Squalene synthase inhibitors suppress triglyceride biosynthesis through the farnesol pathway in rat hepatocytes Published, JLR Papers in Press, October 16, 2002. DOI 10.1194/jlr.M200316-JLR200

@article{Hiyoshi2003SqualeneSI,
  title={Squalene synthase inhibitors suppress triglyceride biosynthesis through the farnesol pathway in rat hepatocytes Published, JLR Papers in Press, October 16, 2002. DOI 10.1194/jlr.M200316-JLR200},
  author={Hironobu Hiyoshi and Mamoru Yanagimachi and Masashi Ito and Nobuyuki Yasuda and Toshimi Okada and Hironori Ikuta and Daisuke Shinmyo and Keigo Tanaka and Nobuyuki Kurusu and Ichiro Yoshida and Shinya Abe and Takao Saeki and Hiroshi Tanaka},
  journal={Journal of Lipid Research},
  year={2003},
  volume={44},
  pages={128 - 135}
}
We recently demonstrated that squalene synthase (SQS) inhibitors reduce plasma triglyceride through an LDL receptor-independent mechanism in Watanabe heritable hyperlipidemic rabbits (Hiyoshi et al. 2001. Eur. J. Pharmacol. 431: 345–352). The present study deals with the mechanism of the inhibition of triglyceride biosynthesis by the SQS inhibitors ER-27856 and RPR-107393 in rat primary cultured hepatocytes. Atorvastatin, an HMG-CoA reductase inhibitor, had no effect on triglyceride… Expand
Increased cholesterol biosynthesis and hypercholesterolemia in mice overexpressing squalene synthase in the liver Published, JLR Papers in Press, June 1, 2006.
TLDR
It is demonstrated that transient upregulation of SS stimulates cholesterol biosynthesis as well as lipoprotein production, providing the first in vivo evidence that SS plays a regulatory role in cholesterol metabolism through modulation of HMG-CoA reductase activity and cholesterol biosynthetic activity. Expand
Pharmacologic Inhibition of Squalene Synthase and Other Downstream Enzymes of the Cholesterol Synthesis Pathway: A New Therapeutic Approach to Treatment of Hypercholesterolemia
Hypercholesterolemia is a major risk factor for the development of atherosclerotic vascular diseases. The most popular agents for cholesterol reduction are the statin drugs, which are competitiveExpand
Differential Regulation of Gene Expression by Cholesterol Biosynthesis Inhibitors That Reduce (Pravastatin) or Enhance (Squalestatin 1) Nonsterol Isoprenoid Levels in Primary Cultured Mouse and Rat Hepatocytes
TLDR
The findings indicate that SSIs uniquely influence cellular lipid metabolism and cell cycle regulation, probably due to FPP catabolism through the farnesol pathway. Expand
Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver[S]
TLDR
Liver-specific ablation of SS inhibits hepatic cholesterol biosynthesis and induces hypolipidemia without increasing significant mortality. Expand
Farnesol Decreases Serum Triglycerides in Rats: Identification of Mechanisms Including Up-Regulation of PPARα and Down-Regulation of Fatty Acid Synthase in Hepatocytes
TLDR
It is suggested that farnesol may contribute to this protective effect by lowering serum TG levels by down-regulation of FAS and attenuated lipogenesis may also contribute to hypotriglyceridemic effects offarnesol in vivo. Expand
9-oxo-10(E),12(E)-Octadecadienoic acid derived from tomato is a potent PPAR α agonist to decrease triglyceride accumulation in mouse primary hepatocytes.
TLDR
Findings suggest that tomatoes containing 9-oxo-ODA that acts on PPARα are valuable for ameliorating abnormalities of lipid metabolism. Expand
Regulation of Fatty Acid Synthesis by Farnesyl Pyrophosphate*
TLDR
FPP regulates fatty acid synthesis by a mechanism that is likely independent of the SREBP pathway, and prevented the increase in FAS mRNA in mevalonate-depleted cells without altering S REBP-2 activation. Expand
Farnesol, an isoprenoid, improves metabolic abnormalities in mice via both PPARα-dependent and -independent pathways.
