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Seladin-1/DHCR24: a key protein of cell homeostasis and cholesterol biosynthesis

Seladin-1/DHCR24: a key protein of cell homeostasis and cholesterol biosynthesis

Postepy Higieny i Medycyny Doswiadczalnej 63: 318-330

ISSN/ISBN: 1732-2693

PMID: 19597241

Seladin-1 is a multifunctional protein encoded by DHCR24 gene and due to its enzymatic, antioxidant,and anti-apoptotic activities, it is considered as neuroprotective agent. Seladin-1 was identified as a gene down-regulated in brain regions selectively degenerated in Alzheimer's disease. Mutations of DHCR24 gene result in inhibition of the enzymatic activity of seladin-1, causing an accumulation of desmosterol and leading to a lethal disorder called desmosterolosis. Asan enzyme of cholesterol biosynthesis, seladin-1 enhances the formation of lipid rafts and caveoles.These membrane structures are involved in the maintenance of signaling pathways and metabolic processes, such as the degradation of amyloid precursor protein, which is especially significant in the pathophysiology of Alzheimer's disease. Independently of its enzymatic activity in cholesterol biosynthesis, seladin-1 acts as a caspase-3 inhibitor, a mediator of response to oxidative and oncogenic stress, and a reactive oxygen species scavenger. However, the effects of these activities seem to be indirectly modulated by membrane cholesterol level, which in turn gives priority to seladin-1's enzymatic function in cholesterol biosynthesis, among its other functions. Seladin-1 is ubiquitously expressed, with the highest expression level in the brain and adrenal glands. Differences in seladin-1 expression profile were reported in transformed cells originating from many tissue types. Although the mechanisms of the regulation of seladin-1 activity demand further elucidation, it has already been shown that DHCR24 gene was activated byLXRa/RXRa in skin, by ERa in neurons, and by AR in prostate. Apart from estrogens and androgens,thyroid hormones, and IGF-1 also take part in the stimulation of seladin-1 expression.

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