Massive Production of Farnesol-Derived Dicarboxylic Acids in Mice Treated with the Squalene Synthase Inhibitor Zaragozic Acid A

Vaidya, Sanskruti; Bostedor, Richard G.; Kurtz, Marc M.; Bergstrom, James D.; Bansal, Vinay S.

doi:10.1006/abbi.1998.0704

Cited by 50 publications

(41 citation statements)

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“…SQS inhibitors increase farnesol and farnesol-derived dicarboxylic acids in vitro (17), and an increase was also reported in mice, rats, and beagle dogs (4,(18)(19)(20). To study the effects of farnesol and its derivatives on triglyceride biosynthesis, we added 100 M farnesol, squalene, farnesyl acetate, 3,7,11-trimethyl-2,6,10-dodecatriene-1,12-dioic acid methylester, 3,7-dimethyl-2,6-decadiene-1,10-dioic acid methylester, 3,7-dimethyl-2,6-octadiene-1,8-dioic acid methylester, 3-methyl-2-hexamonoene-1,6-dioic acid methylester, and suberic acid to hepatocytes, and evaluated their ability to inhibit triglyceride biosynthesis ( Fig.…”

Section: Effect Of Farnesol and Its Derivatives On Lipid Biosynthesismentioning

confidence: 75%

“…It was reported that inhibition of SQS increased farnesol levels in cultured cells (17). In animal experiments, SQS inhibitors increased farnesol and farnesol-derived dicarboxylic acids in liver tissues (4,18,19). Bostedor and colleagues identified common dicarboxylic acids that were increased in urine of rats and dogs treated with either zaragozic acid A, a SQS inhibitor, or farnesol (20).…”

Section: Discussionmentioning

confidence: 99%

“…SQS inhibitors have been reported to increase farnesol and farnesol-derived dicarboxylic acids owing to the in-crease of FPP utilization in other branching pathways of isoprenoid metabolism (4,(17)(18)(19)(20). Farnesol is produced from FPP by farnesyl pyrophosphatase (21).…”

mentioning

confidence: 99%

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Squalene synthase inhibitors suppress triglyceride biosynthesis through the farnesol pathway in rat hepatocytes

Hiyoshi

Yanagimachi

Ito

et al. 2003

Journal of Lipid Research

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Section: Effect Of Farnesol and Its Derivatives On Lipid Biosynthesismentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Squalene synthase inhibitors suppress triglyceride biosynthesis through the farnesol pathway in rat hepatocytes

Hiyoshi

Yanagimachi

Ito

et al. 2003

Journal of Lipid Research

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“…1A ) showed that the mRNA (HMGCR). However, development of SS inhibitors such as zaragozic acid and lapaquistat acetate (TAK-475) has been halted because of safety concerns ( 6,7 ).…”

Section: Resultsmentioning

confidence: 99%

Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver

Nagashima

Yagyu

Tozawa

et al. 2015

Journal of Lipid Research

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Mammals have developed sophisticated and complex systems to maintain cellular content of cholesterol, an essential component of cellular membranes and a precursor of bile acids and steroid hormones ( 1 ). In addition to dietary intake, cholesterol is supplied by de novo synthesis from acetate. Squalene synthase (SS; farnesyl-diphosphate farnesyltransferase, EC2.5.1.21) catalyzes the reductive head-to-head condensation of two molecules of farnesyl diphosphate (FPP) to form squalene, the fi rst committed intermediate in the cholesterol biosynthetic pathway ( 2, 3 ). SS contains ‫ف‬ 416 amino acids and is anchored to endoplasmic reticulum by a short C-terminal membrane-spanning domain, with its large N-terminal catalytic domain facing the cytosol, where water-soluble FPP and NADPH are present. Hepatic SS is highly regulated at the transcriptional level, not only by cellular cholesterol content ( 4 ) but also by proinfl ammatory cytokines: TNF-␣ and interleukin 1 ␤ ( 5 ). This enzyme has been an attractive target for cholesterol-lowering therapy because the inhibition of this step theoretically may not perturb the nonsterol pathway, which is a potential problem in the use of statins, inhibitors of HMG-CoA reductase Abstract Squalene synthase (SS) catalyzes the biosynthesis of squalene, the fi rst specifi c intermediate in the cholesterol biosynthetic pathway. To test the feasibility of lowering plasma cholesterol by inhibiting hepatic SS, we generated mice in which SS is specifi cally knocked out in the liver (L-SSKO) using Cre-loxP technology. Hepatic SS activity of L-SSKO mice was reduced by >90%. In addition, cholesterol biosynthesis in the liver slices was almost eliminated. Although the hepatic squalene contents were markedly reduced in L-SSKO mice, the hepatic contents of cholesterol and its precursors distal to squalene were indistinguishable from those of control mice, indicating the presence of suffi cient centripetal fl ow of cholesterol and/or its precursors from the extrahepatic tissues. L-SSKO mice showed a transient liver dysfunction with moderate hepatomegaly presumably secondary to increased farnesol production. In a fed state, the plasma total cholesterol and triglyceride were signifi cantly reduced in L-SSKO mice, primarily owing to reduced hepatic VLDL secretion. In a fasted state, the hypolipidemic effect was lost. mRNA expression of liver X receptor ␣ target genes was reduced, while that of sterol-regulatory element binding protein 2 target genes was increased. In conclusion, liver-specifi c ablation of SS inhibits hepatic cholesterol biosynthesis and induces hypolipidemia without increasing signifi cant mortality. -Nagashima, S

