Altered Lipid Domains Facilitate Enhanced Pulmonary Vasoconstriction after Chronic Hypoxia.

Chronic hypoxia (CH) augments depolarization-induced pulmonary vasoconstriction through superoxide-dependent, Rho kinase-mediated Ca2+ sensitization. Nicotinamide adenine dinucleotide phosphate oxidase and EGFR (epidermal growth factor receptor) signaling contributes to this response. Caveolin-1 regulates the activity of a variety of proteins, including EGFR and nicotinamide adenine dinucleotide phosphate oxidase, and membrane cholesterol is an important regulator of caveolin-1 protein interactions. We hypothesized that derangement of these membrane lipid domain components augments depolarization-induced Ca2+ sensitization and resultant vasoconstriction after CH. Although exposure of rats to CH (4 wk, ∼380 mm Hg) did not alter caveolin-1 expression in intrapulmonary arteries or the incidence of caveolae in arterial smooth muscle, CH markedly reduced smooth muscle membrane cholesterol content as assessed by filipin fluorescence. Effects of CH on vasoreactivity and superoxide generation were examined using pressurized, Ca2+-permeabilized, endothelium-disrupted pulmonary arteries (∼150 µm inner diameter) from CH and control rats. Depolarizing concentrations of KCl evoked greater constriction in arteries from CH rats than in those obtained from control rats, and increased superoxide production as assessed by dihydroethidium fluorescence only in arteries from CH rats. Both cholesterol supplementation and the caveolin-1 scaffolding domain peptide antennapedia-Cav prevented these effects of CH, with each treatment restoring membrane cholesterol in CH arteries to control levels. Enhanced EGF-dependent vasoconstriction after CH similarly required reduced membrane cholesterol. However, these responses to CH were not associated with changes in EGFR expression or activity, suggesting that cholesterol regulates this signaling pathway downstream of EGFR. We conclude that alterations in membrane lipid domain signaling resulting from reduced cholesterol content facilitate enhanced depolarization- and EGF-induced pulmonary vasoconstriction after CH.

Effects of coconut oil associated with a physical exercises program on body composition and lipid profile / Efeitos do óleo de coco associado com um programa de exercícios físicos sobre a composição corporal e perfil lipídico

ABSTRACT The aim of this study was to evalute the effects of supplementation of coconut oil associated with a physical exercise program on body composition and lipid profile in normolipid eutrophic women. The sample was composed of 20 women randomized divided into two groups, supplemented exercise group with 13 mL/day of coconut oil (GES, n= 10) and unsuppemented exercie group with coconut oil (GEU), n= 10). Perimeters measurements of central adiposity, fat (%), fat mass, lean mass, total cholesterol, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c) and triglycerides concentrations were evaluated in the beginning and in the final of 12 weeks of intervention. For intragroup and intergroup comparisons was used dependentes and independentes sample t-test. The results showed that 12 weeks of intervention modified the central adiposity in the GES group, decreased 2,6% the waist cincunference compared to GEU group (p<0.05). The fat (%), fat mass and lean mass did not change after 12 weeks of intervention between GES and GEU groups (p>0.05). In the comparation of lipid profile between groups, GES group decreased 3% the LDL-c while the GEU group increased 13.7% the total cholesterol and 14.2% the LDL-c concentration (p<0.05). In conclusion, coconut oil associated with a physical exercise program did not modify the body composition and attenuate the changes in the lipid profile in normolipid eutrophic women.

