Emerging studies indicate that the immune system can regulate systemic metabolism. Here, we show that thymic stromal lymphopoietin (TSLP) stimulates T cells to induce selective white adipose loss, which protects against obesity, improves glucose metabolism, and mitigates nonalcoholic steatohepatitis. Unexpectedly, adipose loss was not caused by alterations in food intake, absorption, or energy expenditure.
View Article and Find Full Text PDFObjective: To gain mechanistic insights into the role of (lipase A), the gene encoding LAL (lysosomal acid lipase) protein, in human macrophages.
Approach And Results: We used CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9) technology to knock out in human induced pluripotent stem cells and then differentiate to macrophage (human-induced pluripotent stem cells-derived macrophage [IPSDM]) to explore the human macrophage loss-of-function phenotypes. was abundantly expressed in monocyte-derived macrophages and was markedly induced on IPSDM differentiation to comparable levels as in human monocyte-derived macrophage.
Phospholipid transfer protein (PLTP) may affect macrophage reverse cholesterol transport (mRCT) through its role in the metabolism of HDL. Ex vivo cholesterol efflux capacity and in vivo mRCT were assessed in PLTP deletion and PLTP overexpression mice. PLTP deletion mice had reduced HDL mass and cholesterol efflux capacity, but unchanged in vivo mRCT.
View Article and Find Full Text PDFBackground: Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib.
Methods: We performed a trial of the effects of anacetrapib on ApoB kinetics.
Background: Genome-wide association studies have established ADAMTS7 as a locus for coronary artery disease in humans. However, these studies fail to provide directionality for the association between ADAMTS7 and coronary artery disease. Previous reports have implicated ADAMTS7 in the regulation of vascular smooth muscle cell migration, but a role for and the direction of impact of this gene in atherogenesis have not been shown in relevant model systems.
View Article and Find Full Text PDFRationale: Noncoding gene variants at the SORT1 locus are strongly associated with low-density lipoprotein cholesterol (LDL-C) levels, as well as with coronary artery disease. SORT1 encodes a protein called sortilin, and hepatic sortilin modulates LDL metabolism by targeting apolipoprotein B-containing lipoproteins to the lysosome. Sortilin is also expressed in macrophages, but its role in macrophage uptake of LDL and in atherosclerosis independent of plasma LDL-C levels is unknown.
View Article and Find Full Text PDFArterioscler Thromb Vasc Biol
August 2012
Objective: ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats-13) cleaves von Willebrand factor, thereby modulating thrombosis and inflammation. Low plasma ADAMTS13 activity is associated with cardiovascular events, including myocardial and cerebral infarction. Here, we investigated the role of ADAMTS13 in the development of early atherosclerosis in a murine model.
View Article and Find Full Text PDFObjective: Peroxisome proliferator-activated receptor-α (PPARα) activation has been shown in vitro to increase macrophage cholesterol efflux, the initial step in reverse cholesterol transport (RCT). However, it remains unclear whether PPARα activation promotes macrophage RCT in vivo.
Methods And Results: We demonstrated that a specific potent PPARα agonist GW7647 inhibited atherosclerosis and promoted macrophage RCT in hypercholesterolemic mice expressing the human apolipoprotein A-I (apoA-I) gene.
Background: Lecithin:cholesterol acyltransferase (LCAT) catalyzes the formation of plasma cholesteryl ester, plays a key role in high-density lipoprotein metabolism, and has been believed to be critical in the process of reverse cholesterol transport (RCT).
Methods And Results: The role of LCAT in RCT from macrophages was quantified with a validated assay involving intraperitoneal injection in mice of (3)H-cholesterol-labeled J774 macrophages and monitoring the appearance of tracer in plasma, liver, bile, and feces. Human LCAT overexpression in human apolipoprotein A-I transgenic mice substantially increased plasma high-density lipoprotein cholesterol levels but surprisingly did not increase macrophage RCT.
Aim: Information about the effects of HMG-CoA reductase inhibitor (statin) treatment on lipoprotein subclasses has been severely limited. Nuclear magnetic resonance (NMR) spectrometry has emerged as a new methodology to quantify lipoprotein subclass concentrations. In the present study, we attempted to evaluate the hypolipidemic effects of atorvastatin utilizing this method.
