The liver X receptors (LXRs) are ligand-activated transcription factors that regulate the expression of genes controlling lipid metabolism. Oxysterols bind LXRs with high affinity in vitro and are implicated as ligands for the receptor. We showed previously that accumulation of selected dietary sterols, in particular stigmasterol, is associated with activation of LXR in vivo. In the course of the defining of structural features of stigmasterol that confer LXR agonist activity, we determined that the presence of an unsaturated bond in the side chain of the sterol was necessary and sufficient for activity, with the C-24 unsaturated cholesterol precursor sterols desmosterol and zymosterol exerting the largest effects. Desmosterol failed to increase expression of the LXR target gene, ABCA1, in LXR␣/-deficient mouse fibroblasts, but was fully active in cells lacking cholesterol 24-, 25-, and 27-hydroxylase; thus, the effect of desmosterol was LXR-dependent and did not require conversion to a side chain oxysterol. Desmosterol bound to purified LXR␣ and LXR in vitro and supported the recruitment of steroid receptor coactivator 1. Desmosterol also inhibited processing of the sterol response element-binding protein-2 and reduced expression of hydroxymethylglutaryl-CoA reductase. These observations are consistent with specific intermediates in the cholesterol biosynthetic pathway regulating lipid homeostasis through both the LXR and sterol response element-binding protein pathways.The liver X receptors (LXR␣ and LXR) 4 are ligand-dependent transcription factors belonging to the nuclear hormone receptor superfamily (1). Although the two transcription factors are encoded by separate genes, LXR␣ and LXR share 78% similarity within the ligand-binding domains (2). LXR (NR1H2) is ubiquitously expressed, whereas LXR␣ (NR1H3) has a more restricted distribution with the highest expression observed in the liver, adipose tissue, intestine, kidney, and macrophages (3). LXRs regulate multiple genes involved in lipid metabolism, including those involved in sterol transport (4, 5) and fatty acid biosynthesis (6 -8). More recently, LXRs have been found to play a role in the regulation of glucose metabolism (9, 10), immunity, and cellular responses to various environmental stresses (11)(12)(13)(14).To function as a transcription factor, LXR must heterodimerize with retinoid X receptor (RXRs) and then bind to LXR-response elements in target genes. The LXR-response elements consist of two direct hexanucleotide repeats separated by four nucleotides (DR4 element) (3). The binding of LXR or RXR ligands results in a conformational change in the heterodimer and recruitment of nuclear receptor coactivators such as steroid receptor coactivator-1 (SRC-1), resulting in the activation of gene transcription (16). Several compounds have been identified that are potent LXR agonists, including various oxysterols (17, 18). Position-specific monooxidation of the sterol side chain leads to high affinity binding and activation of LXR (19). Analysis of...
LAs can cause rapid cell death, which is primarily due to necrosis. Lidocaine and bupivacaine can trigger apoptosis with either increased time of exposure or increased concentration. These effects might be related to postoperative neurologic injury. Lidocaine, linked to the highest incidence of transient neurological symptoms, was not the most toxic LA, whereas bupivacaine, a drug causing a very low incidence of transient neurological symptoms, was the most toxic LA in our cell model. This suggests that cytotoxicity-induced nerve injury might have different mechanisms for different LAs and different target(s) other than neurons.