RESUMO O objetivo deste estudo foi avaliar os efeitos da suplementação de óleo de coco associado com um programa de exercícios físicos sobre a composição corporal e perfil lipídico em mulheres eutróficas normolipidicas. A amostra foi composta de 20 mulheres divididas aleatoriamente em 2 grupos, grupo exercício suplementado com 13 mL/dia de óleo de coco (GCO; n=10) e grupo exercício não suplementado com óleo de coco (GSO; n=10). Foram avaliados medidas perimétricas de adiposidade central, gordura (%), massa gorda, massa magra, níveis séricos de colesterol total, LDL-c, HDL-c e triglicérides no início e no final de 12 semanas de intervenção. Para as comparações intragrupos e entre os grupos foi utilizado o teste T para amostras dependentes e independentes. Os resultados mostraram que 12 semanas de intervenção modificou a adiposidade central no grupo GCO, diminuindo 2,6% a circunferência da cintura comparado ao grupo GSO (p<0,05). A gordura (%), massa gorda e massa magra não se modificaram após 12 semanas de intervenção nos grupos GCO e GSO (p<0,05). Na comparação do perfil lipídico entre os grupos, o grupo GCO diminui 3% o LDL-c enquanto que o grupo GSO aumentou 13,7% o colesterol total e 14,2% o LDL-c (p<0,05). Em conclusão, o óleo de coco associado com um programa de exercício físico aeróbico não modifica a composição corporal e atenua as alterações no perfil lipídico em mulheres eutróficas normolipidicas.

The pro- or antiarrhythmic actions of polyunsaturated fatty acids and of cholesterol.

In this review, the pro- and anti-arrhythmic effects of a diet rich in fish oil fatty acids and of hypercholesterolemia will be discussed in relation to two major mechanisms of arrhythmogenesis (triggered activity and re-entry). Whereas a diet rich in fish oil is pro-arrhythmic in relation to re-entry based arrhythmias (as occur in acute myocardial ischemia) and anti-arrhythmic in relation to triggered activity based arrhythmias (as occur in heart failure), the reverse is true for hypercholesterolemia. Changing the lipid composition of cardiomyocytes likely has powerful pro- or anti-arrhythmic consequences, depending on the mechanism of arrhythmias, and has corresponding therapeutic potential.

Biological relevance of fatty acyl heterogeneity to the neural membrane dynamics of rhesus macaques during normative aging.

Lipidomic analyses of the frontal cortex of Rhesus macaques across three selected age groups (young, sexually-mature, old) revealed that docosahexaenoic acids (DHAs) displayed notable and unique accretions in sexually-mature macaques for all phospholipid classes examined, which were not observable in all remaining polyunsaturated fatty acids (PUFAs) investigated. On the other hand, arachidonic acid (ARA) exhibited sharp attritions in the membrane lipidomes of sexually-mature macaques, a decline which was attenuated only for cardiolipins (CLs). DHA enrichment in phospholipids was lost in old macaques, with accompanying augmentations in very-long-chain sphingomyelins (VLC-SMs). Age-dependent alterations in membrane lipidomes point to a possibly complex temporal interplay between DHA-enriched membrane microdomains and SM-/cholesterol-rich rafts in neural membranes during normative aging. Lipid co-regulation data revealed an increasingly intense degree of co-regulation between membrane lipid classes with age, and suggest that reduction in CLs during normative brain aging may prompt alternative membrane lipid synthetic pathways driven by a compromised energy availability in the aging brain.

Role for phospholipid acyl chains and cholesterol in pulmonary infections and inflammation.

Bacterial and viral respiratory tract infections result in millions of deaths worldwide and are currently the leading cause of death from infection. Acute inflammation is an essential element of host defense against infection, but can be damaging to the host when left unchecked. Effective host defense requires multiple lipid mediators, which collectively have proinflammatory and/or proresolving effects on the lung. During pulmonary infections, phospholipid acyl chains and cholesterol can be chemically and enzymatically oxidized, as well as truncated and modified, producing complex mixtures of bioactive lipids. We review recent evidence that phospholipids and cholesterol and their derivatives regulate pulmonary innate and adaptive immunity during infection. We first highlight data that oxidized phospholipids generated in the lung during infection stimulate pattern recognition receptors, such as TLRs and scavenger receptors, thereby amplifying the pulmonary inflammatory response. Next, we discuss evidence that oxidation of endogenous pools of cholesterol during pulmonary infections produces oxysterols that also modify the function of both innate and adaptive immune cells. Last, we conclude with data that n-3 polyunsaturated fatty acids, both in the form of phospholipid acyl chains and through enzymatic processing into endogenous proresolving lipid mediators, aid in the resolution of lung inflammation through distinct mechanisms. Unraveling the complex mechanisms of induction and function of distinct classes of bioactive lipids, both native and modified, may hold promise for developing new therapeutic strategies for improving pulmonary outcomes in response to infection.

