Histopathologic findings after treatment with different oxidosqualene cyclase (OSC) inhibitors in hamsters and dogs

Funk, Jürgen; Landes, Christian

doi:10.1016/j.etp.2005.02.006

Cited by 20 publications

(9 citation statements)

References 34 publications

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“…Given the role of 24,25EC in cholesterol homeostasis and the importance of OSC in determining its endogenous production, it is not surprising that this enzyme is of considerable interest as a pharmacological target [14,17,22,23]. Funk and Landes [33] reported that treatment of hamsters and dogs with OSC inhibitors produced various histopathological lesions, including early-stage cataracts. However, these authors concluded that all adverse effects described were exaggerated at the high dosage levels employed and suggested that use of lower doses of hepatosensitive OSC inhibitors should reduce the probability of adverse side-effects in humans [33].…”

Section: Discussionmentioning

confidence: 99%

“…Funk and Landes [33] reported that treatment of hamsters and dogs with OSC inhibitors produced various histopathological lesions, including early-stage cataracts. However, these authors concluded that all adverse effects described were exaggerated at the high dosage levels employed and suggested that use of lower doses of hepatosensitive OSC inhibitors should reduce the probability of adverse side-effects in humans [33]. Instead of blocking the entire mevalonate pathway with statins, the idea of manipulating a pre-existing and self-regulating pathway for the production of a physiological oxysterol mediator, that can augment cholesterol removal and decrease uptake and synthesis, is attractive and warrants further evaluation.…”

Section: Discussionmentioning

confidence: 99%

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Synthesis of the oxysterol, 24(S), 25-epoxycholesterol, parallels cholesterol production and may protect against cellular accumulation of newly-synthesized cholesterol

2007

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Aim: The effects of 24(S),25-epoxycholesterol (24,25EC) on aspects of cholesterol homeostasis is welldocumented. When added to cells, 24,25EC decreases cholesterol synthesis and up-regulates cholesterol efflux genes, including ABCA1. Synthesis of 24,25EC occurs in a shunt of the mevalonate pathway which also produces cholesterol. Therefore, 24,25EC synthesis should be subject to the same negative feedback regulation as cholesterol synthesis. To date, no role has been ascribed to 24,25EC in light of the fact that increased accumulation of cholesterol should decrease formation of this oxysterol through feedback inhibition. This leads to the intriguing paradox: why inhibit production of an apparently important regulator of cholesterol homeostasis when it is needed most? Methods:We used a combination of pharmacological and genetic approaches in Chinese Hamster Ovary cell-lines to investigate this paradox. Endogenous synthesis of 24,25EC was manipulated using partial inhibition of the enzyme, Oxidosqualene Cyclase. Changes in cholesterol and 24,25EC synthesis were determined using metabolic labelling with [1-14 C]-acetate, thin-layer chromatography and phosphorimaging. Transcriptional effects mediated via SREBP and LXR were analysed by luciferase reporter assays. Results:We showed that cholesterol addition to cells lead to a rapid and preferential inhibition of 24,25EC synthesis. Addition of 24,25EC resulted in parallel inhibition of 24,25EC and cholesterol synthesis. Furthermore, we used a variety of approaches to examine the relationship between cholesterol and 24,25EC synthesis, including cell-lines with different rates of cholesterol synthesis, varying cholesterol synthetic rates by pre-treatment with a statin, or lipoprotein cholesterol loading of macrophages. In all cases, we showed that 24,25EC synthesis faithfully tracked cholesterol synthesis. Moreover, changes in 24,25EC synthesis exerted downstream effects, reducing SREBP transcriptional activity whilst increasing ABCA1 and LXR transcriptional activity. Conclusion:Our results show that 24,25EC synthesis parallels cholesterol synthesis, consistent with this oxysterol functioning as a safety valve to protect against the accumulation of newly-synthesised cholesterol (as opposed to exogenously-derived cholesterol). Considering that 24,25EC is capable of being produced in all cholesterogenic cells, we propose that production of 24,25EC may represent a ubiquitous defence mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Synthesis of the oxysterol, 24(S), 25-epoxycholesterol, parallels cholesterol production and may protect against cellular accumulation of newly-synthesized cholesterol

2007

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“…It had been previously shown that in the Shumiya rat that cataracts were associated with deletion of exon 4 of LSS (Mori et al, 2006). In addition, drug candidates for inhibiting cholesterol synthesis, each inhibitors of LSS, caused the formation of lens cataracts (Fouchet et al, 2008; Funk and Landes, 2005; Pyrah et al, 2001). A mechanism of action was proposed by (Cenedella et al, 2004) where inhibition of lanosterol synthesis (and therefore products downstream of it) resulted in a “stiffer” membrane, thereby altering the way in which proteins associate with the membranes.…”

Section: Dietary Factors Associated With Altered Lens Cataract Risksmentioning

confidence: 99%

Small molecules, both dietary and endogenous, influence the onset of lens cataracts

Barnes

Quinlan

2017

Experimental Eye Research

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How the lens ages successfully is a lesson in biological adaption and the emergent properties of its complement of cells and proteins. This living tissue contains some of the oldest proteins in our bodies and yet they remain functional for decades, despite exposure to UV light, to reactive oxygen species and all the other hazards to protein function. This remarkable feat is achieved by a shrewd investment in very stable proteins as lens crystallins, by providing a reservoir of ATP-independent protein chaperones unequalled by any other tissue and by an oxidation-resistant environment. In addition, glutathione, a free radical scavenger, is present in mM concentrations and the plasma membranes contain oxidation-resistant sphingolipids, so what compromises lens function as it ages? In this review, we examine the role of small molecules in the prevention or causation of cataracts, including those associated with diet, metabolic pathways and drug therapy (steroids).

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“…A concern with high doses of OSC inhibitors is increased risk of cataracts (Funk and Landes, 2005). However, low doses of OSC inhibitors, required for partial inhibition, should theoretically avoid side-effects in humans.…”

Section: Oxidosqualene Cyclase (Osc)mentioning

confidence: 99%

Drug targets beyond HMG-CoA reductase: Why venture beyond the statins?

Gelissen

Brown

2011

Front. Biol.

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In this review, we aim to convey a brief, select history of the development of cholesterol-lowering therapies. We focus particularly on the highly successful statins as well as setbacks that should serve as cautionary tales. We go on to preview recent developments that may complement, if not one day replace, the statins. Our focus is on pharmacological interventions, particularly those targeting the cholesterol biosynthetic pathway. Also, we examine therapies under current investigation that target the assembly of atherogenic lipoproteins (via apolipoprotein B or microsomal triglyceride transfer protein), the stability of the low-density lipoprotein-receptor (via PCSK9, proprotein convertase subtilisin kexin 9), or are designed to increase high-density lipoprotein-cholesterol (via inhibition of cholesteryl ester transfer protein).

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Histopathologic findings after treatment with different oxidosqualene cyclase (OSC) inhibitors in hamsters and dogs

Cited by 20 publications

References 34 publications

Synthesis of the oxysterol, 24(S), 25-epoxycholesterol, parallels cholesterol production and may protect against cellular accumulation of newly-synthesized cholesterol

Synthesis of the oxysterol, 24(S), 25-epoxycholesterol, parallels cholesterol production and may protect against cellular accumulation of newly-synthesized cholesterol

Small molecules, both dietary and endogenous, influence the onset of lens cataracts

Drug targets beyond HMG-CoA reductase: Why venture beyond the statins?

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