The Liver-Selective Thyromimetic T-0681 Influences Reverse Cholesterol Transport and Atherosclerosis Development in Mice

Liver-selective thyromimetics have been reported to efficiently reduce plasma cholesterol through the hepatic induction of both, the low-density lipoprotein receptor (LDLr) and the high-density lipoprotein (HDL) receptor; the scavenger receptor class B type I (SR-BI). Here, we investigated the effect of the thyromimetic T-0681 on reverse cholesterol transport (RCT) and atherosclerosis, and studied the underlying mechanisms using different mouse models, including mice lacking LDLr, SR-BI, and apoE, as well as CETP transgenic mice.T-0681 treatment promoted bile acid production and biliary sterol secretion consistently in the majority of the studied mouse models, which was associated with a marked reduction of plasma cholesterol. Using an assay of macrophage RCT in mice, we found T-0681 to significantly increase fecal excretion of macrophage-derived neutral and acidic sterols. No positive effect on RCT was found in CETP transgenic mice, most likely due to the observed decrease in plasma CETP mass. Studies in SR-BI KO and LDLr KO mice suggested hepatic LDLr to be necessary for the action of T-0681 on lipid metabolism, as the compound did not have any influence on plasma cholesterol levels in mice lacking this receptor. Finally, prolonged treatment with T-0681 reduced the development of atherosclerosis by 60% in apoE KOs on Western type diet. In contrast, at an earlier time-point T-0681 slightly increased small fatty streak lesions, in part due to an impaired macrophage cholesterol efflux capacity, when compared to controls.The present results show that liver-selective thyromimetics can promote RCT and that such compounds may protect from atherosclerosis partly through induction of bile acid metabolism and biliary sterol secretion. On-going clinical trials will show whether selective thyromimetics do prevent atherosclerosis also in humans

Reduced plasma high-density lipoprotein cholesterol in hyperthyroid mice coincides with decreased hepatic adenosine 5 '-triphosphate-binding cassette transporter 1 expression

The aim of the study was to investigate the influence of severe hyperthyroidism on plasma high-density lipoprotein cholesterol (HDL-C). Recently, it was shown in mice that increasing doses of T(3) up-regulate hepatic expression of scavenger receptor class B, type I, resulting in increased clearance of plasma HDL-C. Here, we show that severe hyperthyroidism in mice did not affect hepatic expression of scavenger receptor class B, type I, but reduced hepatic expression of ATP-binding cassette transporter 1, accompanied by a 40% reduction of HDL-C. The sterol content of bile, liver, and feces was markedly increased, accompanied by up-regulation of hepatic cholesterol 7 alpha-hydroxylase, and ATP-binding cassette transporter 5, which is known to promote biliary sterol secretion upon dimerization with ATP-binding cassette transporter 8. Both control and hyperthyroid mice exerted identical plasma clearance of iv injected [(3)H] HDL-C, supporting the view that severe hyperthyroidism does not affect HDL-C clearance but, rather, its formation via hepatic ATP-binding cassette transporter 1

Inhibition of hepatic scavenger receptor-class B type I by RNA interference decreases atherosclerosis in rabbits

AbstractObjectiveScavenger receptor-class B type I (SR-BI), the receptor for HDL-cholesterol, plays a key role in HDL metabolism, whole body cholesterol homeostasis, and reverse cholesterol transport. We investigated the in vivo impact of hepatic SR-BI inhibition on lipoprotein metabolism and the development of atherosclerosis employing RNA interference.MethodsSmall hairpin RNA plasmid specific for rabbit SR-BI was complexed with galactosylated poly-l-lysine, allowing an organ-selective, receptor-mediated gene transfer. Rabbits were fed a cholesterol-rich diet, and were injected with plasmid-complexes once a week.ResultsAfter 2 weeks of treatment hepatic SR-BI mRNA levels were reduced by 80% accompanied by reduced SR-BI protein levels and a modulation of the lipoprotein profile. Rabbits treated with SR-BI-specific plasmid-complexes displayed higher cholesteryl ester transfer from HDL to apoB-containing lipoproteins, lower HDL-cholesterol, and higher VLDL-cholesterol levels, when compared to controls. In a long-term study, this gene therapeutic intervention led to a similar modulation of the lipoprotein profile, to lower total cholesterol levels, and most importantly to a 50% reduction of the relative atherosclerotic lesion area.ConclusionOur results are another indication that the role of SR-BI in lipoprotein metabolism and atherogenesis in rabbits – a CETP-expressing animal model displaying a manlike lipoprotein profile may be different from the one found in rodents