Cholesterol sensitises the transient receptor potential channel TRPV3 to lower temperatures and activator concentrations.

TRPV3, a thermosensitive cation channel, is predominantly expressed in keratinocytes. It contributes to physiological processes such as thermosensation, nociception, and skin development. TRPV3 is polymodally regulated by chemical agonists, innocuous heat, intracellular acidification or by membrane depolarization. By manipulating the content of plasma membrane cholesterol, a key modulator of the physicochemical properties of biological membranes, we here addressed the question, how the lipid environment influences TRPV3. Cholesterol supplementation robustly potentiated TRPV3 channel activity by sensitising it to lower concentrations of chemical activators. In addition, the thermal activation of TRPV3 is significantly shifted to lower temperatures in cholesterol-enriched cells. The sensitising effect of cholesterol was not caused by an increased plasma membrane targeting of the channel. In HaCaT keratinocytes, which natively express TRPV3, a cholesterol-mediated sensitisation of TRPV3-like responses was reproduced. The cholesterol-dependent modulation of TRPV3 activity may provide a molecular mechanism to interpret its involvement in keratinocyte differentiation.

JAK2-V617F-mediated signalling is dependent on lipid rafts and statins inhibit JAK2-V617F-dependent cell growth.

Aberrant JAK2 signalling plays an important role in the aetiology of myeloproliferative neoplasms (MPNs). JAK2 inhibitors, however, do not readily eliminate neoplastic MPN cells and thus do not induce patient remission. Further understanding JAK2 signalling in MPNs may uncover novel avenues for therapeutic intervention. Recent work has suggested a potential role for cellular cholesterol in the activation of JAK2 by the erythropoietin receptor and in the development of an MPN-like disorder in mice. Our study demonstrates for the first time that the MPN-associated JAK2-V617F kinase localizes to lipid rafts and that JAK2-V617F-dependent signalling is inhibited by lipid raft disrupting agents, which target membrane cholesterol, a critical component of rafts. We also show for the first time that statins, 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, widely used to treat hypercholesterolaemia, induce apoptosis and inhibit JAK2-V617F-dependent cell growth. These cells are more sensitive to statin treatment than non-JAK2-V617F-dependent cells. Importantly, statin treatment inhibited erythropoietin-independent erythroid colony formation of primary cells from MPN patients, but had no effect on erythroid colony formation from healthy individuals. Our study is the first to demonstrate that JAK2-V617F signalling is dependent on lipid rafts and that statins may be effective in a potential therapeutic approach for MPNs.

Intracellular signaling cascades induced by relaxin in the stimulation of capacitation and acrosome reaction in fresh and frozen-thawed bovine spermatozoa.

Relaxin is one of the 6-kDa peptide hormones, which acts as a pleiotropic endocrine and paracrine factor. Our previous studies revealed that sperm capacitating medium containing relaxin induced capacitation and acrosome reaction (AR) in fresh and frozen-thawed porcine or bovine spermatozoa. However, the intracellular signaling cascades involved with capacitation or AR induced by relaxin was unknown. Therefore, the present study was designed to investigate the intracellular signaling cascades involved with capacitation and AR induced by relaxin in fresh and frozen-thawed bovine spermatozoa. Spermatozoa were incubated in sperm Tyrode's albumin lactate pyruvate (Sp-TALP) medium supplemented with (40 ng ml(-1)) or without relaxin, and subjected to evaluation of chlortetracycline staining pattern, cholesterol efflux, Ca(2+)-influx, intracellular cyclic adenosine monophosphate (cAMP) and protein tyrosine phosphorylation. Capacitation and AR were increased (P<0.05) in both fresh and frozen-thawed spermatozoa incubated with relaxin. Cholesterol effluxes were greater in the fresh (P<0.01) and frozen-thawed (P<0.05) spermatozoa incubated with relaxin than the spermatozoa incubated without relaxin. Ca(2+)-influxes were also significantly stimulated by relaxin in the fresh (P<0.01) and frozen-thawed (P<0.05) spermatozoa. The Sp-TALP medium containing relaxin influenced the generation of intracellular cAMP in the fresh (P<0.01) and frozen-thawed (P<0.05) spermatozoa, and exhibited higher exposure of protein tyrosine phosphorylation in both sperm types than the medium devoid of relaxin. Therefore, the results postulate that relaxin exerts the intracellular signaling cascades involved with capacitation and AR through accelerating the cholesterol efflux, Ca(2+)-influx, intracellular cAMP and protein tyrosine phosphorylation in fresh and frozen-thawed bovine spermatozoa.

