Effects of various oxygenated sterols on cellular sterol biosynthesis in chinese hamster lung cells resistant to 25-hydroxycholesterol

Cavenee, Webster K.; Gibbons, Geoffrey F.; Chen, Harry W.; Kandutsch, Andrew A.

doi:10.1016/0005-2760(79)90027-4

Cited by 28 publications

(8 citation statements)

References 19 publications

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“…Despite the potency with which oxysterols regulate gene transcription by the SREBP and LXRα pathways, there remains uncertainty concerning the structure(s) of the naturally occurring regulatory oxysterols and the enzymology involved in their biosynthesis and metabolism. This paper revisits some of our previous work in this area (23)(24)(25)(26), which suggests that the oxygenated, naturally occurring cholesterol precursors II and III (Scheme 1) may have a regulatory role, either as inhibitors of SREBP maturation or as activating ligands for LXRα. This paper will also reassess the results of some of our original studies on the regulation of cholesterol biosynthesis (27,28) in terms of factors that affect the steady-state concentration and turnover of natural regulatory oxysterols.…”

supporting

confidence: 51%

“…Again, in the Dede cells, the overall rates of sterol synthesis were more susceptible to inhibition than HMG-CoA reductase. A mutant strain of Dede cells (A2-1) selected for resistance to the metabolic effects of 25-hydroxycholesterol was also resistant to the inhibitory effect of the 32-oxygenated lanostenol derivatives on HMG-CoA reductase activity (23,24). Similar inhibitory effects of the lanostenol derivatives on rates of sterol synthesis and HMG-CoA reductase activities were also observed in L-cells, a subline of mouse fibroblasts (23).…”

Section: Resultsmentioning

confidence: 92%

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The role of cytochrome P450 in the regulation of cholesterol biosynthesis

Gibbons

2002

Lipids

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A ubiquitously expressed member of the cytochrome P450 superfamily, CYP51, encodes lanosterol 14alpha-demethylase, the first step in the conversion of lanosterol into cholesterol in mammals. The biosynthetic intermediates of lanosterol 14alpha-demethylation are oxysterols, which inhibit HMG-CoA reductase and sterol synthesis in mammalian cells in vitro. These oxysterols (5alpha-lanost-8-en-3beta,32-diol and 3beta-hydroxy-5alpha-lanost-8-en-32-al) are efficiently converted into cholesterol in vitro and are generally considered to be natural cholesterol precursors. When added to hepatocytes in high concentrations, besides their conversion into cholesterol, they are also rapidly metabolized into more polar sterols and into steryl esters. The 15alpha- and 15beta-hydroxy epimers of 5alpha-lanost-8-en-3beta-ol are also rapidly metabolized into more polar sterols and steryl esters but are not converted efficiently into cholesterol. Polar sterol formation from all these oxysterols is dependent on an active form of cytochrome P450. Oxysterols are potent regulators of the activities of transcription factors of the sterol regulatory element-binding protein family and of liver X-receptor alpha. It is proposed that the rapid, cytochrome P450-dependent metabolism of naturally occurring regulatory oxysterols provides a route for their deactivation so that they become incapable of affecting gene transcription. Inhibition of cytochrome P450 by the drug ketoconazole prevents the inactivation of such oxysterols, leading to a prolonged suppression of hepatic HMG-CoA reductase in vivo and in vitro.

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confidence: 51%

Section: Resultsmentioning

confidence: 92%

The role of cytochrome P450 in the regulation of cholesterol biosynthesis

Gibbons

2002

Lipids

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“…It is felt that cholesterol is so poorly soluble that it will not adequately cross cell membranes to cause regulation. Others have suggested that unmodified cholesterol is not the regulatory sterol at all, but that oxygenated cholesterol accounts for the observed changes in cholesterol metabolism (42)(43)(44)(45)(46)(47)(48). Thus, in most studies to date, 25hydroxycholesterol is added together with cholesterol (usually in ethanol) to potentiate the desired regulation (7,8,(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Regulation of sterol regulatory element-binding proteins by cholesterol flux in CaCo-2 cells

