Persistent Müllerian duct syndrome due to anti-Müllerian hormone receptor 2 microdeletions: a diagnostic challenge.

The persistent Müllerian duct syndrome (PMDS) is defined by the persistence of Müllerian derivatives in an otherwise normally virilized 46,XY male. It is usually caused by mutations in either the anti-Müllerian hormone (AMH) or AMH receptor type 2 (AMHR2) genes. We report the first cases of PMDS resulting from a microdeletion of the chromosomal region 12q13.13, the locus of the gene for AMHR2. One case involved a homozygous microdeletion of five exons of the AMHR2 gene. In the second case, the whole AMHR2 gene was deleted from the maternally inherited chromosome. The patient's paternal allele carried a stop mutation, which was initially thought to be homozygous by Sanger sequencing. Diagnostic methods are discussed, with an emphasis on comparative genomic hybridization and targeted massive parallel sequencing.

SALL4 and NFATC2: two major actors of interstitial 20q13.2 duplication.

Interstitial duplication within the long arm of chromosome 20 is an uncommon chromosome structural abnormality. We report here the clinical and molecular characterization associated with pure 20q13.2 duplication in three unrelated patients. The most frequent clinical features were developmental delay, facial dysmorphism, cardiac malformation and skeletal anomalies. All DNA gains occurred de novo, ranging from 1.1 Mb to 11.5 Mb. Compared with previously reported conventional cytogenetic analyses, oligonucleotides array CGH allowed us to refine breakpoints and determine the genes of interest in the region. Involvement of SALL4 in cardiac malformations and NFATC2 gene disruption in both cardiac and skeletal anomalies are discussed.

Array comparative genomic hybridization analysis of small supernumerary marker chromosomes in human infertility.

Small supernumerary marker chromosomes (sSMC) are structurally abnormal chromosomes that cannot be unambiguously identified by conventional banding cytogenetics. This study describes four patients with sSMC in relation with infertility. Patient 1 had primary infertility. His brother, fertile, carried the same sSMC (patient 2). Patient 3 presented polycystic ovary syndrome and patient 4 primary ovarian insufficiency. Cytogenetic studies, array comparative genomic hybridization (CGH) and sperm analyses were compared with cases previously reported. sSMC corresponded to the 15q11.2 region (patients 1 and 2), the centromeric chromosome 15 region (patient 3) and the 21p11.2 region (patient 4). Array CGH showed 3.6-Mb gain for patients 1 and 2 and 0.266-Mb gain for patient 4. Sperm fluorescent in-situ hybridization analyses found ratios of 0.37 and 0.30 of sperm nuclei with sSMC(15) for patients 1 and 2, respectively (P < 0.001). An increase of sperm nuclei with disomy X, Y and 18 was noted for patient 1 compared with control and patient 2 (P < 0.001). Among the genes mapped in the unbalanced chromosomal regions, POTE B and BAGE are related to the testis and ovary, respectively. The implication of sSMC in infertility could be due to duplication, but also to mechanical effects perturbing meiosis.

Kinetics of gene expression and signaling in bovine cumulus cells throughout IVM in different mediums in relation to oocyte developmental competence, cumulus apoptosis and progesterone secretion.

In vitro maturation of oocytes is a crucial step in assisted reproductive technologies in cattle; however, the molecular mechanisms of cumulus contribution to oocyte developmental potential require more investigation. Based on transcriptomic data, we studied by using real-time RT-PCR and western blot in bovine cumulus cells, the kinetics of expression of several candidate genes involved in oxidative stress response, apoptosis, steroid metabolism and signal transmission throughout IVM. Phosphorylations of the components of the main signaling pathways were also analyzed. In addition, IVM was performed in different maturation mediums which influenced the cumulus apoptosis, progesterone secretion and oocyte developmental competence. Glutathione-S-transferase A1 (GSTA1) transcript and protein abundance significantly decreased throughout IVM progression. Similarly, transcript levels of FSH receptor and aromatase (CYP19A1) and protein levels of three steroidogenic enzymes (steroidogenic acute regulatory protein, cytochrome P450scc and 3-beta-hydroxysteroid dehydrogenase) decreased along with progression of maturation and especially since 10 hours of IVM. Expression of progesterone receptor (PGR) and clusterin (CLU) mRNA and phosphorylations of protein kinases AKT, MAPK P38 and SMAD2 were particularly increased at 10 hours of IVM. This expression pattern supposed the role of these factors during oocyte metaphase-I check point of meiosis. Levels of CLU, GSTA1 and FSHR transcripts were higher in 199 basic hormone-free medium as compared to the medium 199EM, enriched in gonadotropins and growth factors, in which we recorded the higher developmental rate and progesterone secretion. Higher phosphorylation levels of SMAD2, AKT and MAP kinase JNK1, but not of MAP kinases ERK1/ERK2 or P38, was positively correlated with oocyte developmental competence and progesterone secretion and negatively correlated with cumulus apoptosis rate. These factors and signaling pathways in cumulus cells are potentially involved in controlling different stages of oocyte nuclear maturation and acquirement of its developmental potential.

