Insulin resistance and type 2 diabetes are pathogenetically linked to increased risk of cardiovascular disease. While insulin resistance is defined by a dysregulation in hepatic insulin signaling, it is unclear how this impairment relates to the development of cardiovascular disease. Recently, there has been evidence showing that in insulin resistant individuals, cardiovascular disease is associated with a defect in reverse cholesterol transport – the cardioprotective process by which excess cholesterol is removed from the periphery, and returned to the liver for biliary excretion. Reverse cholesterol transport is facilitated by high-density lipoprotein (HDL) metabolism. Thus, malfunction in HDL turnover during reverse cholesterol transport may contribute to the buildup of atherosclerotic plaques, and subsequent cardiovascular disease in insulin resistant individuals. In this thesis, we seek to establish a better understanding of HDL metabolism and reverse cholesterol transport, as they relate to key transcription factors that mediate hepatic insulin signaling, namely the insulin-repressible forkhead transcription factors, FoxO1, FoxO3, and FoxO4 (FoxOs). We demonstrate that mice with liver-specific triple FoxO knockout (L-FoxO1,3,4) have increased HDL-cholesterol (HDL-C), associated with decreased expression of HDL-C clearance factors, scavenger receptor class B type I (SR-BI) and hepatic lipase, and defective selective uptake of HDL-cholesteryl ester by the liver. As such, we uncover a novel mechanism by which HDL-mediated reverse cholesterol transport to the liver is regulated by the hepatic insulin-->FoxO signaling pathway.

dsc-4(qm182), a mutation that suppresses the lengthened defecation cycle of clk-1 also suppresses the delay in germline development. dsc-4 encodes a putative orthologue of microsomal triglyceride transfer protein (MTP), a protein essential for the assembly and secretion of apo-B-containing low density lipoproteins (LDL). The effect of dsc-4 on clk-1(qm30), coupled to studies of apoB homologues in worms led to a model suggesting the possibility of using C. elegans in the study of LDL-like lipoprotein particles. The impact of the level of lipoproteins is particularly evident in the germline developmental rate of the worms. / We report here a further elucidation of clk-1 mutants in the study of the biology of LDL-like particles. In particular, we investigated the effect of targeting LDL receptor-like genes by RNA interference (RNAi) on the egg laying rate of clk-1(qm30). We find positive modulating effects by disruption of these putative LDL receptors. In confirmation of our model of lipoprotein metabolism in clk-1 mutants, we find that disruption of these putative LDL receptors produces strikingly different effects in wild-type, clk-1(qm30) or clk-1(qm30); dsc-4(qm182) animals. / In addition, we report unexpected effects of various clk-1 alleles on the phenotypes of animals in which lrp-1 and rme-2 are disrupted. Specifically, we observe an allele specific amelioration of the phenotypes associated with disruption of these genes (abnormal molting and sterility, respectively). We discuss the possible significance of these findings. (Abstract shortened by UMI.)

No description available.

Grape seed proanthocyanidins (GSP) as a cholesterol-lowering nutraceutical has been investigated in both humans and animals, however, little is known of how it interacts with the genes and proteins involved in lipoprotein metabolism in vivo. So the first objective of the present study was to investigate the effect of GSP supplementation on blood cholesterol level and gene expression of cholesterol-regulating enzymes in Golden Syrian hamsters maintained on a 0.1% cholesterol diet. / Hypercholesterolemia is one of the major proven risk factors for atherosclerosis. Decreasing blood total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels with cholesterol-lowering nutraceuticals and dietary intake modification could slow or reverse the progression of cardiovascular disease. / In conclusion, the present study confirmed that hypocholesterolemic activity of GSP was most likely mediated by enhancement of bile acid excretion and up-regulation of CYP7A1. The present study also demonstrated that frequent cholesterol and myristic acid intake is associated with elevation of plasma TC level, while beta-sitosterol intake frequency had no effect on plasma cholesterol for a given amount. / In the beta-sitosterol consumption frequency study, hamsters fed the basal diet with a gavage-administration of 3 mg cholesterol 3 times (control), or a gavage-administration of 3 mg beta-sitosterol with 3 mg cholesterol 3 times per day (high beta-sitosterol intake frequency), or a gavage-administration of 9 mg beta-sitosterol with 3 mg cholesterol for one time and 3 mg cholesterol for the