Regulation of isoprenoid metabolism in rat liver: Near constant chain lengths of dolichyl phosphate and ubiquinone are maintained during greatly altered rates of cholesterogenesis

Keller, R. Kennedy; Vilsaint, F.

doi:10.1016/0005-2760(93)90072-h

Cited by 8 publications

(5 citation statements)

References 37 publications

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“…In the present work, we found an approximate 50 % increase in the steady-state levels of both dolichol and coenzyme Q in the livers of rats treated with AY9944, but no effect on the chain lengths of these lipids. Previous studies in our laboratory [18] have shown that administering mevalonate to a cholesterol-fed rat (conditions expected to increase the steady-state level of IPP) resulted in greatly increased chain lengths of dolichol and coenzyme Q, but with no effect on the total levels of these nonsterol isoprenoids (see Table 2 and Fig. 4).…”

Section: Discussionmentioning

confidence: 81%

“…Previous studies in our laboratory [18] have shown that administering mevalonate to a cholesterol-fed rat (conditions expected to increase the steady-state level of IPP) resulted in greatly increased chain lengths of dolichol and coenzyme Q, but with no effect on the total levels of these nonsterol isoprenoids (see Table 2 and Fig. 4).…”

Section: Discussionmentioning

confidence: 85%

“…The ether extracts were pooled, taken to dryness, dissolved in 0.5 ml 2-propanol/methanol (1:4, v/v), filtered, and stored at -20°C until ready for HPLC analysis. The dolichol and coenzyme Q fractions from above were subjected to HPLC analysis as previously described [18]. The total dolichol mass was determined by summing the quantified mass of each peak (Dol-17, Dol-18, Dol-19, and Dol-20) and using the mass of the internal standard (Dol-21) to correct for yield).…”

Section: Analysis Of Dolichol and Coenzyme Qmentioning

confidence: 99%

“…The total dolichol mass was determined by summing the quantified mass of each peak (Dol-17, Dol-18, Dol-19, and Dol-20) and using the mass of the internal standard (Dol-21) to correct for yield). For the quantification of coenzyme Q, samples eluted from the preparative TLC plate (see above) were subjected to HPLC [18]. The mass of the Q 9 and Q 10 fractions was determined, and the % recovery of the internal standard (Q 7 ) was used to correct for yield.…”

Section: Analysis Of Dolichol and Coenzyme Qmentioning

confidence: 99%

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Hepatic Isoprenoid Metabolism in a Rat Model of Smith‐Lemli‐Opitz Syndrome

Keller

Mitchell

Goulah

et al. 2013

Lipids

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Elevated (4 to 7-fold) levels of urinary dolichol and coenzyme Q and substantially longer chain lengths for urinary dolichols have been reported in Smith-Lemli-Opitz Syndrome (SLOS) patients, compared to normal subjects. We investigated the possibility of similar alterations in hepatic, nonsterol isoprenoids in a well-established rat model of SLOS. In this model, the ratio of 7-dehydrocholesterol (7DHC) to cholesterol (Chol) in serum approached 15:1; however, total sterol mass in serum decreased by >80 %. Livers from treated rats had 7DHC/Chol ratios of ~32:1, but the steady-state levels of total sterols were >40 % those of livers from age-matched (3-month-old) control animals. No significant differences in the levels of LDL receptor or HMG-CoA reductase were observed. The levels of dolichol and coenzyme Q were elevated only modestly (by 64 and 31 %, respectively; p < 0.05, N = 6) in the livers of the SLOS rat model compared to controls; moreover, the chain lengths of these isoprenoids were not different in the two groups. We conclude that hepatic isoprenoid synthesis is marginally elevated in this animal model of SLOS, but without preferential shunting to the nonsterol branches (dolichol and coenzyme Q) of the pathway and without alteration of normal dolichol chain lengths.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 85%

Section: Analysis Of Dolichol and Coenzyme Qmentioning

confidence: 99%

Section: Analysis Of Dolichol and Coenzyme Qmentioning

confidence: 99%

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Hepatic Isoprenoid Metabolism in a Rat Model of Smith‐Lemli‐Opitz Syndrome

Keller

Mitchell

Goulah

et al. 2013

Lipids

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“…However, this scenario seems unlikely. Studies have shown that isoprenoid hepatic concentrations and rates of synthesis are not modified under conditions that greatly alter cholesterologenesis (Keller and Vilsaint 1993). These studies were performed in the rat though and the consequences of cholesterol synthesis deficiency may have a different impact on branched pathways in humans.…”

Section: Discussionmentioning

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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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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Squalene synthase inhibition alters metabolism of nonsterols in rat liver

1996

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metaboli

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Regulation of isoprenoid metabolism in rat liver: Near constant chain lengths of dolichyl phosphate and ubiquinone are maintained during greatly altered rates of cholesterogenesis

Cited by 8 publications

References 37 publications

Hepatic Isoprenoid Metabolism in a Rat Model of Smith‐Lemli‐Opitz Syndrome

Hepatic Isoprenoid Metabolism in a Rat Model of Smith‐Lemli‐Opitz Syndrome

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

Squalene synthase inhibition alters metabolism of nonsterols in rat liver

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