Liver X receptor activation promotes macrophage-to-feces reverse cholesterol transport in a dyslipidemic hamster model

organism under different nutritional environments. This adaptation requires major changes in the hepatic metabolic gene program. One gene family, long-chain acyl-CoA synthetase (ACSL), encodes enzymes that play key roles in lipid metabolism in liver, as well as other metabolic tissues ( 1-5 ). ACSL catalyzes the formation of fatty acyl-CoA from ATP, CoA, and long-chain fatty acids (FAs). This reaction is the fi rst step in FA metabolism following transport of nonesterifi ed FA into mammalian cells. This activation process is essential for cellular utilization of FA via different metabolic pathways, including the cellular ␤ -oxidation system responsible for FA oxidation (catabolism) and the anabolic pathways for the synthesis of phospholipids, cholesterol esters, and triglycerides (TG). To date, fi ve isoforms of ACSL (ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6) have been characterized in humans, mice, and rats ( 3 ). These isoforms differ considerably in their characteristics, including substrate specifi city, enzyme kinetics, and tissue and subcellular distribution. These individual characteristics contribute to their different cellular functions and metabolic outcomes (6)(7)(8)(9)(10)(11)(12)(13)(14). Because each isoform of the ACSL family has a distinct function in directing acyl-CoA to one or more specifi c downstream pathways, the level of expression/activity of individual ACSL isozymes could directly infl uence FA metabolic fates in liver tissue.Nutritional status and hormone levels differently affect the gene expression of ACSL family members in liver tissue ( 15-17 ). In mice fed a normal chow diet, fasting increased the mRNA abundance of ACSL4 and ACSL1 in the liver, and fasting decreased ACSL3 and ACSL5 mRNA levels. In liver of Wister rat, fasting had little effect on ACSL5 mRNA expression, but refeeding markedly increased Abstract Long-chain acyl-CoA synthetases (ACSL) play key roles in fatty acid metabolism in liver and other metabolic tissues in an isozyme-specifi c manner. In this study, we examined the effects of a fructose-enriched diet on expressions of ACSL isoforms in the liver of hamsters. We showed that the fructose diet markedly reduced the mRNA and protein expressions of ACSL3 in hamster liver without signifi cant effects on other ACSLs. The decrease in ACSL3 abundance was accompanied by a reduction in ACSL-catalyzed synthesis of arachidonyl-CoA and oleoyl-CoA in liver homogenates of hamsters fed the fructose diet as opposed to normal diet. We further showed that fructose diet specifically reduced expressions of three key components of the LXR signaling pathway, namely, liver X receptor (LXR) ␣ , LXR ␤ , and retinoid X receptor (RXR) ␤ . Exogenous expression and activation of LXR ␣ / ␤ increased hamster ACSL3 promoter activities in a LXR-responsive element (LXRE)-dependent fashion. Finally, we showed that treating hamsters with LXR agonist GW3965 increased hepatic ACSL3 expression without affecting other ACSL isoforms. Furthermore, the ligand-induced increases of ACSL3 expression were accompan...

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“…8A ). The effects of GW3965 on serum triglycerides have been previously reported in hamsters ( 40,41 ) and other rodent models ( 42 ).…”

Section: Effects Of Diet and Lxr Ligand Activation On Serum And Hepatmentioning

confidence: 99%

High-fructose diet downregulates long-chain acyl-CoA synthetase 3 expression in liver of hamsters via impairing LXR/RXR signaling pathway

Dong

Kan

Singh

et al. 2013

Journal of Lipid Research

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“…LXR agonists including the compound T0901317 have been shown to upregulate TICE (29), but LXR agonist treatment is accompanied by significant side effects including increased TG and LDL-C levels (87). Studies involving intestinal-specific activation of LXR have demonstrated enhanced macrophage RCT and atheroprotection (88,89), but as yet the effects of intestinal-specific LXR activation have not been traced back to TICE.…”