other two times (low beta-sitosterol intake frequency). The results demonstrated that for a given dose of beta-sitosterol, the administration frequency had no or little effect on plasma lipoprotein profiles. The present study also found that cholesterol-lowering activity of beta-sitosterol was mediated by its inhibition on the intestinal cholesterol absorption with up-regulation of NPC1L1, ATP binding cassette transporters G5 and G8 (ABCG5/8) and MTP. / In the cholesterol consumption frequency study, hamsters were given daily 9 mg of cholesterol either in diet (high cholesterol intake frequency) or a gavage-administration of 3 times 3 mg (regular cholesterol intake frequency) and 1 time 9 mg (low cholesterol intake frequency). The results demonstrated that there was an increasing trend in concentrations of plasma TC, Non-HDL-C, TC/HDL-C ratio and TG in association with the cholesterol intake frequency. It is the first time to demonstrate that the increasing cholesterol intake frequency increased the apparent cholesterol absorption. Elevation of plasma TC and cholesterol absorption is most likely mediated by up-regulation of intestinal Niemann-Pick C1-like 1 (NPC1L1), acyl coenzyme A: cholesterol acyltransferase 2 (ACAT2), and microsomal triacylglycerol transport protein (MTP) gene expression. / In the myristic acid consumption frequency study, hamsters were given daily 210 mg of myristic acid either in diet (high myristic acid intake frequency) or a gavage-administration of 3 times 70 mg (regular myristic acid intake frequency) and 1 time 210 mg (low myristic acid intake frequency). The results showed that the increasing consumption frequency elevated plasma TC, Non-HDL-C and HDL-C levels. Elevation of plasma TC and HDL-C is most likely mediated by up-regulation of NPC1L1 and down-regulation of scavenger receptor BI (SR-BI) gene expression via enhancement of dietary myristic acid absorption. / The results affirmed supplementation of 0.5% or 1.0% GSP could decrease plasma TC, non-high density lipoprotein cholesterol (Non-HDL-C) and triglyceride (TG) levels. In addition, dietary GSP was able to increase the excretion of bile acids by 3--4 folds, this was partially mediated by up-regulation of Cholesterol 7 alpha-hydroxylase (CYP7A1) in both transcriptional and translational levels. It was concluded that the hypocholesterolemic activity of GSP was most likely mediated by enhancement of bile acid excretion and up-regulation of CYP7A1. / The second objective of the present study was to investigate the effect of cholesterol, myristic acid and beta-sitosterol consumption frequency on plasma lipoprotein profiles in hamsters. Numerous studies reported that dietary cholesterol and saturated fatty acids elevated plasma TC level, whereas dietary phytosterols in moderate and high doses favorably reduced plasma TC and LDL levels. However, it is still unknown whether consumption frequency of sterols and fatty acids could affect plasma cholesterol level and lipid profiles. / Jiao, Rui. / Adviser: Chen Zhen Yu. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 123-150). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Cardiovascular disease (CVD) is a major health problem in developed countries and, with increasing prevalence in developing countries and Eastern Europe. Due to the increased incidence with advancing age, there is a need to develop primary preventive interventions to prolong the period of healthy life. Diet has a substantial influence on health and aging. The composition of the human diet plays an important role in the management of lipid and lipoprotein. In this respect, we have focused on the effects of two kinds of functional foods, tea seed oil and dietary onion on their hypocholesterolemic activities and underlying mechanisms in the present study. / Clearly, there are many claims on health benefits of Alliums , however, most, with the exception of garlic, have not received any rigorous or even gentle scientific investigation. Thus, the present study was carried out to explore hypocholesterolemic effects of onion supplementation. After fed for 2 weeks of the high fat high cholesterol diet, thirty-six 8-week male hamsters were divided into four groups. Control group was continued fed with high fat high cholesterol diet, while the other two experimental groups were fed control diet plus 1% (1OP) and 5% (5OP) onion powder for 8 weeks. It was found that feeding high dose of onion powder diet significantly prevented the increase in serum TC, Non-HDL-C and the ratio of non-HDL-C/HDL respectively in hamsters fed a 0.1% cholesterol diet. In contrast, the ratio of HDL/TC in high dose group was significantly increased than that in the control. Low onion dose group tended to have the similar effects as high dose group but, statistically, no difference was observed between