View Article and Find Full Text PDFObjective: The mechanism by which non-nucleoside reverse transcriptase inhibitors (NNRTIs) increase HDL cholesterol (HDL-C) in HIV+ patients and the benefits of this with respect to cardiovascular risk are not known. Studies were conducted to test the hypothesis that NNRTIs have a beneficial effect on HDL-C and reverse cholesterol transport (RCT).
Methods: LDLr-/- and hA-I transgenic mice were fed a Western diet containing either nevirapine (20mg/kg per day), efavirenz (10mg/kg per day), or diet alone.
Background: Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from high-density lipoproteins to apolipoprotein (apo) B-containing lipoproteins and in humans plays an important role in lipoprotein metabolism. However, the role that CETP plays in mediation of reverse cholesterol transport (RCT) remains unclear. We used a validated in vivo assay of macrophage RCT to test the effect of CETP expression in mice (which naturally lack CETP) on macrophage RCT, including in mice that lack the low-density lipoprotein receptor or the scavenger receptor class B, type I.
View Article and Find Full Text PDFApolipoprotein A-I (apoA-I), the major protein constituent within high-density lipoprotein (HDL), has been associated with antiatherogenic protection by mechanisms that include reverse cholesterol transport and antiinflammatory functions. To evaluate the proposed protective function of apoA-I, proteins modified by nitrating oxidants were evaluated in the aortic tissue and plasma of mice lacking the low-density lipoprotein receptor and apobec (LA) and LA mice with genetic deletion of apoA-I (LA-apoA-I(-/-)). The levels of nitrated proteins in aortic tissue quantified by liquid chromatography with online electrospray ionization tandem mass spectrometry (LC/ESI/MS/MS) were 6-fold higher in the LA-apoA-I(-/-) as compared with the LA mice.
View Article and Find Full Text PDFAim: Remnant lipoprotein is an emerging risk factor for coronary artery disease (CAD); however, the development of a specific remnant lipoprotein assay has struggled due to its heterogeneous nature. This study aimed to evaluate the clinical importance of a newly developed assay for remnant lipoprotein, RemL-C, in patients with CAD.
Methods: This assay utilizes surfactant and phospholipase-D to selectively degrade and solubilize remnant lipoprotein.
Background: Hypertriglyceridemia is often associated with elevated remnants, small dense LDL and decreased HDL-cholesterol (C). The objective of this study was to investigate the efficacy of bezafibrate on lipoprotein subfractions profile and inflammation markers in patients with hypertriglyceridemia.
Methods: Twenty-four hypertriglyceridemic subjects took bezafibrate, 400 mg daily, for 4 weeks.
Hypertriglyceridemia is often associated with small dense low density lipoprotein (LDL), elevated remnants, and decreased high density lipoprotein (HDL)-cholesterol (C), which comprise the dyslipidemic triad. The objective of this study was to investigate the effect of fenofibrate on the lipoprotein subfraction profile and inflammation markers in hypertriglyceridemic men. Twenty hypertriglyceridemic men were administered fenofibrate, 200 mg daily, for 8 weeks.
View Article and Find Full Text PDFThe prevalence of obesity has become increasingly common worldwide, in particular western countries. Obesity, together with insulin resistance, leads to metabolic syndrome in which other coronary risk factors including hyperlipidemia and hypertension cluster in one individual. Hyperlipidemia in metabolic syndrome is characterized increased triglyceride(TG), decreased HDL-C, and small dense LDL, called dyslipidemic triad.
View Article and Find Full Text PDFWe thoroughly examined a 26-year-old Japanese male who experienced perioperative ventricular tachycardia. After inhaling sevoflurane, his nasal cavity was soaked with 1:100,000 epinephrine and he was intubated through the nose. Junctional tachycardia occurred five minutes after intubation, changing to ventricular tachycardia.
View Article and Find Full Text PDFFamilial HDL deficiency (FHD) is a rare autosomal dominant lipoprotein disorder. We describe a novel genetic variant of the apolipoprotein A-I (apoA-I) gene resulting in FHD. The proband is a 51-year-old woman who was hospitalized due to severe heart failure.
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