Habitual consumption of eggs does not alter the beneficial effects of endurance training on plasma lipids and lipoprotein metabolism in untrained men and women.

Changes in plasma lipid and apolipoprotein profiles were evaluated in 12 healthy, unfit subjects (VO(2peak) 39.1+/-2.8 ml.kg(-1).min(-1); 5 women, 7 men) at baseline and following endurance exercise training. The exercise protocol consisted of a 6-week endurance exercise training program (4-5 days week(-1); 60 min.session(-1); > or =65% HR(max)). Subjects were randomly assigned to consume an egg- (n=6; 12 eggs.week(-1)) or no-egg (n=6; 0 eggs.week(-1))-based, eucaloric, standardized diet for 8 weeks. Both diets were macronutrient balanced [60% carbohydrate, 30% fat, 10% protein (0.8 g.kg(-1).day(-1))] and individually designed for weight maintenance. Plasma lipids were measured twice within the same week at baseline and following exercise training. At baseline, subjects were normolipidemic with values of 163.9+/-41.8, 84.8+/-36.7, 60.6+/-15.4 and 93.1+/-52 mg dl(-1) for total cholesterol, LDL cholesterol and HDL cholesterol and triglyceride concentrations, respectively. A two-way ANOVA was used to analyze diet and exercise effects and interactions. In both groups, endurance exercise training resulted in a significant 10% increase in HDL-C (P<.05), a 19% decrease in Apo B concentrations (P<.05) and reductions in plasma CETP activity (P<.05). Plasma LDL-C decreased by 21% (P=.06). No main effects of diet or interactions with plasma lipids or Apo B concentrations were observed. These data demonstrate that endurance training improved the plasma lipid profiles of previously unfit, normolipidemic subjects independent of dietary cholesterol intake from eggs.

The effect of AMP-activated kinase activation on gonadotrophin-releasing hormone secretion in GT1-7 cells and its potential role in hypothalamic regulation of the oestrous cyclicity in rats.

Hypothalamic AMP-activated kinase (AMPK) is a key regulator of food intake in mammals. Its role in reproduction at the central level and, more precisely, in gonadotrophin-releasing hormone (GnRH) release has never been investigated. We showed that each subunit of AMPK is present in immortalised GnRH neurones (GT1-7 cells). Treatment with 5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (AICAR) and metformin, two activators of AMPK, increased dose-dependent and time-dependent phosphorylation of AMPKalpha atThr172 in GT1-7 cells. Phosphorylation of acetyl-coenzyme A carboxylase at ser79 also increased. Treatment with AICAR (5 mM) or metformin (5 mM) for 4 h inhibited GnRH release in the presence or absence of GnRH (10(-8) M). Specific AMPK inhibitor compound C completely eliminated the effects of AICAR or metformin on GnRH release. Finally, we determined the central effects of AICAR in vivo on food intake and oestrous cyclicity. Ten-week-old female rats received a 50 microg AICAR or a saline i.c.v. injection. We detected increased AMPK and acetyl-CoA carboxylase phosphorylation, specifically in the hypothalamus, 30 min after AICAR injection. Food intake was significantly higher (P < 0.05) in animals treated with AICAR than in animals injected with saline, 24 h after injection. This effect was abolished after 1 week. Moreover, during the 4 weeks following injection, the interval between two oestrous stages was significantly lower in the AICAR group than in the saline group. Our findings suggest that AMPK activation may act directly at the hypothalamic level to affect fertility by modulating GnRH release and oestrous cyclicity.

Intrahepatic fat accumulation and alterations in lipoprotein composition in obese adolescents: a perfect proatherogenic state.

