Sterols oxysterols

In another study, the in vitro modulation of rat adipocyte ghost membrane fluidity by cholesterol oxysterols was investigated [55]. It was found that cholesterol oxy-sterols interact differently with rat adipocyte membranes. Cholestanone interacts predominantly with the phospholipids located at the inner leaflet (e.g. PE), whereas cholesterol interacts preferably with the phospholipids (PC) of the outer layer. 

Oxysterols are reported to act as potent inhibitors of growth in mammalian cell systems because of their interference with sterol biosynthesis (13). Upon superficial examination, brassinosteroids could be regarded as just highly oxygenated sterols. Therefore, two oxysterols (24-ketolanosterol and 7-... 

That the effect of BR is not simply due to the "oxidized" sterol structure is supported by our observation that oxysterols, which are strong inhibitors in mammalian cell cultures, were nearly inactive in our system. Again this points to... 

Squalene is converted into the first sterol, lanosterol, by the action of squalene epoxidase and oxidosqualene lanosterol cyclase. The catalytic mechanism for the cyclase s four cyclization reactions was revealed when the crystal stmcture of the human enzyme was obtained (R. Thoma, 2004). Oxidosqualene lanosterol cyclase is considered an attractive target for developing inhibitors of the cholesterol biosynthetic pathway because its inhibition leads to the production of 24,25-epoxycholesterol (M.W. Huff, 2005). This oxysterol is a potent ligand activator of the liver X receptor (LXR) and leads to expression of several genes that promote cellular cholesterol efflux, such as ABCAl, ABCG5, and ABCG8 (Section 4.1). Thus, inhibitors of oxidosqualene lanosterol cyclase could be therapeutically advantageous because they would reduce cholesterol synthesis and promote cholesterol efflux (M.W. Huff, 2005). 

Isoprenoid synthesis is regulated by sterol and non-sterol components of the biosynthetic pathway, oxysterols, and also by physiological factors. The cholesterol content of the... 

Excess cholesterol can also be metabolized to CE. ACAT is the ER enzyme that catalyzes the esterification of cellular sterols with fatty acids. In vivo, ACAT plays an important physiological role in intestinal absorption of dietary cholesterol, in intestinal and hepatic lipoprotein assembly, in transformation of macrophages into CE laden foam cells, and in control of the cellular free cholesterol pool that serves as substrate for bile acid and steroid hormone formation. ACAT is an allosteric enzyme, thought to be regulated by an ER cholesterol pool that is in equilibrium with the pool that regulates cholesterol biosynthesis. ACAT is activated more effectively by oxysterols than by cholesterol itself, likely due to differences in their solubility. As the fatty acyl donor, ACAT prefers endogenously synthesized, monounsaturated fatty acyl-CoA. 

Fig. 4. The bile acid biosynthetic pathways. The classical pathway operates entirely in the liver and cholesterol 7a-hydroxylase (CYP7A1) initiates the pathway. In other tissues, the entry of cholesterol into the alternate pathways is facilitated by sterol 27-hydroxylase (CYP27A1), cholesterol 24-hydroxylase (CYP46A1), and cholesterol 25-hydroxylase (CH25H). The oxysterols generated by these enzynies are 7a-hydroxylated by oxysterol 7a-hydroxylases CYP7B1 and CYP39A1, and the products enter the latter steps of the classical pathway.

The existence of an alternate pathway for the synthesis of bile acids was suspected because it was possible for oxysterols to be converted into bile acids (N. Wachtel, 1968). It is now recognized that a variety of oxysterols produced by an assortment of cell types can be converted into bile acids. The production of these oxysterols is catalyzed by several sterol hydroxylases sterol 27-hydroxylase (CYP27A1) (J.J. Cali, 1991), cholesterol 25-hydroxylase (CH25H) (E.G. Lund, 1998), and cholesterol 24-hydroxylase (CYP46A1) (E.G. Lund, 1999). Cholesterol 25-hydroxylase is not a cytochrome P-450 monooxygenase, unlike the two other enzymes. Almost all of the 24-hydroxycholesterol that ends up in the liver originates from the brain, and it has been suggested that the production of... 

Oxysterols have diverse roles in cholesterol efflux, a critical topic in foam cell biology. On the one hand, cells incubated with 7-ketocholesterol and 25-hydroxycholesterol have decreased cholesterol efflux. Possible mechanisms include inhibition of membrane desorption of cholesterol or phospholipids or, as mentioned above, inhibition of lysosomal sphingomyelinase leading to lysosomal sequestration of cholesterol (M. Aviram, 1995). On the other hand, the conversion of cholesterol by macrophage sterol 27-hydroxylase to 27-hydroxycholesterol and 3[l-hydroxy-5-cholestenoic acid, which are efficiently effluxed from cells, has been proposed to promote sterol efflux from foam cells (1. Bjorkhem,... 

Additionally, cholesterol oxidation can occur in in vivo by enzymes or by lipid peroxidation. Enzymatic formation of oxysterols can be divided into two classes (a) direct enzymatic action on cholesterol or another related sterol and (b) enzymatic activity leading to the formation of radicals, which in turn attack cholesterol. All reactions of the first type seem at present to be cytochrome P-450 dependent [16]. 

A number of oxysterols, which suppress HMGR when added to cell cultures, are natural precursors of cholesterol or products of its metabolism to bile acids or steroid hormones [18]. These sterols include the bile acid intermediates 7a- and 26-hydroxycholesterol, the steroid hormone precursors 20a- and 22R-hydroxycholesterol. 24(s)-hydroxycholesterol (cerebrosterol) was foimd by Kandutch et al [18] that other oxysterol metabolites capable of repressing the reductase may also be produced. Kandutch et al [18] foimd several unidentified oxysterols capable of suppressing activity in extracts of cultured cells. Inhibitory oxysterols are, therefore, produced in all cells that synthesize cholesterol as an end product, as well as in cells that synthesize cholesterol and metabolize it to other steroid products. 

The expression cholesterol oxidation products (COP) or oxysterols refers to a group of sterols similar in structure to cholesterol but containing an additional hydroxyl, ketone, or epoxide group, on the sterol nucleus or a hydroxyl group on the side chain of the molecule. Table 6.2 presents the names of most prominent COP formed in foods, plasma, and tissues. 

Fig. 12. Panel A Inhibitory effects of various polyunsaturated fatty acids (PUFA) on sterol regulatory element binding protein (SREBP)-lc promoter activity. EtOH, ethanol SA, saturated fatty acid OL, oleic acid LA, linoleic acid DHA, docosa-hexaenoic acid EPA, eicosapentaenoic acid AA, arachidonic acid. Panel B Mechanism by which polyunsaturated fatty acids suppress the SREBP-1 c promoter activity, through an effect on the liver X receptor (LXR)/9-c/s-retinoic acid receptor (RXR) activation pathway [redrawn from Yoshikawa etal. (129), reproduced with permission]. PUFA competitively interfere with binding of the endogenous ligand (possibly oxysterols) to LXR, thereby repressing LXR/RXR transactivity and SREBP-lc and lipogenic gene expression. Meanwhile, PUFA can bind and activate peroxisome proliferator activated receptor-a (PPARa) to induce 3-oxidation of fatty acids. PPRE PPAR response element LXRE LXR response element.

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