the control and low dose groups. Besides, both doses of onion powder diets could significantly countered the increase in serum TG levels. High dose of onion supplementation tended to increase output of fecal neutral and acidic sterols, resulting in reduction of cholesterol retained and absorption. High dose of onion powder diet could significantly up- regulate SREBP-2, LXRbeta, and CYP7A1 protein expressions. The hypocholesterolemic activities of onion might due to the richness in alkyl and alkenyl sulfoxide compounds, anthocyanin, quercetin and cycloalliin, all of which have therapeutic effects. / In conclusion, diet plays an important role in reducing the risk of CVD. This has led to the search for specific foods and food components that may help to improve the serum lipoprotein profile. In present study, tea seed oil and onion was proved to help favorably modify the plasma lipoprotein profile, serving as health supplementation. However, their potential mechanisms were not fully studied and need to be further explored. / Interest in tea seed oil (named tea oil) as a cooking oil is increasing. However, its effect on blood cholesterol is not known. This study was therefore conducted to compare the hypocholesterolemic activity of tea oil with grape seed, canola and corn oils. Fifty 8-week-old male hamsters were first fed a high fat diet (5% lard), and supplemented with 0.1% cholesterol for 2 weeks and then divided into five groups. Control group was continuously fed high fat high cholesterol diet, while the experimental groups were fed high fat, high cholesterol diet plus 10% tea oil, grape seed oil, canola oil and corn oil for 12 weeks. Results showed that plasma total cholesterol (TC), non-HDL-cholesterol (non-HDL-C) and triacylglycerols (TG) in hamsters fed a 0.1% cholesterol diet containing tea, grape, canola or corn oil was significantly reduced compared with those in lard-fed group. Tea oil decreased only non-HDL-C and had no or little effect on HDL-C concentration, while grape oil reduced both. Besides, tea oil-fed hamsters excreted less neutral but greater acidic sterols compared with other three oils. Unlike grape oil, tea oil up-regulated sterol regulatory element binding protein (SREBP-2) and LDL receptor. Differences between tea oil and the tested vegetable oils could be attributable partially to >80% oleic acid in tea oil. / Guan, Lei. / Adviser: Chung Hau Yin. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 98-125). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Alpha-tocopherol, the most abundant form of vitamin E in man, is transported in the circulation by plasma lipoproteins. It plays important roles, not only in preventing lipid peroxidation, but also in modulating several cell functions such as cell signaling and gene expression. While chylomicrons transport dietary alpha-tocopherol after intestinal absorption, LDL and HDL are the major carriers of alpha-tocopherol in fasting plasma and largely contribute to its delivery to cells and tissues. Exchanges of alpha-tocopherol occur between plasma lipoproteins. In addition, alpha-tocopherol transfers have also been observed, in both directions, between plasma lipoproteins and artificial chylomicrons such as intravenous lipid emulsion particles used in parenteral nutrition. In acute conditions, intravenous supply of vitamin E via lipid emulsions, which bypasses the intestinal tract, may offer some advantages over oral administration to rapidly increase alpha-tocopherol plasma concentration. However, many questions remain unanswered regarding kinetics and factors facilitating vitamin E exchanges between lipid emulsions and plasma lipoproteins. The first part of this work aimed at characterizing alpha-tocopherol transfers between alpha-tocopherol rich emulsion particles and plasma lipoproteins as well as the potential for plasma proteins to modulate such transfers. An in vitro model of incubation was used in which emulsion triglyceride concentration was relatively low and lipoprotein levels comparable to those commonly found in the circulation. Results indicate a high capacity for LDL and HDL to acquire extra-amounts of alpha-tocopherol by rapid mass transfers from alpha-tocopherol-rich emulsion particles. Data further shows that, at a fixed alpha-tocopherol concentration provided by emulsion particles, the limiting factor for alpha-tocopherol enrichment is not the capacity of plasma lipoproteins to accommodate extra-amounts of alpha-tocopherol but the facilitating effect of plasma proteins on alpha-tocopherol transfer, the duration of the incubation and possibly the competition between different acceptor particles. Two lipid transfer proteins, PLTP and CETP, appear to largely mediate facilitation of alpha-tocopherol transfer; however, other plasma proteins may be involved. Data further shows that alpha-tocopherol enriched LDL and HDL can readily transfer newly acquired alpha-tocopherol to cells, without any regulation by plasma proteins.