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

Hiyoshi, Hironobu; Yanagimachi, Mamoru; Ito, Masashi; Yasuda, Nobuyuki; Okada, Toshimi; Ikuta, Hironori; Shinmyo, Daisuke; Tanaka, Keigo; Kurusu, Nobuyuki; Yoshida, Ichiro; Abe, Shinya; Saeki, Takao; Tanaka, Hiroshi

doi:10.1194/jlr.m200316-jlr200

Cited by 48 publications

(49 citation statements)

References 55 publications

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“…5A ) and fatty acid synthesis ( Fig. 1E ) were increased, overall hepatic triglyceride synthesis might be suppressed because of the decreased expression of SREBP-1c, the key transcriptional factor regulating lipogenesis ( 16 ), and accumulation of farnesol and its derivatives, which inhibit triglyceride biosynthesis ( 35 ). It is also noteworthy that expressions of many of LXR-␣ target genes were decreased as discussed before.…”

Section: Discussionmentioning

confidence: 90%

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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Section: Discussionmentioning

confidence: 90%

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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“…In this regard, it is interesting to note that some SS inhibitors, but not statins, inhibit VLDL secretion from the liver (17,34,42). These considerations suggest the intriguing possibility that nonsterol mevalonate metabolites, for example, farnesol, or newly synthesized cholesterol regulate VLDL secretion (42); this awaits further investigation. Defective LDL clearance may also contribute to the development of hypercholesterolemia, because the mRNA expression of the LDLR gene is downregulated ( Table 1).…”

Section: Discussionmentioning

confidence: 99%

Increased cholesterol biosynthesis and hypercholesterolemia in mice overexpressing squalene synthase in the liver

Okazaki

Tazoe

Okazaki

et al. 2006

Journal of Lipid Research

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Squalene synthase (SS) is the first committed enzyme for cholesterol biosynthesis, located at a branch point in the mevalonate pathway. To examine the role of SS in the overall cholesterol metabolism, we transiently overexpressed mouse SS in the livers of mice using adenovirusmediated gene transfer. Overexpression of SS increased de novo cholesterol biosynthesis with increased 3-hydroxy-3-methyglutaryl-CoA (HMG-CoA) reductase activity, in spite of the downregulation of its own mRNA expression. Furthermore, overexpression of SS increased plasma concentrations of LDL, irrespective of the presence of functional LDL receptor (LDLR). Thus, the hypercholesterolemia is primarily caused by increased hepatic production of cholesterol-rich VLDL, as demonstrated by the increases in plasma cholesterol levels after intravenous injection of Triton WR1339. mRNA expression of LDLR was decreased, suggesting that defective LDL clearance contributed to the development of hypercholesterolemia. Curiously, the liver was enlarged, with a larger number of Ki-67-positive cells. These results demonstrate 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 biosynthesis. Cholesterol biosynthesis is subject to tight regulation by a multivalent feedback mechanism at both the transcriptional and the posttranscriptional level (1). The transcriptional regulation is mediated through the action of sterol-regulatory element binding proteins (SREBPs), membrane-bound transcription factors that enhance transcription of genes encoding cholesterol biosynthetic enzymes and the LDL receptor (LDLR) (2). The translational regulation of 3-hydroxy-3-methyglutaryl-CoA (HMG-CoA) reductase (EC1.1.1.34), the rate-limiting enzyme in cholesterol biosynthesis, is mediated by nonsterol mevalonate-derived isoprenoids, which act by an undefined mechanism (3). Its degradation is regulated by both sterols and nonsterol end products of mevalonate metabolism (4, 5). The sterolregulated degradation of HMG-CoA reductase is mediated Abbreviations: Ad-SS, recombinant adenovirus carrying SS cDNA under the control of cytomegalovirus promoter; apoB, apolipoprotein B; E, embryonic day; ER, endoplasmic reticulum; LDLR, LDL receptor; m.o.i., multiplicity of infection; SREBP, sterol-regulatory element binding protein; SS, squalene synthase; TC total cholesterol; TG, triglyceride; TUNEL, terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling.

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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%

“…Instead, results from the present study suggest that the effects of FPP were due to the isoprenoid itself, its alcohol derivative, FOH, or its degradation products. 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).…”

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

Cited by 48 publications

References 55 publications

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

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

Increased cholesterol biosynthesis and hypercholesterolemia in mice overexpressing squalene synthase in the liver

Regulation of Fatty Acid Synthesis by Farnesyl Pyrophosphate

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