Liver X Receptor Agonists as Potential Therapeutic Agents for Dyslipidemia and Atherosclerosis

Lund, Erik; Menke, John; Sparrow, Carl P.

doi:10.1161/01.atv.0000056743.42348.59

Cited by 126 publications

(83 citation statements)

References 93 publications

(92 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Of note, the ABCA1 gene was also not changed in LXRa shRNA-treated animals. This result strengthens the hypothesis that LXRb is the more relevant subtype controlling ABCA1 transcription (23,24). The present study therefore adds further support to the working hypothesis that it is possible to separate the favorable LXR-mediated anti-atherosclerotic properties from the unfavorable lipogenic effects.…”

Section: Discussionsupporting

confidence: 89%

Improved lipid profile through liver-specific knockdown of liver X receptor α in KKAy diabetic mice

Rippmann

Schoelch

Nolte

et al. 2009

Journal of Lipid Research

View full text Add to dashboard Cite

Nuclear hormone receptors liver X receptor (LXRa and LXRb) ligands are attractive approaches for the treatment of dyslipidemia and atherosclerosis. To further elucidate the function of LXRa in liver lipid metabolism in a disease-relevant animal model, the KKAy mouse, we used adenoviral vectors to selectively knock down LXRa gene expression. Out of five different short hairpin RNAs (shRNAs) that were tested in vitro, one construct was selected for detailed analysis of LXRa knockdown in vivo. Reduction of LXRa transcript levels to 48 6 13% compared with control virus transduction resulted in a significant downregulation of the LXRa-regulated lipogenic genes sterol-regulatory element binding protein-1c (SREBP1c) and stearoyl CoA desaturase 1 in vivo. Interestingly, ABCA1 and phoshoenolpyruvate carboxykinase 1 expression was not affected, whereas lipoprotein lipase (LPL) expression was found to be increased. In addition, 8 days after virus transduction, both plasma and liver triglycerides (TGs) were reduced by about 50%. Changes in TG levels were not due to reduced food intake in virustreated animals, because pair-fed mice showed unchanged TG levels. Taken together, liver-specific knockdown of LXRa in vivo by shRNA reduced expression of lipogenic master genes, like SREBP1c, and improved the lipid profile of hypertriglyceridemic KKAy mice.-Rippmann, J. F., C. Schoelch, T. Nolte, H. Pavliska, A. van Marle, H. van Es, and J. Prestle. Improved lipid profile through liver-specific knockdown of liver X receptor a in KKA y diabetic mice. J. Lipid Res. 2009. 50: 22-31. Supplementary key words nuclear hormone receptor • hypertriglyceridemia • short hairpin RNA • adenoviral gene transfer • triglycerides • gene expression Disorders in lipid metabolism still represent a major unmet medical need. Lipid disorders are main risk factors for cardiovascular diseases like atherosclerosis, which is the leading cause of death in industrialized countries. Statins, drugs that inhibit HMG-CoA reductase, are effective in lowering LDL cholesterol levels, but they have only moderate effects on plasma triglyceride (TG) and HDLcholesterol levels.The nuclear hormone receptors liver X receptors LXRa and LXRb are important cellular cholesterol sensors. Activated by oxygenated sterols, they form obligate heterodimers with retinoid X receptor and regulate expression of genes involved in cholesterol and lipid metabolism, as well as glucose homeostasis and inflammation (as reviewed in Refs.

show abstract

Section: Discussionsupporting

confidence: 89%

Improved lipid profile through liver-specific knockdown of liver X receptor α in KKAy diabetic mice

Rippmann

Schoelch

Nolte

et al. 2009

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…21,30 However, the effects of LXR agonists on diabetic nephropathy have not been elucidated. In the present study, we have shown that the LXR agonist T0901317 ameliorated albuminuria, glomerular mesangial expansion, and interstitial fibrosis without affecting blood glucose and triglyceride levels in STZ-induced diabetic mice.…”

Section: Discussionmentioning

confidence: 99%

Activation of Liver X Receptor Inhibits Osteopontin and Ameliorates Diabetic Nephropathy

