t0901317 has been researched along with Dyslipidemias* in 4 studies
1 review(s) available for t0901317 and Dyslipidemias
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Liver X receptors (LXR) as therapeutic targets in dyslipidemia.
Liver X receptors (LXR) alpha and beta belong to a family of nuclear receptors which form heterodimers with the retinoid X receptor (RXR) and, upon ligand binding, stimulate the expression of target genes. LXR were initially described as orphan receptors and later oxidized cholesterol derivatives (oxysterols) were identified as their natural ligands. In addition, several synthetic LXR agonists such as T0901317 and GW3965 were synthesized. Oxysterols are formed in amounts proportional to cholesterol content in the cell and therefore LXR operate as cholesterol sensors which protect from cholesterol overload by inhibiting intestinal cholesterol absorption, stimulating cholesterol efflux from cells to high-density lipoproteins (HDL), its transport to the liver, conversion to bile acids, and biliary excretion. In addition, LXR agonists activate fatty acid synthesis by stimulating the expression of a lipogenic transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c), leading to the elevation of plasma triglycerides and liver steatosis. Lipogenic effect seems is the most important negative feature of LXR agonists considered as potential hypolipidemic drugs. Some of currently used drugs also affect LXR signaling. For example, statins may impair LXR signaling by inhibiting oxysterol synthesis, whereas fibrates and thiazolidinediones increase LXR expression and activity. Topics: Animals; Benzoates; Benzylamines; Cholesterol; DNA-Binding Proteins; Dyslipidemias; Hydrocarbons, Fluorinated; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver X Receptors; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear; Sulfonamides | 2008 |
3 other study(ies) available for t0901317 and Dyslipidemias
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Induction of stearoyl-CoA desaturase protects human arterial endothelial cells against lipotoxicity.
Endothelial lipotoxicity has been implicated in the pathogenesis of multiple stages of cardiovascular disease from early endothelial dysfunction to manifest atherosclerosis and its complications. Saturated free fatty acids are the major inducers of endothelial cell apoptosis and inflammatory cytokines. In humans, the enzyme human stearoyl-CoA desaturase-1 (hSCD-1) is the limiting step of the desaturation of saturated to monounsaturated fatty acids. Since we could demonstrate the expression of SCD-1 in primary human arterial endothelial cells (HAECs), we aimed to prove a beneficial role of upregulated hSCD-1 expression. In contrast to other cells that are less susceptible to lipotoxicity, hSCD-1 was not upregulated in HAECs upon palmitate treatment. Following that, we could show that upregulation of hSCD-1 using the LXR activator TO-901317 in HAECs protects the cells against palmitate-induced lipotoxicity, cell apoptosis, and expression of inflammatory cytokines IL-6 and IL-8. Increased hSCD-1 activity was determined as increased C16:1/16:0 ratio and enhanced triglyceride storage in palmitate treated cells. The beneficial effect was clearly attributed to enhanced hSCD-1 activity. Overexpression of hSCD-1 blocked palmitate-induced cytotoxicity, and knockdown of hSCD-1 using siRNA abolished the protective effect of TO-901317 in HEK-293 cells. Additionally, inhibition of hSCD-1 with 10/12 CLA blocked the effect of TO-901317 on palmitate-induced lipotoxicity, cell apoptosis, and inflammatory cytokine induction in HAECs. We conclude that upregulation of hSCD-1 leads to a desaturation of saturated fatty acids and facilitates their esterification and storage, thereby preventing downstream effects of lipotoxicity in HAECs. These findings add a novel aspect to the atheroprotective actions of LXR activators in cardiovascular disease. Topics: Blotting, Western; Cell Survival; DNA-Binding Proteins; Dyslipidemias; Endothelial Cells; Enzyme Induction; Fatty Acids, Nonesterified; Humans; Hydrocarbons, Fluorinated; Interleukin-6; Interleukin-8; Liver X Receptors; Orphan Nuclear Receptors; Palmitates; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Stearoyl-CoA Desaturase; Sulfonamides; Transfection; Up-Regulation | 2008 |
Beneficial effect of 3,4,5,6-tetrahydroxyxanthone on dyslipidemia in apolipoprotein E-deficient mice.
