosterol. Although the genetic and biochemical causes underlying both syndromes are known, the pathophysiological processes leading to the developmental defects remain unclear. To study the pathophysiological mechanisms underlying SLOS and lathosterolosis neurological symptoms, we performed quantitative proteomics analysis of SLOS and lathosterolosis mouse brain tissue and identified multiple biological pathways affected in Dhcr7 ⌬3-5/⌬3-5 and Sc5d ؊/؊ E18.5 embryos. These include alterations in mevalonate metabolism, apoptosis, glycolysis, oxidative stress, protein biosynthesis, intracellular trafficking, and cytoskeleton. Comparison of proteome alterations in both Dhcr7 ⌬3-5/⌬3-5 and Sc5d ؊/؊ brain tissues helps elucidate whether perturbed protein expression was due to decreased cholesterol or a toxic effect of sterol precursors. Validation of the proteomics results confirmed increased expression of isoprenoid and cholesterol synthetic enzymes. This alteration of isoprenoid synthesis may underlie the altered posttranslational modification of Rab7, a small GTPase that is functionally dependent on prenylation with geranylgeranyl, that we identified and validated in this study. These data suggested that although cholesterol synthesis is impaired in both Dhcr7⌬3-5/⌬3-5 and Sc5d ؊/؊ embryonic brain tissues the synthesis of nonsterol isoprenoids may be increased and thus contribute to SLOS and lathosterolosis pathology. This proteomics study has provided insight into the pathophysiological mechanisms of SLOS and lathosterolosis, and understanding these pathophysiological changes will help guide clinical therapy for SLOS and lathosterolosis.

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Increased nonsterol isoprenoids, dolichol and ubiquinone, in the Smith-Lemli-Opitz syndrome: effects of dietary cholesterol

Cited by 10 publications

References 52 publications

No evidence for mevalonate shunting in moderately affected children with Smith‐Lemli‐Opitz syndrome

No evidence for mevalonate shunting in moderately affected children with Smith‐Lemli‐Opitz syndrome

Malformation syndromes caused by disorders of cholesterol synthesis

Quantitative Proteomics Analysis of Inborn Errors of Cholesterol Synthesis

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