Post-lanosterol biosynthesis of cholesterol and cancer

Lasunción, Miguel A.; Martín-Sánchez, Covadonga; Canfrán‐Duque, Alberto; Busto, Rebeca

doi:10.1016/j.coph.2012.07.001

Cited by 26 publications

(18 citation statements)

References 64 publications

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“…However, this effect is unlikely to have a significant role in primary lymphocytes as these cells have negligible cholesterol biosynthesis and no cholesterol precursors could be detected with any treatment. These findings are consistent with the very low cholesterol biosynthetic rates usually found in non‐proliferating cells (Lasuncion et al ., ).…”

Section: Discussionmentioning

confidence: 97%

“…Moreover, when tamoxifen and lovastatin were combined the stimulation of LDLR activity was synergistic (Suarez et al, 2004). Cell lines are proliferating cells that require a high provision of cholesterol for membrane biosynthesis (Lasuncion et al, 2012). In the present work, we studied whether the stimulating effect of tamoxifen and its combination with lovastatin on LDLR activity can be reproduced in nonproliferating primary human cells.…”

Section: Ici 182780 Toremifenementioning

confidence: 98%

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Clinically used selective oestrogen receptor modulators increase LDL receptor activity in primary human lymphocytes

Cerrato

Fernández-Suárez

Alonso

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSETreatment with selective oestrogen receptor modulators (SERMs) reduces low-density lipoprotein (LDL) cholesterol levels. We assessed the effect of tamoxifen, raloxifene and toremifene and their combinations with lovastatin on LDL receptor activity in lymphocytes from normolipidaemic and familial hypercholesterolaemic (FH) subjects, and human HepG2 hepatocytes and MOLT-4 lymphoblasts. EXPERIMENTAL APPROACHLymphocytes were isolated from peripheral blood, treated with different compounds, and 1,1′-dioctadecyl-3,3,3,3′-tetramethylindocarbocyanine perchlorate (DiI)-labelled LDL uptake was analysed by flow cytometry. KEY RESULTSTamoxifen, toremifene and raloxifene, in this order, stimulated DiI-LDL uptake by lymphocytes by inhibiting LDL-derived cholesterol trafficking and subsequent down-regulation of LDL receptor expression. Differently to what occurred in HepG2 and MOLT-4 cells, only tamoxifen consistently displayed a potentiating effect with lovastatin in primary lymphocytes. The SERM-mediated increase in LDL receptor activity was not altered by the anti-oestrogen ICI 182 780 nor was it reproduced by 17β-oestradiol. However, the tamoxifen-active metabolite endoxifen was equally effective as tamoxifen. The SERMs produced similar effects on LDL receptor activity in heterozygous FH lymphocytes as in normal lymphocytes, although none of them had a potentiating effect with lovastatin in heterozygous FH lymphocytes. The SERMs had no effect in homozygous FH lymphocytes. CONCLUSIONS AND IMPLICATIONSClinically used SERMs up-regulate LDL receptors in primary human lymphocytes. There is a mild enhancement between SERMs and lovastatin of lymphocyte LDLR activity, the potentiation being greater in HepG2 and MOLT-4 cells. The effect of SERMs is independent of oestrogen receptors but is preserved in the tamoxifen-active metabolite endoxifen. This mechanism may contribute to the cholesterol-lowering action of SERMs.

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Section: Discussionmentioning

confidence: 97%

Section: Ici 182780 Toremifenementioning

confidence: 98%

Clinically used selective oestrogen receptor modulators increase LDL receptor activity in primary human lymphocytes

Cerrato

Fernández-Suárez

Alonso

et al. 2015

British J Pharmacology

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“…Indeed, any alterations in triglycerides accumulation and catabolism or in cholesterol synthesis determine impaired hepatocellular proliferation. [17][18][19] In the first hours after PH, the regenerating liver accumulates fat consisting mainly of triglycerides, constituting the major energy source for cell metabolism. During liver regeneration, the peak of fat accumulation in mice tissue is between 12 and 24 h following PH, at a time when levels of cholesterol and triglycerides in the serum instead decrease.…”

Section: Introductionmentioning

confidence: 99%

Impaired cell proliferation in regenerating liver of 3 β-hydroxysterol Δ14-reductase (TM7SF2) knock-out mice

et al. 2016

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The liver is the most important organ in cholesterol metabolism, which is instrumental in regulating cell proliferation and differentiation. The gene Tm7sf2 codifies for 3 b-hydroxysterol-D 14 -reductase (C14-SR), an endoplasmic reticulum resident protein catalyzing the reduction of C14-unsaturated sterols during cholesterol biosynthesis from lanosterol. In this study we analyzed the role of C14-SR in vivo during cell proliferation by evaluating liver regeneration in Tm7sf2 knockout (KO) and wild-type (WT) mice. Tm7sf2 KO mice showed no alteration in cholesterol content. However, accumulation and delayed catabolism of hepatic triglycerides was observed, resulting in persistent steatosis at all times post hepatectomy. Moreover, delayed cell cycle progression to the G1/S phase was observed in Tm7sf2 KO mice, resulting in reduced cell division at the time points examined. This was associated to abnormal ER stress response, leading to alteration in p53 content and, consequently, induction of p21 expression in Tm7sf2 KO mice. In conclusion, our results indicate that Tm7sf2 deficiency during liver regeneration alters lipid metabolism and generates a stress condition, which, in turn, transiently unbalances hepatocytes cell cycle progression.

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“…Particularly in cancer cell lines, cholesterol has also been shown to be crucial for cell proliferation and differentiation. Cholesterol biosynthesis has been proposed as a possible intervention site in malignant cells, particularly in tissues with restricted access to plasma lipoproteins . Chemically speaking, in the first instance, both lipid classes seem to be rather unrelated (cyclic alcohols versus aliphatic carboxylic acids), but several biological facts underline the interconnection of both.…”

mentioning

confidence: 99%

“…Cholesterol biosynthesis has been proposed as a possible intervention site in malignant cells, particularly in tissues with restricted access to plasma lipoproteins. [6] Chemically speaking, in the first instance, both lipid classes seem to be rather unrelated (cyclic alcohols versus aliphatic carboxylic acids), but several biological facts underline the interconnection of both. Just recently, a crucial role of sterol lipids has been reported by Spann et al, integrating desmosterol accumulation with (anti-)inflammatory responses in foam cells.…”

mentioning

confidence: 99%

Comprehensive gas chromatography–electron ionisation mass spectrometric analysis of fatty acids and sterols using sequential one‐pot silylation: quantification and isotopologue analysis

Kloos

Lingeman

Bracher

et al. 2014

Rapid Comm Mass Spectrometry

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Post-lanosterol biosynthesis of cholesterol and cancer

Cited by 26 publications

References 64 publications

Clinically used selective oestrogen receptor modulators increase LDL receptor activity in primary human lymphocytes

Clinically used selective oestrogen receptor modulators increase LDL receptor activity in primary human lymphocytes

Impaired cell proliferation in regenerating liver of 3 β-hydroxysterol Δ14-reductase (TM7SF2) knock-out mice

Comprehensive gas chromatography–electron ionisation mass spectrometric analysis of fatty acids and sterols using sequential one‐pot silylation: quantification and isotopologue analysis

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