Section: F Increases Tice Through Duodenal Explants and Can Act As Amentioning

confidence: 99%

Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux

Meriwether

Sulaiman

Wagner

et al. 2016

Journal of Lipid Research

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Increasing evidence, both direct and indirect, indicates that the small intestine (SI) may be an important modulator of atherosclerosis. As a result, the SI offers promising therapeutic targets for the prevention and treatment of this disease.The SI is linked to atherosclerosis in at least four respects. First, intestinal inflammation in the form of inflammatory bowel disease (IBD) has been linked to an increased prevalence of early stage vascular disease in patients without the classical cardiovascular risk factors (1-3). Second, our own recent research has established a link between aberrant levels of lipid signals in the SI and both dyslipidemia and atherosclerosis. Intestinally derived unsaturated lysophosphatidic acids (LPAs) and eicosanoids can both induce dyslipidemia as well as systemic inflammation in LDL receptor null (LDLR / ) mice (4, 5). Dietary LPA can also induce atherogenesis (6), and the levels of unsaturated LPAs in the SI correlate with the extent of atherosclerosis in LDLR / mice fed a Western diet (WD) (7). Third, the SI is an important source of apoAI (8), and at least in mice 30% of the steady-state plasma HDLcholesterol pool is derived from the SI (9). Moreover, while HDL can interrupt atherogenesis by preventing oxidative Abstract The site and mechanism of action of the apoA-I mimetic peptide 4F are incompletely understood. Transintestinal cholesterol efflux (TICE) is a process involved in the clearance of excess cholesterol from the body. While TICE is responsible for at least 30% of the clearance of neutral sterols from the circulation into the intestinal lumen, few pharmacological agents have been identified that modulate this pathway. We show first that circulating 4F selectively targets the small intestine (SI) and that it is predominantly transported into the intestinal lumen. This transport of 4F into the SI lumen is transintestinal in nature, and it is modulated by TICE. We also show that circulating 4F increases reverse cholesterol transport from macrophages and cholesterol efflux from lipoproteins via the TICE pathway. We identify the cause of this modulation of TICE either as 4F being a cholesterol acceptor with respect to enterocytes, from which 4F enhances cholesterol efflux, or as 4F being an intestinal chaperone with respect to TICE. Our results assign a novel role for 4F as a modulator of the TICE pathway and suggest that the anti-inflammatory functions of 4F may be a partial consequence of the codependent intestinal transport of both 4F and cholesterol.

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“…Preparation of J774 cells and in vivo RCT study were performed as previously described ( 22 ). J774 cells obtained from the American Type Culture Collection (ATCC; Manassas, VA), were grown in suspension in RPMI/HEPES supplemented with 10% FBS and 0.5% gentamicin in suspension in Nalgene Tefl on fl asks.…”

mentioning

confidence: 99%

Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters

Castro-Perez

Briand

Gagen

et al. 2011

Journal of Lipid Research

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Despite therapies such as statins, which reduce circulating levels of low density lipoprotein cholesterol (LDL-C), cardiovascular event rates remain high. Numerous epidemiological studies (e.g., the Framingham Heart Study) indicate that high density lipoprotein cholesterol (HDL-C) levels are inversely correlated with cardiovascular risk ( 1-6 ). Therefore, therapies that increase HDL-C have gained recent attention as possible treatments for dyslipidemia and atherosclerosis.Cholesteryl ester transfer protein (CETP) mediates transfer of cholesteryl ester (CE) and triglyceride (TG) between HDL and apoB-containing lipoproteins such as LDL and therefore, represents an attractive target for increasing HDL-C and reducing LDL-C. Indeed, initial clinical trials with torcetrapib established the validity of CETP inhibition as a mechanism for elevation of HDL-C ( 7, 8 ). However, the phase III outcome trial ILLUMINATE demonstrated that torcetrapib treatment was associated with an increase in cardiovascular events and overall mortality, possibly due to off-target effects on blood pressure and circulating adrenal hormones ( 9 ). A series of preclinical studies further corroborated that torcetrapib had compoundspecifi c off-target activity that was unrelated to CETP inhibition ( 10-12 ).Anacetrapib (ANA) is a potent CETP inhibitor that has not demonstrated the off-target activities of torcetrapib in preclinical or clinical studies ( 10,(13)(14)(15). ANA treatment increases HDL-C by over 100% and lowers LDL-C by 30-40% as a monotherapy and when coadministered with statins ( 13-15 ). In a recent 1.5 year safety study in ‫ف‬ 1,600 patients with cardiovascular disease ( 15 ) Cardiovascular disease continues to be a major contributor to morbidity and mortality throughout the world. 29 July 2011. Published, JLR Papers in Press, August 14, 2011 DOI 10.1194 Manuscript received 13 April 2011 and in revised form

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Liver X receptor activation promotes macrophage-to-feces reverse cholesterol transport in a dyslipidemic hamster model

Cited by 32 publications

References 38 publications

High-fructose diet downregulates long-chain acyl-CoA synthetase 3 expression in liver of hamsters via impairing LXR/RXR signaling pathway

High-fructose diet downregulates long-chain acyl-CoA synthetase 3 expression in liver of hamsters via impairing LXR/RXR signaling pathway

Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux

Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters

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