<p>Short-term prophylactic vitamin E supplementation has been suggested to be beneficial in some patients in acute conditions who present reduced plasma vitamin E concentrations in association with important changes in plasma lipids and severe oxidative stress. However, it was not clear whether low plasma vitamin E concentration in critically ill patients is related to changes in the composition of plasma lipoproteins or to a decrease in the number of alpha-tocopherol carriers. In the second part of this work, two clinical studies were conducted to analyze changes of lipoprotein concentration and composition in relation to inflammatory reaction and oxidative stress in selected subgroups of critically ill patients, namely patients undergoing cardiac surgery with different procedures. Important changes in LDL and HDL lipid content were observed, some of which contrast with previous observations made in critically ill septic patients. The reduced plasma level of alpha-tocopherol measured after cardiac surgery is entirely due to a reduced number of circulating LDL and HDL particles. Data suggests that such reduced number in alpha-tocopherol carriers post-surgery may impede the delivery of alpha-tocopherol to cells in conditions of increased requirements due to oxidative stress. Avoidance of extracorporeal circulation during cardiac surgery does not reduce inflammation-related changes in plasma lipids but largely prevents oxidative stress. This data on changes occurring in plasma lipoproteins may help to better define strategies against pro-inflammatory changes or oxidative stress. If further studies would confirm a clinical benefit with evidence-based rationale, alpha-tocopherol enriched lipid emulsions may be used to guarantee a sufficient alpha-tocopherol supply in acute conditions associated with fewer alpha-tocopherol transporters and increased requirements due to high risk of oxidative tissue injury.<p> / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

Assignment (MMed)--University of Stellenbosch, 2007. / ENGLISH ABSTRACT: Lipoprotein X (LpX) is an abnormal cholesterol-containing particle that may be present in the serum of subjects with cholestasis, lecithin:cholesterol acyltransferase (LCAT) deficiency and parenteral nutrition. The biochemistry, metabolism, clinical significance and laboratory analysis of LpX is discussed in this study. This laboratory-based project investigated icteric samples received at the Chemical Pathology laboratory, Tygerberg Hospital, for serum predictors of LpX and the use of a modified non-denaturing polyacrylamide gradient gel electrophoresis system in the detection of LpX. The study showed that the non-denaturing polyacrylamide gradient gel electrophoresis system (2-8%) is a useful test in demonstrating LpX in icteric plasma and has potential for a screening test in LCAT deficiency. Serum concentration of conjugated bilirubin, alkaline phosphatase, gamma glutamyltransferase, free cholesterol, phospholipid, free cholesterol: total cholesterol ratio and conjugated bilirubin: total bilirubin ratio are all good predictors of LpX. The ratio of free cholesterol to total cholesterol (FC/TC > 0.6) was the best predictor of LpX. In the setting of obstructive liver disease LpX is seen in 66% of patients if total cholesterol is > 7.5 mmol/L. / AFRIKAANSE OPSOMMING: Lipoproteien X (LpX) is ‘n abnormale cholesterol-bevattende partikel wat teenwoordig mag wees in die serum van persone met cholestase, lesitien:cholesterol asieltransferase (LCAT) gebrek en parenterale voeding. Die biochemie, metabolisme, kliniese belang en laboratorium analise van LpX word bespreek in hierdie werkstuk. Hierdie laboratorium-gebaseerde projek het geelsugtige monsters ondersoek wat ontvang is by die Chemiese Patologie laboratorium, Tygerberg Hospitaal, vir serum voorspellers van LpX en die gebruik van ‘n gemodifiseerde nie-denaturerende polie-akrielamied gradiënt gel elektroforese sisteem in die demonstrasie van LpX. Die bevindinge was dat die nie-denaturerende polie-akrielamied gradient gel elektroforese sisteem (2-8%) is ‘n nuttige toets om LpX te demonstreer in geelsugtige plasma en het potensiaal as ‘n siftingstoets in LCAT gebrek. Serum konsentrasie van gekonjugeerde bilirubien, alkaliese fosfatase, gamma glutamieltransferase, vry cholesterol, fosfolipied, vry cholesterol:totale cholesterol verhouding en gekonjugeerde bilirubien:totale bilirubien verhouding is alles goeie voorspellers van LpX. Die verhouding van vry cholesterol tot totale cholesterol (VC/TC > 0.6) was die beste voorspeller van LpX. In gevalle van obstruktiewe lewersiekte word LpX gesien in 66% van pasiente as die totale cholesterol meer as 7.5 mmol/l is.