OBJECTIVE: Among other metabolic consequences, a dyslipidemic profile often accompanies childhood obesity. In adults, type 2 diabetes and hepatic steatosis have been shown to alter lipoprotein subclass distribution and size; however, these alterations have not yet been shown in children or adolescents. Therefore, our objective was to determine the effect of hepatic steatosis on lipoprotein concentration and size in obese adolescents. RESEARCH DESIGN AND METHODS: Using fast magnetic resonance imaging, we measured intrahepatic fat content in 49 obese adolescents with normal glucose tolerance. The presence or absence of hepatic steatosis was determined by a threshold value for hepatic fat fraction (HFF) of 5.5%; therefore, the cohort was divided into two groups (HFF > or <5.5%). Fasting lipoprotein subclasses were determined using nuclear magnetic resonance spectroscopy. RESULTS: Overall, the high-HFF group had 88% higher concentrations of large VLDL compared with the low-HFF group (P < 0.001). Likewise, the high-HFF group had significantly higher concentrations of small dense LDL (P < 0.007); however, the low-HFF group had significantly higher concentrations of large HDL (P < 0.001). Stepwise multiple regression analysis revealed that high HFF was the strongest single correlate, accounting for 32.6% of the variance in large VLDL concentrations (P < 0.002). CONCLUSIONS: The presence of fatty liver was associated with a pronounced dyslipidemic profile characterized by large VLDL, small dense LDL, and decreased large HDL concentrations. This proatherogenic phenotype was strongly related to the intrahepatic lipid content.

Interethnic differences in muscle, liver and abdominal fat partitioning in obese adolescents.

The prevalence of insulin resistance and type 2 diabetes (T2D) in obese youth is rapidly increasing, especially in Hispanics and African Americans compared to Caucasians. Insulin resistance is known to be associated with increases in intramyocellular (IMCL) and hepatic fat content. We determined if there are ethnic differences in IMCL and hepatic fat content in a multiethnic cohort of 55 obese adolescents. We used (1)H magnetic resonance spectroscopy (MRS) to quantify IMCL levels in the soleus muscle, oral glucose tolerance testing to estimate insulin sensitivity, magnetic resonance imaging (MRI) to measure abdominal fat distribution. Liver fat content was measured by fast-MRI. Despite similar age and % total body fat among the groups, IMCL was significantly higher in the Hispanics (1.71% [1.43%, 2.0%]) than in the African-Americans (1.04% [0.75%, 1.34%], p = 0.013) and the Caucasians (1.2% [0.94%, 1.5%], p = 0.04). Liver fat content was undetectable in the African Americans whereas it was two fold higher than normal in both Caucasians and Hispanics. Visceral fat was significantly lower in African Americans (41.5 cm(2) [34.6, 49.6]) and was similar in Caucasians (65.2 cm(2) [55.9, 76.0]) and Hispanics (70.5 cm(2) [59.9, 83.1]). In a multiple regression analysis, we found that ethnicity independent of age, gender and % body fat accounts for 10% of the difference in IMCL. Our study indicates that obese Hispanic adolescents have a greater IMCL lipid content than both Caucasians and African Americans, of comparable weight, age and gender. Excessive accumulation of fat in the liver was found in both Caucasian and Hispanic groups as opposed to virtually undetectable levels in the African Americans. Thus, irrespective of obesity, there seem to be some clear ethnic differences in the amount of lipid accumulated in skeletal muscle, liver and abdominal cavity.

Effects of a carbohydrate-restricted diet with and without supplemental soluble fiber on plasma low-density lipoprotein cholesterol and other clinical markers of cardiovascular risk.

Carbohydrate-restricted diets (CRDs) promote weight loss, reductions in plasma triacylglycerol (TAG) levels, and increases in high-density lipoprotein cholesterol (HDL-C) levels but may cause undesirable low-density lipoprotein cholesterol (LDL-C) responses in some people. The objective of the present study was to determine the effect of adding soluble fiber to a CRD on plasma LDL-C and other traditionally measured markers of cardiovascular disease. Using a parallel-arm, double-blind, placebo-controlled design, 30 overweight and obese men (body mass index, 25-35 kg/m(2)) were randomly assigned to supplement a CRD with soluble fiber (Konjac-mannan, 3g/d) (n = 15) or placebo (n = 15). Plasma lipids, anthropometrics, body composition, blood pressure, and nutrient intake were evaluated at baseline and at 6 and 12 weeks. Compliance was excellent as assessed by 7-day weighed dietary records and ketonuria. Both groups experienced decreases in (P < .01) body weight, percent body fat, systolic blood pressure, waist circumference, and plasma glucose levels. After 12 weeks, HDL-C and TAG improved significantly in the fiber (10% and -34%) and placebo (14%, -43%) groups. LDL-C decreased by 17.6% (P < .01) at week 6 and 14.1% (P < .01) at week 12 in the fiber group. Conversely, LDL-C reductions were significant in the placebo group only after 12 weeks (-6.0%, P < .05). We conclude that although clearly effective at lowering LDL-C, adding soluble fiber to a CRD during active and significant weight loss provides no additional benefits to the diet alone. Furthermore, a CRD led to clinically important positive alterations in cardiovascular disease risk factors.