Tachibana¹,

Ogawa

Matsushita³

et al. 2012

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Osteopontin is a proinflammatory cytokine and monocyte chemoattractant implicated in the pathogenesis of diabetic nephropathy. Synthetic agonists for liver X receptors (LXRs) suppress the expression of proinflammatory genes, including osteopontin, but whether LXR activation modulates diabetic nephropathy is unknown. We administered the LXR agonist T0901317 to mice with streptozotocin-induced diabetes and evaluated its effects on diabetic nephropathy. The LXR agonist decreased urinary albumin excretion without altering blood glucose levels and substantially attenuated macrophage infiltration, mesangial matrix accumulation, and interstitial fibrosis. LXR activation suppressed the gene expression of inflammatory mediators, including osteopontin, in the kidney cortex. In vitro, LXR activation suppressed osteopontin expression in proximal tubular epithelial cells by inhibiting AP-1-dependent transcriptional activation of the osteopontin promoter. Taken together, these results suggest that inhibition of renal osteopontin by LXR agonists may have therapeutic potential for diabetic nephropathy.

show abstract

“…In terms of LXR ligands, we have focused on 24(S),25-epoxycholesterol, but it is known that cholesterol can also give rise to oxysterol LXR ligands [31,32]. Thus the addition of cholesterol, like addition of 24(S),25-epoxycholesterol, restored ABCA1 gene expression in SREBP-defective cells ( Figure 3D).…”

Section: Discussionmentioning

confidence: 99%

SREBP-2 positively regulates transcription of the cholesterol efflux gene, ABCA1, by generating oxysterol ligands for LXR

Wong

Quinn

Brown

2006

Biochemical Journal

124

108

View full text Add to dashboard Cite

Cholesterol accumulation and removal are regulated by two different transcription factors. SREBP-2 (sterol-regulatory-elementbinding protein-2) is best known to up-regulate genes involved in cholesterol biosynthesis and uptake, whereas LXR (liver X receptor) is best known for up-regulating cholesterol efflux genes. An important cholesterol efflux gene that is regulated by LXR is the ATP-binding cassette transporter, ABCA1 (ATPbinding cassette transporter-A1). We have previously shown that statin treatment down-regulated ABCA1 expression in human macrophages, probably by inhibiting synthesis of the LXR ligand 24(S),25-epoxycholesterol. However, it was subsequently reported that ABCA1 expression is down-regulated by SREBP-2 through binding of SREBP-2 to an E-box element in ABCA1's proximal promoter. As statin treatment induces SREBP-2 activation, this may provide an alternative explanation for the statinmediated down-regulation of ABCA1. In the present study, we employed a set of CHO (Chinese-hamster ovary) mutant cell lines to investigate the role of SREBP-2 in the regulation of ABCA1. We observed increased ABCA1 mRNA levels in SREBP-2-overexpressing cells and decreased levels in cells lacking a functional SREBP-2 pathway, which were restored when the SREBP-2 pathway was reinstated. Moreover, ABCA1 gene expression was positively associated with synthesis of 24(S),25-epoxycholesterol in these cell lines. In studies using a human ABCA1 promoter reporter assay, mutation of the E-box motif had a similar response as the wild-type construct to either statin treatment or addition of 24(S),25-epoxycholesterol. By contrast, these responses were completely ablated when the DR4 element to which LXR binds was mutated. These results support the idea that 24(S),25-epoxycholesterol and statin treatment influence ABCA1 transcription via supply of an LXR ligand and not through an SREBP-2/E-boxrelated mechanism. In addition, our results indicate a critical role of SREBP-2 as a positive regulator of ABCA1 gene expression by enabling the generation of oxysterol ligands for LXR.

show abstract

Liver X Receptor Agonists as Potential Therapeutic Agents for Dyslipidemia and Atherosclerosis

Cited by 126 publications

References 93 publications

Improved lipid profile through liver-specific knockdown of liver X receptor α in KKAy diabetic mice

Improved lipid profile through liver-specific knockdown of liver X receptor α in KKAy diabetic mice

Activation of Liver X Receptor Inhibits Osteopontin and Ameliorates Diabetic Nephropathy

SREBP-2 positively regulates transcription of the cholesterol efflux gene, ABCA1, by generating oxysterol ligands for LXR

Contact Info

Product

Resources

About