Thesis (PhD) -- University of Stellenbosch, 2001. / ENGLISH ABSTRACT: The advent of the new millennium saw the complete sequencing of the entire human genome. Only approximately 30 000 genes, much less than was initially predicted, have been identified to be responsible for the genetic diversity in humans. This discovery has prompted a shift in the approach to disease research, since one gene can be involved in numerous diseases. This phenomenon seems to be especially true for the low-density lipoprotein receptor (LDLR) gene. Various substances beside sterols can induce transcription of the LDLR gene. Non-communicable diseases (e.g. hypertension) are common in the developing world and contribute significantly to mortality rates. The fmding that a promoter variant (-175 g~t) in the LDLR gene is associated with elevated diastolic blood pressure may explain the phenomenon of high LDL-cholesterollevels in hypertensive individuals. Studies have demonstrated that the lowering of cholesterol, especially LDL-cholesterol, can reduce the incidence of hypertension. The -175 g~t variant is located in a newly described cis-acting regulatory element which contains a putative binding site for Yin Yang (YY)-l and also demonstrates great homology to the cAMP response element (CRE) which bind the Ca2+- dependent transcription factor, CRE binding protein (CREB). The fact that Ca2+ can induce transcription of the LDLR gene may, at least in part, explain the association between the - 175g~t variant and elevated diastolic blood pressure. Cholesterol is important for various processes, such as apoptosis, maintenance of cellular membranes and immune function. The -59 c-ot mutation in repeat 2 of the LDLR gene abolishes binding of the sterol regulatory element binding protein(SREBP) to the SRE-l site. SREBP is proteolytically activated during apoptosis by two caspases (CPP32 and Mch3) to induce cholesterol levels. Our results imply that the -59C/T mutation, in repeat 2 of the LDLR gene promoter, may inhibit apoptosis under normal immunological conditions. Atherosclerosis can be considered an immunological disease, since various humoral and cellular immune processes can be detected throughout the course of the disease. The fmding that certain lipoproteins can protect against infection by binding and lysing of pathogens, or competing with pathogens for cellular receptors, prompted the investigation into the potential role of variation in the LDLR gene promoter in immune function. A significant difference in allelic distribution was detected between asymptomatic HIY -infected subjects and fast progressors for the -124 c-ot variant (P=O.006), shown to increase (~160%) transcriptional activity of the LDLR gene. Of relevance to this particular study is the fact that human herpesvirus (HHV) 6 can transactivate CD4 promoters through a partial CRE site. It has been shown that the CREB and YYl can regulate viral and cellular promoters, and these transcription factors can potentially bind to the LDLR promoter at the FP2 site. The mutation enrichment in the LDLR gene promoter seen in the South African Black and Coloured population groups can possibly provide insight into the pathogenesis of various diseases. This could also potentially, provide novel targets for treatment, since manipulation of cholesterol levels may affect the pathogenesis of various diseases. / AFRIKAANSE OPSOMMING: Die volledige DNA volgorde bepaling van die mensgenoom is voltooi vroeg in die nuwe millennium. Slegs ongeveer 30 000 gene is geidentifiseer, heelwat minder as wat in die verlede voorspel is, wat verantwoordelik is vir die genetiese diversiteit in die mens. Hierdie ontdekking het gelei tot 'n verandering in die benadering van navorsing ten opsigte van siektes, aangesien een geen 'n rol by verskeie siektes kan speel. Hierdie gewaarwording blyk veral waar te wees vir die lae digtheids lipoproteien reseptor (LDLR) geen. Verskeie stimuli, buiten sterole, kan transkripie van die LDLR geen inisieer. Verskeie siektes soos hipertensie is algemeen in die ontwikkelende wereld, en dra by tot die hoe mortaliteit syfers. Die bevinding dat 'n promoter variant in die LDLR geen (-175g-H) geassosieer is met verhoogde diastoliese bloeddruk, kan moontlik verhoogde lipiedvlakke in hipertensiewe individue verklaar. Studies het aangetoon dat die verlaging van cholesterol, veral LDL-cholesterol, die voorkorns van hipertensie kan verlaag. Die -175 g~t variant is gelee in 'n cis-regulerende element wat na bewering 