Fibrates ameliorate the course of bacterial sepsis by promoting neutrophil recruitment via CXCR2

Abstract Bacterial sepsis results in high mortality rates, and new therapeutics to control infection are urgently needed. Here, we investigate the therapeutic potential of fibrates in the treatment of bacterial sepsis and examine their effects on innate immunity. Fibrates significantly improved the survival from sepsis in mice infected with Salmonella typhimurium, which was paralleled by markedly increased neutrophil influx to the site of infection resulting in rapid clearance of invading bacteria. As a consequence of fibrate‐mediated early control of infection, the systemic inflammatory response was repressed in fibrate‐treated mice. Mechanistically, we found that fibrates preserve chemotaxis of murine neutrophils by blocking LPS‐induced phosphorylation of ERK. This results in a decrease of G protein‐coupled receptor kinase‐2 expression, thereby inhibiting the LPS‐mediated downregulation of CXCR2, a chemokine receptor critical for neutrophil recruitment. Accordingly, application of a synthetic CXCR2 inhibitor completely abrogated the protective effects of fibrates in septicemia in vivo. Our results unravel a novel function of fibrates in innate immunity and host response to infection and suggest fibrates as a promising adjunct therapy in bacterial sepsis

Fibrates ameliorate the course of bacterial sepsis by promoting neutrophil recruitment via CXCR

Bacterial sepsis results in high mortality rates, and new therapeutics to control infection are urgently needed. Here, we investigate the therapeutic potential of fibrates in the treatment of bacterial sepsis and examine their effects on innate immunity. Fibrates significantly improved the survival from sepsis in mice infected with Salmonella typhimurium, which was paralleled by markedly increased neutrophil influx to the site of infection resulting in rapid clearance of invading bacteria. As a consequence of fibrate-mediated early control of infection, the systemic inflammatory response was repressed in fibrate-treated mice. Mechanistically, we found that fibrates preserve chemotaxis of murine neutrophils by blocking LPS-induced phosphorylation of ERK. This results in a decrease of G protein-coupled receptor kinase-2 expression, thereby inhibiting the LPS-mediated downregulation of CXCR2, a chemokine receptor critical for neutrophil recruitment. Accordingly, application of a synthetic CXCR2 inhibitor completely abrogated the protective effects of fibrates in septicemia in vivo. Our results unravel a novel function of fibrates in innate immunity and host response to infection and suggest fibrates as a promising adjunct therapy in bacterial sepsis

Leoligin, the major lignan from Edelweiss, activates cholesteryl ester transfer protein

► Leoligin significantly activated CETP in human plasma at 100 pM. ► Leoligin concentrations of 1 mM inhibited CETP activity. ► There was no short-term toxicity apparent in mice treated with leoligin

Influence of T-0681 on atherosclerosis development in apoE KO mice.

<p>Western type diet-fed apoE KOs were treated with T-0681 (36 nmol/kg/d) or PBS for 4 weeks (A, B) (N = 7) and 8 weeks (C, D) (N = 10). (A, C) FPLC analysis of pooled plasma from control and T-0681-treated mice. (B, D) Statistical comparison of the atherosclerotic lesion size in histological sections from the aortic root. ***<i>P</i><0.001 versus corresponding control.</p

The liver-selective thyromimetic T-0681 promotes reverse cholesterol transport.

<p>Chow-fed WT mice were treated with T-0681 (36 nmol/kg/d) or PBS. (A) Western blot showing hepatic expression of SR-BI (N = 6). (B) FPLC analysis of pooled plasma from control and T-0681-treated mice (N = 6). (C) Plasma concentrations of apoB and apoA-I (N = 6). (D) Taqman real-time PCR analysis of hepatic ABCA1, ABCG5, ABCG8, and CYP7A1 (N = 4–10). (E) Analysis of fecal sterols (N = 6), and (F), plasma levels of diet-derived phytosterols, normalized to cholesterol (N = 5). (G) Taqman real-time PCR analysis of intestinal cholesterol transporters ABCA1, ABCG5, ABCG8, and NPC1L1 (n = 4–10). *<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001 versus corresponding controls; ns, non significant; data presented in % are normalized to the respective controls.</p

Hepatic regulation of SR-BI, LDLr, ABCG5/G8, CYP7A1 by T-0681.

<p>The table summarizes the relative hepatic expression of the analyzed proteins derived from all the experiments presented in this study. WT, wild-type mice; KO, knock-out mice; 4-wk, 4 weeks study; 8-wk, 8 weeks study; −, no change; ↑, 1.5–2 - fold of control; ↑↑, more than 2-fold of control; ↑↑↑, more than 4-fold of control.</p