Evaluation of the Atherogenic Risk of Isotretinoin-induced and Etretinate-induced Alterations of Lipoprotein Cholesterol Metabolism

Melnik, Bodo C.; Bros, Uwe; Plewig, Gerd

doi:10.1038/jid.1987.8

Cited by 10 publications

(2 citation statements)

References 29 publications

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“…Isotretinoin at pharmacological doses elevates plasma triglycerides and induces overt hypertriglyceridemia. [184][185][186] There are at least three mechanisms involved in the generation of isotretinoininduced hypertriglyceridema:…”

Section: Isotretinoin-induced Hypertriglyceridemiamentioning

confidence: 99%

Isotretinoin and FoxO1

Melnik

2011

Dermato-Endocrinology

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Oral isotretinoin (13-cis retinoic acid) is the most effective drug in the treatment of acne and restores all major pathogenetic factors of acne vulgaris. isotretinoin is regarded as a prodrug which after isomerizisation to all-trans-retinoic acid (ATRA) induces apoptosis in cells cultured from human sebaceous glands, meibomian glands, neuroblastoma cells, hypothalamic cells, hippocampus cells, Dalton's lymphoma ascites cells, B16F-10 melanoma cells, and neuronal crest cells and others. By means of translational research this paper provides substantial indirect evidence for isotretinoin's mode of action by upregulation of forkhead box class O (FoxO) transcription factors. FoxOs play a pivotal role in the regulation of androgen receptor transactivation, insulin/insulin like growth factor-1 (IGF-1)-signaling, peroxisome proliferator-activated receptor-γ (PPArγ)- and liver X receptor-α (LXrα)-mediated lipogenesis, β-catenin signaling, cell proliferation, apoptosis, reactive oxygene homeostasis, innate and acquired immunity, stem cell homeostasis, as well as anti-cancer effects. An accumulating body of evidence suggests that the therapeutic, adverse, teratogenic and chemopreventive effecs of isotretinoin are all mediated by upregulation of FoxO-mediated gene transcription. These FoxO-driven transcriptional changes of the second response of retinoic acid receptor (RAR)-mediated signaling counterbalance gene expression of acne due to increased growth factor signaling with downregulated nuclear FoxO proteins. The proposed isotretinoin→ATRA→RAR→FoxO interaction offers intriguing new insights into the mode of isotretinoin action and explains most therapeutic, adverse and teratogenic effects of isotretinoin in the treatment of acne by a common mode of FoxO-mediated transcriptional regulation.

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Section: Isotretinoin-induced Hypertriglyceridemiamentioning

confidence: 99%

Isotretinoin and FoxO1

Melnik

2011

Dermato-Endocrinology

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“…Retinoids at pharmacological doses increase plasma triglycerides and induce overt hypertriglyceridemia in more than 20% of the patients [104–106]. Hepatic very low density lipoprotein (VLDL) production is facilitated by microsomal triglyceride transfer protein (MTP) in a rate‐limiting step that is regulated by insulin.…”

Section: Foxo1 and The Therapeutic Effect Of Retinoidsmentioning

confidence: 99%

FoxO1 – the key for the pathogenesis and therapy of acne?

Melnik

2010

J Deutsche Derma Gesell

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Five main factors play a pivotal role in the pathogenesis of acne: androgen dependence, follicular retention hyperkeratosis, increased sebaceous lipogenesis, increased colonization with P. acnes, and inflammatory events. This paper offers a solution for the pathogenesis of acne and explains all major pathogenic factors at the genomic level by a relative deficiency of the nuclear transcription factor FoxO1. Nuclear FoxO1 suppresses androgen receptor, other important nuclear receptors and key genes of cell proliferation, lipid biosynthesis and inflammatory cytokines. Elevated growth factors during puberty and persistent growth factor signals due to Western life style stimulate the export of FoxO1 out of the nucleus into the cytoplasm via activation of the phos-phoinositide-3-kinase (PI3K)/Akt pathway. By this mechanism, genes and nuclear receptors involved in acne are derepressed leading to increased androgen receptor-mediated signal transduction, increased cell proliferation of androgen-dependent cells, induction of sebaceous lipogenesis and upregulation of Toll-like-receptor-2-dependent inflammatory cytokines. All known acne-inducing factors exert their action by reduction of nuclear FoxO1 levels. In contrast, retinoids, antibiotics and dietary intervention will increase the nuclear content of FoxO1, thereby normalizing increased transcription of genes involved in acne. Various receptor-mediated growth factor signals are integrated at the level of PI3K/Akt activation which finally results in nuclear FoxO1 deficiency.

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