Effect of squalestatin 1 on the biosynthesis of the mevalonate pathway lipids

Thelin, Anders; Peterson, Elisabeth; Hutson, Julie L.; McCarthy, Alun D.; Ericsson, Johan; Dallner, Gustav

doi:10.1016/0005-2760(94)90049-3

Cited by 33 publications

(14 citation statements)

References 26 publications

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“…Among the hormones, thyroxine induces hepatic biosynthesis of CoQ and may be responsible for the elevated level of this lipid in the livers of rodents maintained at 4°C for 10 days (36, 37). Furthermore, both vitamin A deficiency and inhibition of squalene synthase by squalestatin 1 lead to elevated levels of CoQ in both cultured cells and rats (38,39).…”

Section: Discussionmentioning

confidence: 99%

Polyisoprenoid Epoxides Stimulate the Biosynthesis of Coenzyme Q and Inhibit Cholesterol Synthesis

Bentinger

Tekle

Brismar

et al. 2008

Journal of Biological Chemistry

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In our search for compounds that up-regulate the biosynthesis of coenzyme Q (CoQ), we discovered that irradiation of CoQ with ultraviolet light results in the formation of a number of compounds that influence the synthesis of mevalonate pathway lipids by HepG2 cells. Among the compounds that potently stimulated CoQ synthesis while inhibiting cholesterol synthesis, derivatives of CoQ containing 1-4 epoxide moieties in their polyisoprenoid side chains were identified. Subsequently, chemical epoxidation of all-trans-polyprenols of different lengths revealed that the shorter farnesol and geranylgeraniol derivatives were without effect, whereas the longer derivatives of solanesol enhanced CoQ and markedly reduced cholesterol biosynthesis. In contrast, none of the modified trans-transpoly-cis-polyprenols exerted noticeable effects. Tocotrienol epoxides were especially potent in our system; those with one epoxide moiety in the side-chain generally up-regulated CoQ biosynthesis by 200 -300%, whereas those with two such moieties also decreased cholesterol synthesis by 50 -90%. Prolonged treatment of HepG2 cells with tocotrienol epoxides for 26 days elevated their content of CoQ by 30%. In addition, the levels of mRNA encoding enzymes involved in CoQ biosynthesis were also elevated by the tocotrienol epoxides. The site of inhibition of cholesterol synthesis was shown to be oxidosqualene cyclase. In conclusion, epoxide derivatives of certain all-trans-polyisoprenoids cause pronounced stimulation of CoQ synthesis and, in some cases, simultaneous reduction of cholesterol biosynthesis by HepG2 cells.

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Section: Discussionmentioning

confidence: 99%

Polyisoprenoid Epoxides Stimulate the Biosynthesis of Coenzyme Q and Inhibit Cholesterol Synthesis

Bentinger

Tekle

Brismar

et al. 2008

Journal of Biological Chemistry

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“…For example, it was possible that radiolabeled F-OH could be incorporated into isoprenoid end products by a direct or unconventional reaction mechanism or by being converted to its pyrophosphorylated form before being incorporated into isoprenoid end products. squalene synthase (32)(33)(34)(35)(36), strongly suggested that F-OH was utilized via F-P-P in tobacco cells.…”

Section: Discussionmentioning

confidence: 99%

“…SQ is a well known inhibitor of squalene synthase activity in mammalian cells (32)(33)(34)(35)(36), and preliminary reports indicate that it is an effective inhibitor of this enzyme in plants (37). Tobacco squalene synthase activity was found to be strongly inhibited at subnanomolar concentrations of SQ (Fig.…”

Section: [ 3 H]farnesol Incorporation Into Sterols By Cell Suspensionmentioning

confidence: 96%

Farnesol is utilized for isoprenoid biosynthesis in plant cells via farnesyl pyrophosphate formed by successive monophosphorylation reactions

Thai

Rush

Maul

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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The ability of Nicotiana tabacum cell cultures to utilize farnesol (F-OH) for sterol and sesquiterpene biosynthesis was investigated.[ 3 H]F-OH was readily incorporated into sterols by rapidly growing cell cultures. However, the incorporation rate into sterols was reduced by greater than 70% in elicitor-treated cell cultures whereas a substantial proportion of the radioactivity was redirected into capsidiol, an extracellular sesquiterpene phytoalexin. H]CDP and either F-P-P or GG-P-P, but not F-P. These results document the presence of at least two CTP-mediated kinases that provide a mechanism for the utilization of F-OH and GG-OH for the biosynthesis of isoprenoid lipids and protein isoprenylation.

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“…To further prove lovastatin's inhibitory effect to be due to cholesterol lowering, squalestatin 1, an inhibitor of the squalene synthase, was also tested for its effect on signal transduction via GPI-anchored proteins. Squalestatin 1 blocks cholesterol biosynthesis at a step distal to mevalonate synthesis and, therefore, does not affect side products of the mevalonate pathway (45). Squalestatin 1 inhibited signal transduction via CD59 similarly to lovastatin (47 Ϯ 14% inhibition; Fig.…”

Section: Calcium Signaling Via Gpi-anchored Proteins-cross-link-mentioning

confidence: 91%

Signal Transduction via Glycosyl Phosphatidylinositol-anchored Proteins in T Cells Is Inhibited by Lowering Cellular Cholesterol

Stulnig¹,

Berger²,

Sigmund³

et al. 1997

Journal of Biological Chemistry

109

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Glycosylphosphatidylinositol (GPI)-anchored proteins can deliver costimulatory signals to lymphocytes, but the exact pathway of signal transduction involved is not yet characterized. GPI-anchored proteins are fixed to the cell surface solely by a phospholipid moiety and are clustered in distinct membrane domains that are formed by an unique lipid composition requiring cholesterol. To elucidate the role of membrane lipids for signal transduction via GPI-anchored proteins, we studied the influence of reduced cellular cholesterol content on calcium signaling via GPI-anchored CD59 and CD48 in Jurkat T cells. Lowering cholesterol by different inhibitors of cellular cholesterol synthesis suppressed calcium response via GPI-anchored proteins by about 50%, whereas stimulation via CD3 was only minimally affected (<10%). The decrease in overall calcium response via GPI-anchored proteins was reflected by inhibition of calcium release from intracellular stores. Cell surface expression of GPI-anchored proteins was not changed quantitatively by lowering cellular cholesterol, and neither was the pattern of immunofluorescence in microscopic examination. In addition, the distribution of GPIanchored proteins in detergent-insoluble complexes remained unaltered. These results suggest that cellular cholesterol is an important prerequisite for signal transduction via GPI-anchored proteins beyond formation of membrane domains.

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Effect of squalestatin 1 on the biosynthesis of the mevalonate pathway lipids

Cited by 33 publications

References 26 publications

Polyisoprenoid Epoxides Stimulate the Biosynthesis of Coenzyme Q and Inhibit Cholesterol Synthesis

Polyisoprenoid Epoxides Stimulate the Biosynthesis of Coenzyme Q and Inhibit Cholesterol Synthesis

Farnesol is utilized for isoprenoid biosynthesis in plant cells via farnesyl pyrophosphate formed by successive monophosphorylation reactions

Signal Transduction via Glycosyl Phosphatidylinositol-anchored Proteins in T Cells Is Inhibited by Lowering Cellular Cholesterol

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