'n bindingsetel vir die Yin Yang (YY)-l transkripsie faktor bevat asook sterk homologie met die cAMP respons element (CRE) toon, wat bind aan die Ca2 +_ afhanklike transkripie faktor, CRE bindings proteiene (CREB). Die feit dat Ca2+ transkripsie van die LDLR geen kan inisieer, kan dalk tot 'n mate, 'n verklaring bied vir die assosiasie tussen die -175 (g~t) variant en verhoogde diastoliese bloeddruk. Cholesterol is noodsaaklik vir verskeie prosesse soos apoptose, die instandhouding van selmembrane sowel as immuun funksies. Die -59 c-ot mutasie in die sterol regulerende element 1 (SRE-l) van die LDLR geen vernietig binding van die sterol regulerende element bindingsprotei'en (SREBP) aan SRE-l. SREBP word proteolities geaktiveer tydens apoptose deur twee kaspases (CPP32 en Mch3) om cholesterolvlakke te induseer. Ons resultate impliseer dat die -59C/T mutasie, in herhaling-2 van die LDLR-geen promoter, apoptose kan inhibeer onder normale immunologiese toestande. Aterosklerose kan beskou word as 'n immunologiese siekte, aangesien verskeie humorale en sellulere immuun prosesse deur die verloop van die siekte waargeneem kan word. Die feit dat Iipoproteiene beskermend kan wees teen infeksies, deur binding en lisering van virusse of kompeteer met patogene vir sellulere reseptore, het aanleiding gegee tot 'n ondersoek na die potensiele rol van variasies in die promoter area van die LDLR geen in immuun funksie. Betekenisvolle verskille in alleel verspreiding vir die -124c~t variant (P=0.006) is waargeneem tussen asimptomatiese MIV -geinfekteerde pasiente en individue met vinnige siekte progressie. In vitro studies het voorheen getoon dat die -124c~t 'n verhoging in LDLR geen transkripsie (160%) tot gevolg het. Dit is noemenswaardig dat 'n vroee studie getoon het dat die mens like herpesvirus-6 (MHV6) transaktivering van die CD4 promoters deur 'n gedeeltelike CRE bindingsetel kan bewerkstellig. Beide CREB en YYl kan virus en sellulere promotors reguleer, en hierdie transkripsie faktore toon bindingshomologie met die FP2 element van die LDLR promotor Die mutasie verryking van die LDLR geen promoter soos waargeneem in Suid Afrikaanse Swart en Kleurling populasies, kan moontlik lig werp op die patogenese van verskeie siektetoestande. Hierdie bevindinge kan potensieel nuwe teikens vir behandeling identifiseer, aangesien manipulasie van cholesterolvlakke 'n effek mag he op die patogenese van verskeie siektes.

Two studies were conducted to determine how HDL cholesteryl ester and apoprotein catabolism might contribute to the observed hypercholesterolemia of copper-deficient rats. Weanling male Sprague-Dawley rats were divided into two dietary treatments; copper-adequate (control, 5-7 mg Cu/kg diet) and copper-deficient (0.6-0.8 mg Cu/kg diet). Deionized water and diet were provided ad libitum. Dietary copper deficiency resulted in enlarged intravascular pools of HDL cholesteryl esters and total protein. HDL were isolated from rats of both treatment groups, radiolabeled, and injected into animals of the respective groups. In Study I, HDL apoproteins were labeled by iodination, whereas HDL in Study II were doubly labeled by additionally incorporating into the particle core [³H]cholesteryl linoleyl ether, which served as a nondegradable analog of HDL cholesteryl ester. At specific time intervals up to 12 hours after injection, blood and tissue samples were removed and analyzed for radioactivity. Plasma disappearance curves indicated that HDL cholesteryl esters were preferentially catabolized 1.6-fold faster than HDL protein in controls and 2.5-fold faster in copper-deficient animals. Clearance of individual apoproteins did not occur at significantly different rates in either treatment group. Absolute mass removal of HDL cholesteryl ester and total protein from the plasma was significantly increased in copper-deficient rats. Virtually all of the increased removal of HDL cholesteryl ester was attributed to the liver, whereas most of the increased uptake of HDL protein was attributed to the bulk tissues and not the liver. Since previous studies indicate that copper deficiency may not result in increased cholesterol excretion, these data suggest that cholesteryl esters delivered to the liver of copper-deficient rats are possibly reassembled into new HDL particles at an increased rate. The observed hypercholesterolemia in this animal model, then, appears to be the result of an imbalance in the net flux of cholesterol between the tissues and the plasma.