Membrane cholesterol modulates cochlear electromechanics.

Changing the concentration of cholesterol in the plasma membrane of isolated outer hair cells modulates electromotility and prestin-associated charge movement, suggesting that a similar manipulation would alter cochlear mechanics. We examined cochlear function before and after depletion of membrane cholesterol with methyl-ß-cyclodextrin (MßCD) in an excised guinea pig temporal bone preparation. The mechanical response of the cochlear partition to acoustic and/or electrical stimulation was monitored using laser interferometry and time-resolved confocal microscopy. The electromechanical response in untreated preparations was asymmetric with greater displacements in response to positive currents. Exposure to MßCD increased the magnitude and asymmetry of the response, without changing the frequency tuning of sound-evoked mechanical responses or cochlear microphonic potentials. Sodium salicylate reversibly blocked the enhanced electromechanical response in cholesterol depleted preparations. The increase of sound-evoked vibrations during positive current injection was enhanced following MßCD in some preparations. Imaging was used to assess cellular integrity which remained unchanged after several hours of exposure to MßCD in several preparations. The enhanced electromechanical response reflects an increase in outer hair cell electromotility and may reveal features of cholesterol distribution and trafficking in outer hair cells.

Inflammation, cytokines, immune response, apolipoprotein E, cholesterol, and oxidative stress in Alzheimer disease: therapeutic implications.

Alzheimer disease (AD) is a heterogeneous and progressive neurodegenerative disease, which in Western society mainly accounts for senile dementia. Today many countries have rising aging populations and are facing an increased prevalence of age-related diseases, such as AD, with increasing health-care costs. Understanding the pathophysiology process of AD plays a prominent role in new strategies for extending the health of the elderly population. Considering the future epidemic of AD, prevention and treatment are important goals of ongoing research. However, a better understanding of AD pathophysiology must be accomplished to make this objective feasible. In this paper, we review some hot topics concerning AD pathophysiology that have an important impact on therapeutic perspectives. Hence, we have focused our attention on inflammation, cytokines, immune response, apolipoprotein E (APOE), cholesterol, oxidative stress, as well as exploring the related therapeutic possibilities, i.e., nonsteroidal antiinflammatory drugs, cytokine blocking antibodies, immunotherapy, diet, and curcumin.

The nutritional and clinical significance of lipid rafts.

PURPOSE OF REVIEW: Lipid rafts are potentially modifiable by diet, particularly (but not exclusively) by dietary fatty acids. This review examines the potential for dietary modification of raft structure and function in the immune system, brain and retinal tissue, the gut, and in cancer cells. RECENT FINDINGS: In-vitro and ex-vivo studies suggest that dietary n-3 polyunsaturated fatty acids (PUFAs) may exert immunosuppressive and anticancer effects through changes in lipid raft organization. In addition, gangliosides and cholesterol may modulate lipid raft organization in a number of tissues, and recent work has highlighted sphingolipids in membrane microdomains as potential targets for inhibition of tumor growth. The roles of fatty acids and gangliosides, especially in relation to lipid rafts, in cognitive development, age-related cognitive decline, psychiatric disorders, and Alzheimer's disease are poorly understood and require further investigation. The roles of lipid rafts in cancer, in microbial pathogenesis, and in insulin resistance are starting to emerge, and indicate compelling evidence for the growing importance of membrane microdomains in health and disease. SUMMARY: In-vitro and animal studies show that n-3 PUFAs, cholesterol, and gangliosides modulate the structure and composition of lipid rafts, potentially influencing a wide range of biological processes, including immune function, neuronal signaling, cancer cell growth, entry of pathogens through the gut barrier, and insulin resistance in metabolic disorders. The physiological, clinical, and nutritional relevance of these observations remains to be determined.

Physiological effects of concentrated barley beta-glucan in mildly hypercholesterolemic adults.