The major pathway for elimination of cholesterol in mammals is via secretion into bile. Biliary cholesterol secretion is mediated by the ATP-binding cassette (ABC) transporters ABCG5 (G5) and ABCG8 (G8) and is stimulated by cholesterol and by the non-cholesterol steroids cholate and diosgenin. To define the relationship between G5G8 expression and biliary cholesterol secretion, we measured G5 and G8 mRNA levels and biliary cholesterol concentrations in genetically manipulated mice expressing 0, 1, 2, 5, 10, or 16 copies of the two genes. Biliary cholesterol levels varied directly with G5G8 copy number and hepatic mRNA levels over a >16-fold range. Thus neither delivery of cholesterol to the transporter nor levels of cholesterol acceptors in bile were limiting under these conditions. In wild-type mice, cholate and diosgenin both increased biliary cholesterol concentrations 2-3-fold. The increase in biliary cholesterol content was dependent on expression of G5 and G8; neither steroid increased biliary cholesterol levels in G5G8 ؊/؊ mice. Cholate treatment was associated with a farnesoid X receptor (FXR)-dependent increase in hepatic mRNA and protein levels of G5 and G8. In contrast to cholate, diosgenin treatment did not affect G5G8 expression. Diosgenin increased the expression of several pregnane X receptor (PXR) target genes and the choleretic effect of diosgenin was reduced by ϳ70% in PXR knock-out mice. Thus G5 and G8 are required to modulate biliary cholesterol secretion in response to cholate and diosgenin, but the choleretic effects of these two steroids are mediated by different mechanisms requiring FXR and PXR, respectively.
Objective-Sitosterolemia is characterized by elevated plasma levels of plant sterols, hypercholesterolemia and premature coronary heart disease (CHD). CHD develops in some subjects with sitosterolemia, despite having normal plasma cholesterol levels, suggesting that high circulating levels of plant sterols may be atherogenic. We tested whether elevated plasma levels of plant sterols (sitosterol and campesterol) were associated with atherosclerosis in genetically modified mice and in middle-aged men and women. Methods and Results-Wild-type and hypercholesterolemic female mice with Ͼ20-fold higher plasma levels of plant sterols because of inactivation of the ATP-binding cassette (ABC) half transporters G5 and G8 (G5G8Ϫ/Ϫmice) were fed chow or Western diets for 7 months. No significant differences in aortic lesion area were found when the sitosterolemic mice were compared with littermate controls. To determine whether plasma levels of plant sterols were associated with coronary atherosclerosis in humans, the relationship between plasma plant sterols and coronary calcium (detected by electron beam computer tomography) was examined in 2542 subjects aged 30 to 67 years. Plasma levels of cholesterol, but not sitosterol or campesterol, were significantly higher in subjects with coronary calcium. Key Words: sitosterolemia Ⅲ ATP-binding cassette transporters Ⅲ atherosclerosis Ⅲ plant sterols T he 2 major classes of dietary sterols are those derived from animals (cholesterol) and those derived from plants (phytosterols). The most abundant dietary phytosterols are sitosterol and campesterol, which differ from cholesterol by an ethyl or methyl group attached to the side chain at C24. Although animal-derived and plant-derived sterols are structurally similar, they are handled differently by mammals. Less than 5% of dietary sitosterol is absorbed by the intestine, 1,2 whereas between 30% and 80% of dietary cholesterol is incorporated into chylomicrons and delivered to the liver. 3 Moreover, the small fraction of dietary plant sterols that reaches the liver is preferentially secreted into the bile. 2 As a result of the low fractional absorption and enhanced biliary secretion of plant sterols, phytosterols comprise Ͻ1% of circulating sterols. 4 Individuals with mutations in either of 2 ATP-binding cassette (ABC) half transporters, ABCG5(G5) or ABCG8(G8), have sitosterolemia. 5,6 This autosomalrecessive disorder is characterized by a Ͼ50-fold elevation in the plasma levels of plant sterols and is frequently associated with the development of tendon and cutaneous xanthomas, as well as premature coronary atherosclerosis (coronary heart disease [CHD]). 7 Although many subjects with sitosterolemia have hypercholesterolemia, the plasma levels of cholesterol can vary dramatically in these individuals and can sometimes be within the normal range. 8 -11 The presence of coronary atherosclerosis in the absence of hypercholesterolemia in some sitosterolemic patients has led to speculation that elevated plasma levels of plant sterols promot...
