ABSTRACT
BACKGROUND AND AIM: Monounsaturated fatty acids in diets are beneficial for the plasma lipoprotein profile, but studies in cell culture point out that they may also be detrimental by inhibiting cholesterol efflux to apo AI. METHODS AND RESULTS: In the present study we used mouse peritoneal macrophages, loaded with cholesterol and upregulated by cyclic AMP or by LXR/RXR ligands and compared the effect of oleic acid on cholesterol efflux to 3 different acceptors. Inhibition of cholesterol efflux by oleic acid ranged from 10 to 25% with HDL or 2.5% mouse serum, while efflux to phosphatidyl choline vesicles was not affected. Previously we reported that the LXR ligand, TO901317, retarded cholesterol removal in vivo from a modified LDL depot in muscle. This could have resulted from inhibition by unsaturated fatty acids or from reduction in macrophage recruitment due to the anti-inflammatory action of LXR. CONCLUSIONS: Our current findings, of retardation of cholesterol clearance from the depot in the presence of low macrophage recruitment, support the latter possibility.
Subject(s)
Cholesterol/metabolism , Macrophages/physiology , Oleic Acid/pharmacology , ATP Binding Cassette Transporter, Subfamily G, Member 1 , ATP-Binding Cassette Transporters/antagonists & inhibitors , ATP-Binding Cassette Transporters/physiology , Animals , Atherosclerosis/therapy , Cell Movement , Cells, Cultured , DNA-Binding Proteins/physiology , Lipoproteins/antagonists & inhibitors , Lipoproteins/physiology , Liver X Receptors , Male , Mice , Mice, Inbred C57BL , Mice, Inbred NZB , Orphan Nuclear Receptors , Receptors, Cytoplasmic and Nuclear/physiology , Scavenger Receptors, Class B/physiologyABSTRACT
Apolipoprotein E (ApoE) plays an important role in the development of atherosclerosis. Previous studies provide evidence for an atheroprotective role of ApoE in mouse models on the ApoE deficient (ApoE-/-) background. However, it is not clear whether this is also true on the LDL-receptor deficient (LDLR-/-) background. Transgenic mice carrying hApoE coding sequences in a chicken lysozyme expression cassette were generated. Transgene expression was directed into macrophages, expressing low levels of hApoE. Expression of the hApoE transgene was not sufficient to correct hypercholesterolemia. However, lesion area at the brachiocephalic artery (BCA) was significantly reduced (-72%) in female hApoE transgenic mice on the LDLR-/- background. This was associated with increased cholesterol efflux in macrophages of transgenic animals on the ApoE-/- background. We conclude that over-expression of ApoE in macrophages might be useful as a therapeutic principle for the prevention of atherosclerosis.
Subject(s)
Apolipoproteins E/metabolism , Arteriosclerosis/metabolism , Macrophages/metabolism , Receptors, LDL/genetics , Animals , Apolipoproteins E/blood , Apolipoproteins E/genetics , Arteriosclerosis/etiology , Cells, Cultured , Cholesterol/blood , Cholesterol/metabolism , Female , Humans , Mice , Mice, Knockout , Mice, Transgenic , RNA, Messenger/metabolism , Receptors, LDL/metabolismABSTRACT
AIM: This review deals with the question whether resistance to obesity affects resistance to atherosclerosis. DATA SYNTHESIS: Resistance to diet-induced obesity in inbred mouse strains involves an adequate response to Leptin, the main regulator of the energy balance cycle. Leptin, an adipokine with both central and peripheral targets, regulates food intake and energy expenditure. Adequate response to leptin involves repression of stearoyl-CoA desaturase, activation of Amp-activated protein-kinase and uncoupling proteins, resulting in fatty acid oxidation and energy expenditure. Most of the obesity-resistant strains are also resistant to atherosclerosis, but so far no information concerning the response to the leptin cycle is available in these strains when bred onto a LDLR(-/-) or apoE(-/-) background. Recent studies in mouse strains on an atherosclerosis permissive background have identified genetic links between obesity and atherosclerosis. Moreover, information derived from studies on mice was applied in order to learn about the metabolic effectors in humans and is included in this review. CONCLUSIONS: The data presented in this review provide recent information concerning metabolic pathways that play an important role in the regulation of energy balance, a prerequisite for resistance to obesity. Hopefully they will provide a background for future genetic studies involved in resistance to atherosclerosis.
