Raising HDL cholesterol without inducing hepatic steatosis and hypertriglyceridemia by a selective LXR modulator

Miao, Bowman; Zondlo, Susan Carr; Gibbs, Sandy; Cromley, Debra; Hosagrahara, Vinayak; Kirchgessner, Todd G.; Billheimer, Jeffrey T.; Mukherjee, Ranjan

doi:10.1194/jlr.m300450-jlr200

Cited by 173 publications

(131 citation statements)

References 27 publications

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“…GW3965, another synthetic LXR ligand, can inhibit the development of atherosclerosis in both LDLR Ϫ/Ϫ and apoE Ϫ/Ϫ mice. It has no effect on lipogenesis in both wild-type and LDLR Ϫ/Ϫ mice, but not in apoE Ϫ/Ϫ mice (21,47). The reduced side effects may be due to the fact that GW3965 is a weak activator of LXR rather than it has a higher selectivity for LXR␤ than LXR␣ (47).…”

Section: Discussionmentioning

confidence: 98%

Inhibition of ERK1/2 and Activation of Liver X Receptor Synergistically Induce Macrophage ABCA1 Expression and Cholesterol Efflux

Zhou

Yin

Guo

et al. 2010

Journal of Biological Chemistry

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ATP-binding cassette transporter A1 (ABCA1), a molecule mediating free cholesterol efflux from peripheral tissues to apoAI and high density lipoprotein (HDL), inhibits the formation of lipid-laden macrophage/foam cells and the development of atherosclerosis. ERK1/2 are important signaling molecules regulating cellular growth and differentiation. The ERK1/2 signaling pathway is implicated in cardiac development and hypertrophy. However, the role of ERK1/2 in the development of atherosclerosis, particularly in macrophage cholesterol homeostasis, is unknown. In this study, we investigated the effects of ERK1/2 activity on macrophage ABCA1 expression and cholesterol efflux. Compared with a minor effect by inhibition of other kinases, inhibition of ERK1/2 significantly increased macrophage cholesterol efflux to apoAI and HDL. In contrast, activation of ERK1/2 reduced macrophage cholesterol efflux and ABCA1 expression. The increased cholesterol efflux by ERK1/2 inhibitors was associated with the increased ABCA1 levels and the binding of apoAI to cells. The increased ABCA1 by ERK1/2 inhibitors was due to increased ABCA1 mRNA and protein stability. The induction of ABCA1 expression and cholesterol efflux by ERK1/2 inhibitors was concentration-dependent. The mechanism study indicated that activation of liver X receptor (LXR) had little effect on ERK1/2 expression and activation. ERK1/2 inhibitors had no effect on macrophage LXR␣/␤ expression, whereas they did not influence the activation or the inhibition of the ABCA1 promoter by LXR or sterol regulatory element-binding protein (SREBP). However, inhibition of ERK1/2 and activation of LXR synergistically induced macrophage cholesterol efflux and ABCA1 expression. Our data suggest that ERK1/2 activity can play an important role in macrophage cholesterol trafficking.Development of atherosclerotic lesions in coronary arteries is an underlying cause of coronary heart disease. Lipid-laden macrophage/foam cells are a prominent part of atherosclerotic lesions (1). Cellular cholesterol content in macrophages is determined by uptake and efflux of cholesterol (2). The type A scavenger receptor and type B scavenger receptor (CD36) mediate the binding and internalization of modified low density lipoprotein (LDL), 3 thus, demonstrating pro-atherogenic properties (3, 4). In contrast, type BI scavenger receptor and ATPbinding cassette transporter A1 (ABCA1) can mediate cellular free cholesterol efflux to extracellular high density lipoprotein (HDL) or lipid-free apolipoprotein AI (apoAI) thereby inhibiting the development of atherosclerosis (5, 6). Compared with bi-directional cholesterol transport across cellular membranes that are mediated by type BI scavenger receptor (7, 8), ABCA1 stimulates free cholesterol efflux from macrophages and other peripheral cell types to apoAI and/or HDL by using the energy from ATP hydrolysis (9). The binding of free cholesterol and phospholipids to apoAI also leads to the generation of nascent HDL (10). ABCA1 can also mediate cholesterol efflux to exog...