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“…A previous study demonstrated that FOH suppresses triglyceride synthesis in the liver (50). It was suggested that the effects of the isoprenoid were due to its dicarboxylic acid degradation products (50,51). Whether FPP is degraded in non-hepatic tissues is unknown.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Fatty Acid Synthesis by Farnesyl Pyrophosphate

Murthy¹,

Tong²,

Hohl

2005

Journal of Biological Chemistry

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Fatty acid biosynthesis is transcriptionally regulated by liver X receptor (LXR) and its gene target, sterol regulatory element binding protein-1c (SREBP-1c). LXR activation is induced by oxysterol end products of the mevalonate pathway and is inhibited by the upstream non-sterol isoprenoid, geranylgeranyl pyrophosphate (GGPP). Whether isoprenoids play a role in regulating the transcription of genes involved in fatty acid biosynthesis is unknown. In CaCo-2 colon epithelial cells, depletion of mevalonate and its derivatives, including oxysterol ligands for LXR, increased fatty acid synthesis. Addition of mevalonate or its isoprenoid derivative, farnesyl pyrophosphate (FPP), prevented this increase. The effects of FPP were likely due to itself or its degradation products, because none of its downstream derivatives, GGPP, ubiquinone, or cholesterol, were effective. Moreover, the effects of FPP could not be accounted for by protein prenylation, because inhibition of farnesylation did not alter fatty acid synthesis in mevalonate-depleted cells incubated with the isoprenoid. Neither was fatty acid synthesis in these cells altered by inhibition of ␤-oxidation. Mevalonate depletion increased fatty acid synthase (FAS) mRNA by transcriptional mechanisms, without increasing gene expression of other enzymes involved in fatty acid biosynthesis or of SREBP-1c. The abundance of mature SREBP-2 but not SREBP-1 was increased following mevalonate depletion. FPP prevented the increase in FAS mRNA in mevalonate-depleted cells without altering SREBP-2 activation. Thus, FPP regulates fatty acid synthesis by a mechanism that is likely independent of the SREBP pathway.The biosynthesis of fatty acids and cholesterol are closely related. Enzymes catalyzing the synthesis and metabolism of both lipids are coordinately regulated by the same transcription factors, the sterol regulatory element-binding proteins (SREBPs) 2 and the liver X receptors (LXRs) (1-3). LXRs belong to a superfamily of nuclear hormone receptors that are ligand-activated transcription factors (3). They form obligate heterodimers with retinoid X receptors (RXRs), another member of this receptor family, and subsequently bind to specific response ele-

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Massive Production of Farnesol-Derived Dicarboxylic Acids in Mice Treated with the Squalene Synthase Inhibitor Zaragozic Acid A

Cited by 50 publications

References 29 publications

Squalene synthase inhibitors suppress triglyceride biosynthesis through the farnesol pathway in rat hepatocytes

Squalene synthase inhibitors suppress triglyceride biosynthesis through the farnesol pathway in rat hepatocytes

Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver

Regulation of Fatty Acid Synthesis by Farnesyl Pyrophosphate

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