TLDR
It is shown that farnesol, a naturally occurring ligand of PPARs, could ameliorate metabolic diseases and that the activation of FXR byfarnesol might contribute partially to the PPARα-independent hepatic triglyceride content-lowering effect. Expand
Synthesis, Characterization and In vitro Evaluation of N-Substituted- Sulfomoyl-Phenyl-Amino Carboxylic Acid Derivatives as Squalene Synthase Inhibitors
Squalene Synthase is one of the cholesterol biosynthetic pathway enzymes, inhibition of which produces potent lipid lowering action. A variety of chemical classes have been evaluated for itsExpand
Emerging lipid-lowering drugs: squalene synthase inhibitors
TLDR
The present review will focus on the chemistry, pharmacology, and lipid-lowering effects of novel squalene synthase inhibitors, which mainly targets LDL-C, but may have some effect on HDL-C and TG. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 61 REFERENCES
RPR 107393, a potent squalene synthase inhibitor and orally effective cholesterol-lowering agent: comparison with inhibitors of HMG-CoA reductase.
TLDR
RPR 107393 is an orally effective hypocholesterolemic agent in rats and marmosets that has greater efficacy than lovastatin or pravastatin in the marmoset and in vitro data demonstrate that these compounds are inhibitors of squalene synthase. Expand
Effect of ER-27856, a novel squalene synthase inhibitor, on plasma cholesterol in rhesus monkeys: comparison with 3-hydroxy-3-methylglutaryl-coa reductase inhibitors.
TLDR
Results demonstrate that ER-27856 had more potent hypocholesterolemic activity and less hepatotoxic effect than HMGRIs, and may contribute to the treatment of hypercholesterolesmic patients. Expand
Squalene synthase inhibitors reduce plasma triglyceride through a low-density lipoprotein receptor-independent mechanism.
TLDR
It is demonstrated that squalene synthase inhibitors reduced plasma triglyceride through an LDL receptor-independent mechanism, which was distinct from that of the triglyceride-lowering action of atorvastatin or bezafibrate. Expand
Farnesol as a regulator of HMG-CoA reductase degradation: characterization and role of farnesyl pyrophosphatase.
TLDR
The enzyme farnesyl pyrophosphatase (FPPase) in Chinese hamster ovary cells is studied and it is demonstrated that FPPase activity increases under conditions of increased metabolic flow through the isoprenoid pathway. Expand
Massive production of farnesol-derived dicarboxylic acids in mice treated with the squalene synthase inhibitor zaragozic acid A.
TLDR
In vivo studies in mice confirmed earlier observations that inhibition of squalene synthase by zaragozic acid A was accompanied by an increase in the incorporation of label from [3H]mevalonate into farnesyl-diphosphate (FPP)-derived isoprenoic acids, and found that FPP is readily converted to farnesoic acid and dicarboxylic acids in the liver. Expand
Non-sterol compounds that regulate cholesterogenesis. Analogues of farnesyl pyrophosphate reduce 3-hydroxy-3-methylglutaryl-coenzyme A reductase levels.
TLDR
Farnesyl acetate and ethyl farnesyl ether stimulate post-transcriptional down-regulation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the biosynthesis of cholesterol and isoprenoids, and directly disrupt sterol synthesis. Expand
Identification of farnesol as the non-sterol derivative of mevalonic acid required for the accelerated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
TLDR
The present studies demonstrate for the first time that the accelerated degradation of HMG-CoA reductase can be initiated in vitro and propose that this isoprenoid alcohol is important in this process in intact cells. Expand
Regulation of 3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase Degradation by the Nonsterol Mevalonate Metabolite Farnesol in Vivo(*)
TLDR
It is concluded that farnesol is a nonsterol, mevalonate-derived product that plays a role in accelerated reductase degradation, and its blockage by several inhibitory conditions that are known to block the degradation induced by meValonate addition is physiologically meaningful. Expand
Effects of NB-598, a potent squalene epoxidase inhibitor, on the apical membrane uptake of cholesterol and basolateral membrane secretion of lipids in Caco-2 cells.
Caco-2 cells grown on membrane filters were used as a model to study the effects of NB-598, an inhibitor of squalene epoxidase, on cholesterol absorption from the intestinal epithelia. NB-598 (10Expand
Prolonged inhibition of cholesterol synthesis by atorvastatin inhibits apo B-100 and triglyceride secretion from HepG2 cells.
TLDR
Results indicate that reduced apo B-100 secretion caused by atorvastatin is a secondary result owing to decreased lipid availability, and that atorVastatin's efficacy depends on the duration of cholesterol synthesis inhibition in the liver. Expand
...
1
2
3
4
5
...