Previous investigations have shown that decreased expression of angiopoietin-like protein 3 (Angptl3) is protective against dyslipidemia in atherosclerosis. The present study was conducted to test the effect of 3,4,5,6-tetrahydroxyxanthone, a xanthone compound, on dyslipidemia in apolipoprotein E-deficient (ApoE-/-) mice. Forty mice were randomly divided into 4 groups (n = 10): control group (C57BL/6J mice), ApoE-/-mice group, and two groups of ApoE-/- mice treated with 3,4,5,6-tetrahydroxyxanthone (10 or 30 mg/kg per day). Eight weeks after treatment, lipid levels in the blood and liver, expression of hepatic Angptl3, and adipose tissue lipoprotein lipase (LPL) were determined. Treatment with 3,4,5,6-tetrahydroxyxanthone (10 or 30 mg/kg) significantly decreased plasma and hepatic total cholesterol and triglyceride concentrations, increased plasma high-density lipoprotein cholesterol, and significantly downregulated expression of Angptl3 mRNA and protein concomitantly with upregulated expression of LPL mRNA. In addition, T0901317 (a liver X receptor ligand) caused elevated expression of hepatic Angptl3 mRNA and protein, and the effect of T0901317 was also abrogated by 3,4,5,6-tetrahydroxyxanthone in vivo and in vitro. The present results suggest that the beneficial effect of 3,4,5,6-tetrahydroxyxanthone on dyslipidemia may be related to reduced expression of Angptl3. Topics: Adipose Tissue; Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Angiopoietins; Animals; Apolipoproteins E; Cells, Cultured; Cholesterol; Disease Models, Animal; Dyslipidemias; Hydrocarbons, Fluorinated; Lipoprotein Lipase; Liver; Male; Mice; Mice, Knockout; Random Allocation; RNA, Messenger; Sulfonamides; Triglycerides; Xanthones | 2008 |
Liver X receptor agonist TO-901317 upregulates SCD1 expression in renal proximal straight tubule.
Liver X receptors (LXRs), including LXRalpha and LXRbeta, are intracellular sterol sensors that regulate expression of genes controlling fatty acid and cholesterol absorption, excretion, catabolism, and cellular efflux. Because the kidney plays an important role in lipid metabolism and dyslipidemia accelerates renal damage, we investigated the effect of TO-901317, an LXR agonist, on the gene expression profile in mouse kidney. Treatment of C57 Bl/6 mice with TO-901317 (3 mg.kg(-1).day(-1)) for 3 days resulted in 51 transcripts that were significantly regulated in the kidney. Among them, the stearoyl-CoA desaturase-1 (SCD1) was upregulated most dramatically. Northern blot analysis revealed that SCD1 mRNA levels were markedly higher than that in control kidneys. Enhanced SCD1 expression by TO-901317 also resulted in increased fatty acid desaturation in the kidney. In control mice, constitutive renal SCD1 expression was low; however, TO-901317 treatment markedly increased SCD1 expression in the outer stripe of the outer medulla as assessed by both in situ hybridization and immunostain. Double-labeling studies further indicated that SCD1 mRNA was selectively expressed in proximal straight tubules negative for aquaporin-2 and Tamm-Horsfall protein. In vitro studies in cultured murine proximal tubule cells further demonstrated that LXR activation enhanced SCD1 transcription via increased sterol regulatory element binding protein-1. Taken together, these data suggest LXR activation of SCD1 expression may play an important role in regulating lipid metabolism and cell function in renal proximal straight tubules. Topics: Animals; Blotting, Northern; DNA-Binding Proteins; Dose-Response Relationship, Drug; Dyslipidemias; Hydrocarbons, Fluorinated; Kidney Tubules; Lipid Metabolism; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Stearoyl-CoA Desaturase; Sulfonamides; Up-Regulation | 2006 |