OBJECTIVE: Barley fiber rich in beta-glucans lowers serum lipids, but is difficult to incorporate into products acceptable to consumers. We investigated the physiological effects of two concentrated barley beta-glucans on cardiovascular disease (CVD) endpoints and body weight in human subjects. METHODS: Hypercholesterolemic men and women (n = 90) were randomly assigned to one of two treatments: low molecular weight (low-MW) or high molecular weight (high-MW) concentrated barley beta-glucan consumed as a daily supplement containing 6 grams beta-glucan/day. Fasting blood samples were collected at baseline and week 6 and analyzed for total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glucose, insulin, homocysteine and C-reactive protein (CRP). Dietary intakes, body weights, blood pressure, hunger ratings, and gastrointestinal symptoms were measured at baseline and 6 weeks. RESULTS: The only difference between treatments in lipid outcomes at week 6 was a reduction of the cholesterol/HDL ratio in the low-MW group and a small increase in the high-MW group. No changes were found in blood pressure, glucose, insulin, and gastrointestinal symptoms. Body weight decreased from baseline to 6 weeks in the high-MW group while body weight increased in the low-MW group. Levels of hunger decreased slightly in the low-MW group and decreased significantly in the high-MW group (P = 0.02) CONCLUSION: Overall, supplementation with isolated barley beta-glucans of different molecular weights had small effects on cardiovascular disease markers. Molecular weight of the barley fiber did alter effects on body weight with the high-MW fiber significantly decreasing body weight.

Adiposity and serum parameters in hamsters fed energy restricted diets supplemented or not with trans-10, cis-12 conjugated linoleic acid

Numerous studies have demonstrated that conjugated linoleic acid (CLA) modulatesbody composition, reducing body fat accumulation in various mammalianspecies. However, very few studies have been carried out to assess the effect of CLAon previously stored body fat. The aim of the present work was to analyse the effectivenessof trans-10,cis-12 CLA in improving alterations produced by high-fat feedingin body fat and serum parameters when it was included in an energy-restricteddiet. For this purpose male Syrian Golden hamsters were fed on high-fat diet for 7weeks in order to increase their body fat content, and a further 25% energy-restricteddiet supplemented or not with 0.5% trans-10,cis-12 CLA for 3 weeks. Adipose tissues,liver and gastrocnemious muscles were dissected and weighed. Adipocyte diameterand number were assessed in epididymal adipose tissue. Total cholesterol, triacylglycerols,non-esterified fatty acids and glucose were measured in serum. Threeweeks of energy restriction resulted in a reduction in body weight and white adiposetissue size in all anatomical locations, without changes in liver and gastrocnemiousmuscle weights. Epididymal adipocyte size was reduced, but total adipocyte numberremained unchanged. Serum cholesterol, triacylglycerols and glucose were significantlyreduced. No differences were observed between the restricted groups (controland CLA supplemented). In conclusion, under our experimental conditions, theaddition of trans-10,cis-12 CLA to the diet does not increase the benefits producedby energy restriction (AU)

No disponible

Serum iron and copper status and oxidative stress in severe and mild preeclampsia.

Our aim was to investigate parameters of iron and copper status and oxidative stress and antioxidant function in women with healthy pregnancy, mild and severe preeclampsia with a view to exploring the possible contribution of these parameters to the aetiology. Thirty healthy, 30 mild preeclamptic and 30 severe preeclamptic pregnant women were included. Serum and placental lipid peroxides, and serum vitamin E and total carotene levels were measured by colorimetric assay. Cholesterol, copper, iron, total iron binding capacity (TIBC), ceruloplasmin and transferrin concentrations were measured by commercially available procedures. Data were analysed statistically using one-way analysis of variance and Pearson correlation test. Logistic regression procedures were used to calculate odds ratios. Lipid peroxides in serum and placental tissue, and iron, copper and ceruloplasmin levels in serum were significantly increased, and transferrin, TIBC, vitamin E/total cholesterol and total carotene/total cholesterol ratios in serum were significantly decreased especially in women with severe preeclampsia. Significant correlations were detected between serum iron and lipid peroxides in serum and placental tissue and between serum iron and vitamin E/total cholesterol in severe preeclamptic pregnancy. Furthermore, there were significant correlations between serum malondialdehyde and ceruloplasmin and vitamin E/total cholesterol in women with severe preeclampsia, and changes in serum and placental lipid peroxides and serum iron concentrations were significantly associated with preeclampsia. In conclusion, ischaemic placental tissue may be a primary source of potentially toxic iron in preeclampsia and the released iron species may contribute to the aetiology and would exacerbate lipid peroxidation and endothelial cell injury, which may be abated by antioxidant supplementation.