Field

Born

Murthy

et al. 2001

Journal of Lipid Research

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The regulation of sterol regulatory element-binding proteins (SREBP) by cholesterol flux was studied in the intestinal cell line CaCo-2. CaCo-2 cells were incubated for 18 h with micelles containing 5 mM taurocholate and 500 M oleic acid or micelles containing either 200 M cholesterol or 150 M lysophosphatidylcholine. In some incubations, an ACAT inhibitor was added or 25-hydroxycholesterol was substituted for cholesterol. The SREBP-1a transcript was 2-fold more abundant than the SREBP-1c transcript. In cells incubated with micelles containing cholesterol, rates of cholesterol synthesis were decreased and rates of esterification were increased. Cholesterol synthesis was decreased further by ACAT inhibition. Cholesterol influx decreased mRNA levels of SREBP-2, HMG-CoA synthase, HMG-CoA reductase, and fatty acid synthase. ACAT inhibition modestly suppressed gene expression further. Neither SREBP-1a nor SREBP-1c mRNA levels were altered by cholesterol. Despite decreases in gene expression of the sterol-responsive genes by cholesterol, the amounts of precursor and mature forms of SREBP-1 and SREBP-2 were not altered. In contrast, if 25-hydroxycholesterol was substituted for cholesterol, both the precursor and mature forms of SREBP-2 were decreased. The polar sterol decreased the mature form of SREBP-1 but the amount of the precursor form was unchanged. In cells incubated with micelles containing lysophosphatidylcholine, which causes cholesterol to efflux from cells, sterolresponsive gene expression was increased. The amounts of precursor and mature forms of SREBP-1 and SREBP-2, however, were not altered. In contrast, if the cells were depleted of cholesterol by incubating them with lovastatin and cyclodextrin, the mature forms of SREBP-1 and SREBP-2 were increased, as were mRNA levels for the sterol-responsive genes.The data would suggest that cholesterol influx/ efflux regulates mRNA levels of sterol-responsive genes independently of changes in the amount of mature SREBP. In contrast, 25-hydroxycholesterol influx or cholesterol depletion alters the amount of mature SREBP, leading to the regulation of sterol-responsive gene expression. -Field, F. J., E. Born, S. Murthy, and S. N. Mathur. Regulation of sterol regulatory element-binding proteins by cholesterol flux in CaCo-2 cells.

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“…CT displayed some biological properties suggesting it may have a physiological role in mammals. For instance, CT induced cytotoxicity in vivo and in vitro in normal and cancerous cells (Carvalho, Silva, Moreira, Simoes, & Sa, 2011;Carvalho, Silva, Moreira, Simoes, & Sa e Melo, 2010;Imai et al, 1980;Kandutsch, Chen, & Heiniger, 1978) and hypocholesterolaemia in animals (Aramaki et al, 1967). As opposed to other oxysterols such as 25-hydroxycholesterol, CT was not an inhibitor of the HMG-CoA reductase, the rate-controlling enzyme of the cholesterol pathway (Cavenee, Gibbons, Chen, & Kandutsch, 1979).…”

Section: Introductionmentioning

confidence: 99%

The 5,6‐epoxycholesterol metabolic pathway in breast cancer: Emergence of new pharmacological targets

Médina

Diallo

Huc-Claustre

et al. 2020

British J Pharmacology

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Metabolic pathways have emerged as cornerstones in carcinogenic deregulation providing new therapeutic strategies for cancer management. Recently, a new branch of cholesterol metabolism has been discovered involving the biochemical transformation of 5,6-epoxycholesterols (5,6-ECs). The 5,6-ECs are metabolized in breast cancers to the tumour promoter oncosterone whereas, in normal breast tissue, they are metabolized to the tumour suppressor metabolite, dendrogenin A (DDA). Blocking the mitogenic and invasive potential of oncosterone will present new opportunities for breast cancer treatment. The reactivation of DDA biosynthesis, or its use as a drug, represents promising therapeutic approaches such as DDA-deficiency complementation, activation of breast cancer cell re-differentiation and breast cancer chemoprevention. This review presents current knowledge of the 5,6-EC metabolic pathway in breast cancer, focusing on the 5,6-EC metabolic enzymes ChEH and HSD11B2 and on 5,6-EC metabolite targets, the oxysterol receptor (LXRβ) and the glucocorticoid receptor.

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Effects of various oxygenated sterols on cellular sterol biosynthesis in chinese hamster lung cells resistant to 25-hydroxycholesterol

Cited by 28 publications

References 19 publications

The role of cytochrome P450 in the regulation of cholesterol biosynthesis

The role of cytochrome P450 in the regulation of cholesterol biosynthesis

Regulation of sterol regulatory element-binding proteins by cholesterol flux in CaCo-2 cells

The 5,6‐epoxycholesterol metabolic pathway in breast cancer: Emergence of new pharmacological targets

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