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  • br Genes involved in oxysterol metabolism The

    2020-07-31


    Genes involved in oxysterol metabolism The main enzymes that participate in the metabolism of oxysterols generally belong into one of two groups: transferases or oxidoreductases [22]. The following chapter describes those genes of oxysterol metabolism whose polymorphisms have been associated with cancer in any way. Acyltransferases, responsible for cholesterol and oxysterol esterification, sterol O-acyltransferase 1 and 2 (genes SOAT1 and SOAT2, respectively), and lecithin-cholesterol acyltransferase (LCAT) [[23], [24], [25]], have not seen their genetic variation associated with cancer to date. Similarly, genetic polymorphism in the oxidoreductases cholesterol 25-hydroxylase (CH25H), catalyzing the synthesis of 25-hydroxycholesterol (25-HC) from cholesterol [24], cytochrome P450 46A1 (CYP46A1), converting cholesterol to 24-hydroxycholesterol [24], and 3β-hydroxysteroid dehydrogenase type 7 (HSD3B7), utilizing oxysterols for bile Garcinol synthesis [26], are not yet associated with cancer. The oxidoreductase 7-dehydrocholesterol (7-DHC) reductase (DHCR7) is primarily a cholesterol biosynthesis enzyme and thus is described in chapter 3.1.3.
    Genes involved in sterol homeostasis and transport Cholesterol contributes to carcinogenesis and cancer cell growth, being vital for membrane biogenesis, among other processes. It is not surprising that cholesterol homeostasis is deregulated in cancer cells [119]. Moreover, higher cholesterol levels were found in various tumors in comparison to non-tumorous tissues (see citations in Smith and Land [120]) and the accumulation of intracellular cholesterol can suppress proapoptotic signals in the cell and contribute to chemotherapy resistance [119,121]. The following chapter summarizes the main genes involved in (chole)sterol biosynthesis, homeostasis regulation, and transport, that in some way interact with oxysterols and have been associated with cancer.
    Oxysterol-binding receptors
    Summary and future prospects
    Declarations of interest
    Author contributions
    Funding This work was supported by the Czech Science Foundation [project no. P303/12/G163], the Ministry of Health of the Czech Republic [project no. AZV 17–28470A], the Ministry of Education Youth and Sports of the Czech Republic [National Sustainability Program I project no. LO1503], and Charles University [project “Center of clinical and experimental liver surgery“ no. UNCE/MED/006].
    Introduction Oxysterols are hydroxylated derivatives of cholesterol that play important functions in lipid metabolism and, as signaling-active and mutagenic compounds, received considerable attention in tumor biology [1]. A number of studies revealed that there is no net movement of cholesterol from the peripheral circulation into the CNS and there is general agreement that the brain covers its cholesterol demand by endogenous biosynthesis [2]. Excess brain cholesterol is hydroxylated mainly to 24S-hydroxycholesterol (24S-OHC) and secreted via the blood–brain barrier into the circulation [2]. 24S-OHC is transported in association with lipoproteins and metabolized by the liver [2]. Alternatively, 24S-OHC acts as a bioactive oxysterol in the brain regulating the expression of enzymes involved in cholesterol homeostasis [3]. Apart from 24S-OHC the brain is capable of synthesizing, besides 27-OHC via CYP27A1, 25-OHC via cholesterol 25-hydroxylase (CH25H).