The raft-promoting property of virion-associated cholesterol, but not the presence of virion-associated Brij 98 rafts, is a determinant of human immunodeficiency virus type 1 infectivity.

Lipid rafts are enriched in cholesterol and sphingomyelin and are isolated on the basis of insolubility in detergents, such as Brij 98 and Triton X-100. Recent work by Holm et al. has shown that rafts insoluble in Brig 98 can be found in human immunodeficiency virus type 1 (HIV-1) virus-like particles, although it is not known whether raft-like structures are present in authentic HIV-1 and it is unclear whether a virion-associated raft-like structure is required for HIV replication. Independently, it was previously reported that virion-associated cholesterol is critical for HIV-1 infectivity, although the specific requirement of virion cholesterol in HIV-1 was not examined. In the present study, we have demonstrated that infectious wild-type HIV-1 contains Brij 98 rafts but only minimal amounts of Triton X-100 rafts. To directly assess the functional requirement of virion-associated rafts and various features of cholesterol on HIV-1 replication, we replaced virion cholesterol with exogenous cholesterol analogues that have demonstrated either raft-promoting or -inhibiting capacity in model membranes. We observed that variable concentrations of exogenous analogues are required to replace a defined amount of virion-associated cholesterol, showing that structurally diverse cholesterol analogues have various affinities toward HIV-1. We found that replacement of 50% of virion cholesterol with these exogenous cholesterol analogues did not eliminate the presence of Brij 98 rafts in HIV-1. However, the infectivity levels of the lipid-modified HIV-1s directly correlate with the raft-promoting capacities of these cholesterol analogues. Our data provide the first direct assessment of virion-associated Brij 98 rafts in retroviral replication and illustrate the importance of the raft-promoting property of virion-associated cholesterol in HIV-1 replication.

[Effect of cholesterol in bile on cholecystokinin receptor in the gallbladder].

OBJECTIVE: To assess the effect of cholesterol in bile on cholecystokinin receptor (CCK-R) in the gallbladder. METHODS: One hundred Guinea pigs were randomly divided into four groups, 25 animals for each. The control group was fed a standard diet, and the cholesterol group fed a diet containing 2% cholesterol. After taking the 2% cholesterol diet for two weeks, the natural group persisted on the standard diet, and the treated group was perfused by traditional Chinese medicine. Serum cholecystokinin (CCK) level in the portal vein and maximal binding capacity (B(max)) and Kd of CCK-R in the gallbladder were measured in the four groups by RIA and RBA, and the concentrations of cholesterol in bile were also observed. RESULTS: Compared with the control group, after high-cholesterol feeding for two weeks, the gallbladder emptying rate [(65.83 +/- 7.32)% approximately (47.22 +/- 5.24)%] and B(max) of CCK-R [(60 +/- 27) approximately (32 +/- 13) fmol/mg protein] and in decreased fasting gallbladder volume (FV) [(0.89 +/- 0.26) approximately (1.34 +/- 0.61) cm(3)] and concentration of cholesterol [(0.44 +/- 0.11) approximately (0.60 +/- 0.13) mmol/L] in bile increased, but no change was in the serum CCK level and Kd of CCK-R in the cholesterol group. Compared with the natural group, after two-week in take of herb decoction of qingre lidan and liqi huoxue, FV [(1.27 +/- 0.60) approximately (0.90 +/- 0.27) cm(3)], RV [(0.85 +/- 0.45) approximately (0.32 +/- 0.12) cm(3)], FB [(0.92 +/- 0.35) approximately (0.73 +/- 0.21) cm(3)], RB [(0.76 +/- 0.34) approximately (0.29 +/- 0.08) cm(3)] in the treated group decreased significantly; but gallbladder emptying rate [(43.06 +/- 4.27)% approximately (67.01 +/- 6.82)%] increased significantly. The concentration of cholesterol in bile was lower in the treated group than in the natural group [(0.59 +/- 0.14) approximately (0.43 +/- 0.10) mmol/L], but no change was found in the serum CCK level. Bmax of CCK-R in the treated group increased significantly [(39 +/- 19) approximately (59 +/- 11) fmol/mg protein], Kd of CCK-R showed no significant changes between the treated group and natural group. CONCLUSION: High cholesterol in gallbladder bile causes defective muscle contraction by down-regulating CCK-R in the gallbladder, so the reduction of cholesterol concentration of bile may contribute to gallbladder contraction.