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Section: Discussionmentioning

confidence: 98%

Inhibition of ERK1/2 and Activation of Liver X Receptor Synergistically Induce Macrophage ABCA1 Expression and Cholesterol Efflux

Zhou

Yin

Guo

et al. 2010

Journal of Biological Chemistry

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“…Many investigators used T0901317 at 50 mg/kg per day and observed lipogenic effects in previous studies. [44][45][46][47][48] To avoid severe hepatic lipogenesis, we used a comparatively low dose (10 mg/kg per day) in this study. Recently, T0901317 and a new steroidal LXR agonist, DMHCA, were reported to decrease the activity of intestinal and renal sodium gradientdependent phosphate transporters, and the gene expressions of lipogenic enzymes with DMHCA were lower than those gene expressions after activation by T0901317.…”

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

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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.

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“…LXR target genes include those that express proteins involved in the efflux of cholesterol from the cell (155,157,174,189) as well as bile acid synthesis (174) and lipogenesis (174). Thus, global LXR activation by synthetic agonists has a plethora of effects, including elevated high-density lipoprotein (HDL) levels (25,28,98,126,147,163,178), hypertriglyceridemia (156,163), hepatic steatosis (65), increased excretion of cholesterol in bile (147,201), reduced efficiency of cholesterol absorption from the intestine (103,157,159,191,206), and increased loss of neutral sterols in feces (201).…”

Section: Cholesterolmentioning

confidence: 99%

Intestinal lipid absorption

Iqbal¹,

Hussain²

2009

American Journal of Physiology-Endocrinology and Metabolism

651

484

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Our knowledge of the uptake and transport of dietary fat and fat-soluble vitamins has advanced considerably. Researchers have identified several new mechanisms by which lipids are taken up by enterocytes and packaged as chylomicrons for export into the lymphatic system or clarified the actions of mechanisms previously known to participate in these processes. Fatty acids are taken up by enterocytes involving protein-mediated as well as proteinindependent processes. Net cholesterol uptake depends on the competing activities of NPC1L1, ABCG5, and ABCG8 present in the apical membrane. We have considerably more detailed information about the uptake of products of lipid hydrolysis, the active transport systems by which they reach the endoplasmic reticulum, the mechanisms by which they are resynthesized into neutral lipids and utilized within the endoplasmic reticulum to form lipoproteins, and the mechanisms by which lipoproteins are secreted from the basolateral side of the enterocyte. apoB and MTP are known to be central to the efficient assembly and secretion of lipoproteins. In recent studies, investigators found that cholesterol, phospholipids, and vitamin E can also be secreted from enterocytes as components of high-density apoB-free/apoAI-containing lipoproteins. Several of these advances will probably be investigated further for their potential as targets for the development of drugs that can suppress cholesterol absorption, thereby reducing the risk of hypercholesterolemia and cardiovascular disease.intestine; dietary fat; triacylglycerol; cholesterol; phospholipids; fat-soluble vitamins; microsomal triglyceride transfer protein DIETARY FATS CONSIST OF A WIDE ARRAY of polar and nonpolar lipids (32, 33). Triacylglycerol (TAG) is the dominant fat in the diet, contributing 90 -95% of the total energy derived from dietary fat. Dietary fats also include phospholipids (PLs), sterols (e.g., cholesterol), and many other lipids (e.g., fatsoluble vitamins). The predominant PL in the intestinal lumen is phosphatidylcholine (PC), which is derived mostly from bile (10 -20 g/day in humans) but also from the diet (ϳ1-2 g/day). The predominant dietary sterols are cholesterol (mostly of animal origin) and ␤-sitosterol (the major plant sterol). Although ␤-sitosterol accounts for 25% of dietary sterols, it is not absorbed by humans under physiological conditions.Researchers have been investigating the various steps involved in lipid digestion, absorption, and metabolism to identify factors that could serve as targets for the development of drugs capable of reducing the risk of lipid-associated disorders, including dyslipidemias and cardiovascular disease. In so doing, they have explored key aspects of lipid digestion hydrolysis, emulsification, and micelle formation. They have also explored key issues of absorption, e.g., the uptake of the products of lipid hydrolysis by enterocytes (the epithelial cells lining the walls of the intestinal lumen) and their transport to intracellular compartments, where fatty acids and sterols are...

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Raising HDL cholesterol without inducing hepatic steatosis and hypertriglyceridemia by a selective LXR modulator

Cited by 173 publications

References 27 publications

Inhibition of ERK1/2 and Activation of Liver X Receptor Synergistically Induce Macrophage ABCA1 Expression and Cholesterol Efflux

Inhibition of ERK1/2 and Activation of Liver X Receptor Synergistically Induce Macrophage ABCA1 Expression and Cholesterol Efflux

Activation of Liver X Receptor Inhibits Osteopontin and Ameliorates Diabetic Nephropathy

Intestinal lipid absorption

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