O papel do exercício físico na prevenção da doença macrovascular aterosclerótica é atribuído em parte à melhoria no metabolismo de lípides, com evidências para regressão e prevenção no desenvolvimento de aterosclerose. Neste estudo, avaliamos o efeito de 6 semanas de treinamento físico aeróbio (protocolo diário em esteira 15 m/min, 30 min, 5 vezes na semana) sobre o transporte reverso de colesterol (TRC) em camundongos C57BL/6 selvagens e transgênicos para CETP humana (CETP-tg). Estes últimos constituem modelo experimental de TRC que se assemelha aos humanos, pela presença da CETP. O TRC é um sistema antiaterogênico, por meio do qual o colesterol é removido de células periféricas e transportado ao fígado para eliminação na bile e excreção fecal. A metodologia utilizada consistiu na injeção intraperitoneal de macrófagos J774 enriquecidos em LDL-acetilada e 3H-colesterol em animais selvagens e CETP-tg sedentários e treinados, após as 6 semanas de estudo. O perfil lipídico não foi modificado após o treinamento físico, no entanto, apenas no grupo CETP-tg treinado houve aumento na concentração de HDL colesterol ao final do estudo. O treinamento físico aeróbio acelerou o TRC em camundongos selvagens, refletido pela maior recuperação de 3H-colesterol no plasma (após 24 h e 48 h da injeção intraperitoneal) e no fígado (após 48 h), em comparação aos animais selvagens sedentários. Este evento associou-se ao aumento de 60% na expressão dos receptores hepáticos SR-BI, em relação ao grupo sedentário. Nos animais CETP-tg, o treinamento físico aumentou o TRC, com maior recuperação de 3H-colesterol - advindo dos macrófagos - no plasma, fígado e também nas fezes (após 24 h e 48 h), em comparação aos animais transgênicos sedentários. Embora a expressão de SR-BI não tenha sido alterada pelo treinamento físico nos animais CETPtg, observou-se nestes animais aumento na expressão hepática do receptor B-E, contribuindo para a maior remoção de colesterol pelo fígado. Os achados apontam para importante papel do exercício físico aeróbio regular sobre o transporte reverso de colesterol de macrófagos, contribuindo para a prevenção contra a gênese e progressão da aterosclerose. / Regular exercise prevents the development of atherosclerosis. We analyzed the role of a six-week aerobic exercise training program in the macrophage reverse cholesterol transport in wild-type (WT) and in human CETP transgenic (CETP-tg) mice. Animals were randomly assigned to sedentary and trained groups (treadmill 15 m/min, 30-min sessions, 5 sessions per week). Plasma lipids were not modified after training, although HDL-cholesterol concentrations levels increased in trained CETP-tg mice only. Plasma CETP activity was not modified after training. A greater recovery of 3H-cholesterol from J774 macrophages injected into peritoneal cavities of mice was found in plasma and in the liver from exercised WT and CETP animals in comparison to sedentary groups. Exercise training induced a greater excretion of 3H-cholesterol in feces only in the CETP-tg mice. The SR-BI expression in the liver was increased and unchanged in trained WT and CETP-tg mice, respectively. The liver expression of LDL receptor was higher in both groups after training. Alternatively, liver X receptor (LXR) increased only in trained WT mice. Aerobic exercise training improves the macrophage RCT in mice, thereby contributing to the prevention and regression of atherosclerosis. The benefit of exercise on the cholesterol excretion in feces in mice was attained only in the presence of CETP, which elucidates the importance of exercise in the prevention of atherosclerosis in humans.