A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease.

Clinical, epidemiological, and laboratory studies suggest that cholesterol may play a role in the pathogenesis of Alzheimer's disease (AD). Transgenic mice exhibiting an Alzheimer's beta-amyloid phenotype were treated with the cholesterol-lowering drug BM15.766 and tested for modulation of beta-amyloid levels. BM15.766 treatment reduced plasma cholesterol, brain Abeta peptides, and beta-amyloid load by greater than twofold. A strong, positive correlation between the amount of plasma cholesterol and Abeta was observed. Furthermore, drug treatment reduced the amyloidogenic processing of the amyloid precursor protein, suggesting alterations in processing in response to cholesterol modulation. This study demonstrates that hypocholesterolemia is associated with reduced Abeta accumulation suggesting that lowering cholesterol by pharmacological means may be an effective approach for reducing the risk of developing AD.

Fish oil (n-3) polyunsaturated fatty acids beneficially affect biliary cholesterol nucleation time in obese women losing weight.

It has been reported that intake of (n-3) polyunsaturated fatty acids (PUFA) reduces the risk of coronary heart disease and decreases biliary cholesterol saturation in the bile of gallstone patients. We investigated the effect of n-3 PUFA on cholesterol saturation index (CSI) and nucleation time (NT) in obese subjects who were losing weight. This was a double-blind, placebo-controlled clinical trial. Obese women (n = 35) with a body mass index (BMI) > or = 30 kg/m(2), with no prior history of gallstones or cholecystectomy by ultrasound were first studied to ensure absence of stones or biliary sludge. The women were then assigned to a hypocaloric regimen [5.02 MJ (1200 kcal)/d] and to receive 1200 mg/d of ursodeoxycholic acid (UDCA), 11.3 g/d of (n-3) PUFA or a placebo for 6 wk. BMI, CSI and NT were recorded at baseline and at the end of the experimental period. BMI decreased 5.75 +/- 2.7%/mo (range, 1.5-12.42%/mo) during the experiment. The CSI did not change in any of the groups. Cholesterol NT decreased significantly in the UDCA and placebo groups, but not in the (n-3) PUFA group. None of the women had developed gallstones at 6 wk. These results suggest that (n-3) PUFA maintain the CSI and NT in obese women during rapid weight loss, which probably results in the prevention of cholesterol gallstone formation.

Polyunsaturated fatty acid regulation of gene expression.

Polyunsaturated fatty acids (PUFAs), specifically the n-3 and n-6 series, play a key role in the progression or prevention of human diseases such as obesity, diabetes, cancer, neurological and heart disease, mainly by affecting cellular membrane lipid composition, metabolism, signal-transduction pathways, and by direct control of gene expression. PUFAs show regulation of gene expression in several tissues, including brain, liver, heart, and adipose. Most recently, research has focused on identifying the mechanisms by which PUFAs regulate lipogenic gene expression. Research to date indicates that PUFA-mediated regulation of the genetic expression and proteolytic maturation of a group of transcription factors termed sterol regulatory element binding proteins (SREBPs) accounts for the suppression of hepatic lipogenic gene expression. However, our recent studies on the transcriptional regulation of the stearoyl-coenzyme A (CoA) desaturase gene, encoding a key enzyme in the cellular synthesis of monounsaturated fatty acids from saturated fatty acids indicates that PUFA can suppress gene transcription by a mechanism independent of SREBP maturation.