Subject(s)
Atherosclerosis/genetics , Disease Models, Animal , Energy Metabolism/genetics , Leptin/physiology , Obesity/genetics , Animals , Atherosclerosis/metabolism , Atherosclerosis/prevention & control , Genetic Predisposition to Disease , Humans , Leptin/genetics , Mice , Mice, Inbred Strains , Mice, Obese , Obesity/metabolism , Obesity/prevention & controlABSTRACT
The aim of this study was to compare some aspects of cholesterol accretion and cholesterol efflux in cellular components of the aortic wall derived from mice resistant or susceptible to atherosclerosis, FVB or C57BL, respectively. Cholesterol efflux, from cholesterol loaded smooth muscle cells or elicited macrophages, to apo A-I or HDL was similar in the two strains under basal conditions, and after cAMP or LXR upregulation. Recruitment of peritoneal macrophages, 3 days after thioglycollate injection, was 65% lower in FVB than in C57BL mice, commensurate with a 40% reduction in MCP-1 in peritoneal lavage. In additional three atherosclerosis resistant strains, NZB, A/J and 129(SvJ), macrophage recruitment was reduced to a similar extent despite high MCP-1 levels. Since impaired macrophage recruitment in CCR2(-/-) or MCP-1(-/-) C57BL mice was reported to reduce atherosclerosis, it seems plausible that in some mouse strains reduction in macrophage mobilization could contribute to atherosclerosis resistance.
Subject(s)
Atherosclerosis/metabolism , Cholesterol/metabolism , Macrophages, Peritoneal/pathology , Muscle, Smooth, Vascular/metabolism , Animals , Aorta, Thoracic/metabolism , Aorta, Thoracic/pathology , Atherosclerosis/pathology , Chemokine CCL2/metabolism , Disease Models, Animal , Disease Progression , Macrophages, Peritoneal/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Inbred NZB , Muscle, Smooth, Vascular/pathology , Phospholipids/metabolismABSTRACT
Activation of LXR in cultured cells results in enhancement of cholesterol efflux to apo Al. To study cholesterol efflux, in vivo cationized LDL was injected into the rectus femoris muscle of mice to create a lipoprotein depot. LXR ligand TO901317, 10 mg/kg, was given by gavage for 8 days, starting 4 days after injection of the lipoprotein. The rate of cholesterol efflux from the depot was compared in treated and control mice. Administration of the ligand resulted in a 70% increase in plasma cholesterol and 40% in phospholipids, but HDL-cholesterol and HDL-phospholipids increased by 43% and 24% only. Efflux of the injected cholesterol from the lipoprotein depot of treated mice was not enhanced but even somewhat delayed. This impairment was unexpected and its cause could be multifactorial. A plausible explanation seems that induced hypercholesterolemia, and a decrease in HDL-cholesterol to total cholesterol ratio, delayed the clearance.
Subject(s)
Anticholesteremic Agents/pharmacology , Cholesterol/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Animals , Anticholesteremic Agents/metabolism , Cells, Cultured , Cholesterol/blood , Cholesterol/chemistry , Cholesterol Esters/chemistry , Cholesterol Esters/metabolism , Cholesterol, LDL/chemistry , Cholesterol, LDL/metabolism , Hydrocarbons, Fluorinated , Ligands , Lipoproteins/blood , Macrophages, Peritoneal/metabolism , Male , Mice , Mice, Inbred C57BL , Muscles/metabolism , SulfonamidesABSTRACT
Recruitment of macrophages plays an important role in initiation of atheroma, but their involvement in cholesterol clearance during regression is unknown. We developed a mouse model to quantitate cholesterol clearance from a depot of cationized LDL injected into a leg muscle, which evokes a sterile inflammatory reaction. In the CCR2(-/-) mice, cholesterol clearance was significantly slower than in C57BL controls because of decrease in cholesteryl ester (CE) hydrolysis, which is mandatory prior to cholesterol efflux. In CCR2(-/-) mice, macrophage recruitment to the injected site, identified by immunohistochemistry, was markedly delayed. CE hydrolysis was also significantly reduced in thioglycollate elicited peritoneal exudate cells of CCR2(-/-) mice, related to paucity of macrophages in the cell differential. The present study provides definite evidence that recruitment of macrophages is required for LDL cholesterol clearance, which plays a prominent role in regression of an atheroma.