The structural features of sterols required to support mammalian cell growth have not been fully defined. Here, we use mutant CHO cells that synthesize only small amounts of cholesterol to test the capacity of various sterols to support growth. Sterols with minor modifications of the side chain (e.g., campesterol, -sitosterol, and desmosterol) supported long-term growth of mutant cells, but sterols with more complex modifications of the side chain, the sterol nucleus, or the 3-hydroxy group did not. After 60 days in culture, the exogenous sterol comprised >90% of cellular sterols. Inactivation of residual endogenous synthesis with the squalene epoxidase inhibitor NB-598 prevented growth in -sitosterol and greatly reduced growth in campesterol. Growth of cells cultured in -sitosterol and NB-598 was restored by adding small amounts of cholesterol to the medium. Surprisingly, enantiomeric cholesterol also supported cell growth, even in the presence of NB-598. Thus, sterols fulfill two roles in mammalian cells: (i) a bulk membrane requirement in which phytosterols can substitute for cholesterol and (ii) other processes that specifically require small amounts of cholesterol but are not enantioselective.ent-cholesterol ͉ phytosterols ͉ NB-598 S terols are essential components of eukaryote membranes. Their incorporation enhances the packing of the acyl chains of phospholipids in the hydrophobic phase of the bilayer, increases its mechanical strength, and reduces its permeability (1). Despite this crucial role, most animal species (e.g., nematodes and arthropods) cannot make sterols and so must get them from the diet. Vertebrates, by contrast, make sterols de novo from acetyl-coenzyme A and so do not require exogenous sterols. Accordingly, studies to probe sterol requirements of eukaryotes have used in invertebrates (2, 3), protazoans (4, 5), or yeast strains defective in sterol synthesis (6-8), so that the sterol composition of the organism can be controlled exogenously.Although phytosterols can account for a substantial portion of total dietary sterols (approximately one-third in humans), vertebrates systematically exclude them from the body. Cholesterol predominates in the membranes of most animals and is virtually the exclusive sterol of vertebrates. Invertebrates such as insects typically convert phytosterols to cholesterol by dealkylating C24 in the side chain, thereby furnishing cholesterol needed by membranes and preventing accumulation of noncholesterol sterols. Mammals and other vertebrates can either make sterols de novo or get cholesterol from the diet. Accumulation of other dietary sterols in these animals is prevented by the action of two ATP-binding cassette transporters, ABCG5 and ABCG8 (9), which function as a heterodimer to limit intestinal absorption and facilitate biliary excretion of noncholesterol sterols (10, 11). Thus, cholesterol comprises the great majority of vertebrate sterols, even in animals ingesting large quantities of phytosterols.The biological basis for selection of cholesterol as t...
The male house mouse excretes into its urine a large quantity of a volatile substance that has a unique lactol/hydroxyketone structure. This substance is capable of binding to the less volatile urinary constituents, such as proteins or peptides, and is active in puberty-acceleration bioassays. The controversies regarding the volatility of the puberty-accelerating pheromones can now be explained by considering a complex of volatile lactol/hydroxyketone and urinary proteins.
Biliary lipids (bile salts, phospholipids, cholesterol, plant sterols) were determined in 89 vertebrate species (cartilaginous and bony fish, reptiles, birds, and mammals), and individual phospholipid classes were measured in 35 species. All samples contained conjugated bile salts (C 27 bile alcohol sulfates and/or N -acyl amidates of C 27 and/or C 24 bile acids). Phospholipids were generally absent in the bile of cartilaginous fish and reptiles and were present in low amounts relative to bile salts in bony fish and most birds. In mammals, the phospholipid-bile salt ratio varied widely. The bile from species with low biliary phospholipid-bile salt ratios often contained a high proportion of sphingomyelin, confirmed by HPLC-MS. In species with a high phospholipid-bile salt ratio, the predominant biliary phospholipid was phosphatidylcholine (PC). The phospholipid-bile salt ratio correlated weakly with the calculated weighted hydrophobic index value. Cholesterol was present in the bile of virtually all species, with plant sterols uniformly being present in only trace amounts. The cholesterol-bile salt ratio tended to be higher in mammals than in nonmammals, but bile of all species was unsaturated. Thus, most nonmammalian vertebrates have relatively low levels of biliary phospholipid and cholesterol, suggesting that cholesterol is eliminated predominantly as bile salts. Mammals have a higher phospholipid and cholesterol to bile salt ratio, with the dominant phospholipid being
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