Subject(s)
Cell Movement , Cholesterol, LDL/metabolism , Macrophages/physiology , Monocytes/physiology , Receptors, Chemokine/physiology , Animals , Biological Transport , Cells, Cultured , Cholesterol/metabolism , Cholesterol Esters/metabolism , Female , Kinetics , Lipids/blood , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscle, Skeletal/cytology , Muscle, Skeletal/metabolism , Receptors, CCR2 , Receptors, Chemokine/geneticsABSTRACT
Cholesterol efflux from peritoneal macrophages of mice C57BL/6 susceptible and C3H resistant to atherosclerosis was compared, using apoprotein A-I as acceptor. The elicited macrophages were labeled with 3H-cholesterol and cholesterol enriched by incubation for 24 h with acetylated LDL. After incubation for 6 or 24 h, 3H-cholesterol efflux to free apoA-I (10 microg/ml) was significantly higher with macrophages derived from C3H mice compared to C57BL/6 mice. The cells were also pretreated with 0.3-0.45 mM cyclic AMP, 10 microM 9-cis-retinoic acid or 10 microM 22(R)-hydroxycholesterol, RXR and LXR ligands. Treatment with cyclic AMP, RXR, or LXR ligands, resulted in enhancement of 3H-cholesterol efflux in both strains. Under all conditions, 3H-cholesterol efflux was significantly higher in C3H compared to C57BL/6 macrophages. In conclusion, the higher cholesterol efflux from C3H macrophages could contribute toward the resistance of this strain to diet-induced atherosclerosis despite hypercholesterolemia.
Subject(s)
Apolipoprotein A-I/metabolism , Cholesterol/metabolism , Macrophages, Peritoneal/metabolism , Alitretinoin , Animals , Apolipoprotein A-I/physiology , Biological Transport/drug effects , Cells, Cultured , Cyclic AMP/pharmacology , DNA-Binding Proteins , Female , Hydroxycholesterols/metabolism , Hydroxycholesterols/pharmacology , Ligands , Liver X Receptors , Macrophages, Peritoneal/drug effects , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Orphan Nuclear Receptors , Phospholipids/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Retinoic Acid/metabolism , Retinoid X Receptors , Transcription Factors/metabolism , Tretinoin/metabolism , Tretinoin/pharmacology , TritiumABSTRACT
Atherosclerosis and its major clinical manifestation, coronary heart disease, is and will remain the main cause of mortality. Reviews on this subject dealt with factors that enhance development of atherosclerosis. This review deals with a new facet, that some individuals are less prone to develop atherosclerosis: (1) despite high cholesterol intake or (2) despite hypercholesterolemia with elevated low-density lipoprotein cholesterol (LDL-C) levels. The variability of response of plasma cholesterol to dietary intake was shown to be regulated by liver x receptor (LXR) that determines the rate of intestinal cholesterol absorption through the ATP-binding cassette (ABC) gene family. Other gene products, such as apolipoprotein-E (apo-E), scavenger receptor-B1 (SR-B1) and acyl coenzyme: cholesterol acyltransferase-2 (ACAT-2) affect cholesterol absorption also. The role of a genetic background for relative resistance to atherosclerosis is highlighted by subjects with familial hypercholesterolemia in whom high plasma cholesterol levels has not curtailed their expected life span. Studies in animals have shown that resistance to atherosclerosis in spite of hypercholesterolemia is affected by factors such as high-density lipoprotein (HDL) phospholipids that enhance reverse cholesterol transport, non-responsiveness to induction or lack of monocyte chemotactic protein-1 (MCP-1), C-C chemokine receptor 2 (CCR2), macrophage colony stimulating factor (MCSF), or vascular cell adhesion molecule-1 (VCAM-1). Since macrophages have been regarded as pro- or anti-atherogenic, evidence was collated that the high activity of scavenger receptors may contribute towards resistance to atherosclerosis if accompanied by adequate amounts of apo-E for cholesterol removal.