Adiponectin in childhood and adolescent obesity and its association with inflammatory markers and components of the metabolic syndrome.

CONTEXT: Adiponectin levels are lower in obese children and adolescents, whereas markers of inflammation and proinflammatory cytokines are higher. Hypoadiponectinemia may contribute to the low-grade systemic chronic inflammatory state associated with childhood obesity. OBJECTIVE: We investigated whether C-reactive protein (CRP), the prototype of inflammation, is related to adiponectin levels independently of insulin resistance and adiposity. DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOME MEASURES: In a multiethnic cohort of 589 obese children and adolescents, we administered a standard oral glucose tolerance test and obtained baseline measurements for adiponectin, plasma lipid profile, CRP, IL-6, and leptin. RESULTS: Stratifying the cohort into quartiles of adiponectin levels and adjusting for potential confounding variables, such as age, gender, ethnicity, body mass index z-score, pubertal status, and insulin sensitivity, the present study revealed that low levels of adiponectin are associated not only with higher CRP levels, but also with components of the metabolic syndrome, such as low high-density lipoprotein cholesterol and a high triglyceride-to-high-density-lipoprotein ratio. CONCLUSIONS: The link between adiponectin levels and a strong marker of inflammation, CRP, is independent of insulin resistance and adiposity in obese children and adolescents. Adiponectin may be one of the signals linking inflammation and obesity. Thus, adiponectin may function as a biomarker of the metabolic syndrome in childhood obesity.

Maintenance of the LDL cholesterol:HDL cholesterol ratio in an elderly population given a dietary cholesterol challenge.

We previously evaluated the responses to dietary cholesterol in children and young adults. In this study, the effects of dietary cholesterol on plasma lipids and LDL atherogenicity were evaluated in 42 elderly subjects (29 postmenopausal women and 13 men > 60 y old). Our exclusion criteria were diabetes, heart disease, and the use of reductase inhibitors. The study followed a randomized crossover design in which subjects were assigned to consume the equivalent of 3 large eggs (EGG) daily or the same amount of a cholesterol-free, fat-free egg substitute (SUB) for a 1-mo period. After a 3-wk washout period, subjects were assigned to the alternate treatment. The concentration of plasma cholesterol after the EGG period varied among subjects. When all subjects were evaluated, there were significant increases in LDL cholesterol (LDL-C) (P < 0.05) and HDL-C (P < 0.001) for both men and women during the EGG period, resulting in no alterations in the LDL-C:HDL-C or the total cholesterol:HDL-C ratios. In addition, the LDL peak diameter was increased during the EGG period for all subjects. In contrast, the measured parameters of LDL oxidation, conjugated diene formation, and LDL lag time did not differ between the EGG and the SUB periods. We conclude from this study that dietary cholesterol provided by eggs does not increase the risk for heart disease in a healthy elderly population.

Weight loss favorably modifies anthropometrics and reverses the metabolic syndrome in premenopausal women.

OBJECTIVE: To determine the effects of a weight loss program, including dietary modifications, increased physical activity and dietary supplement (L-carnitine or placebo) on anthropometrics, leptin, insulin, the metabolic syndrome (MS) and insulin resistance in overweight /obese premenopausal women. METHODS: Participants consumed a hypocaloric diet; 30% protein, 30% fat and 40% carbohydrate in addition to increasing number of steps/day. Carnitine supplementation followed a randomized double blind protocol. Protocol lasted for 10 weeks. Seventy subjects (35 in the control and 35 in the carnitine group) completed the intervention. Anthropometrics, plasma insulin and leptin concentrations and body composition were measured. The number of subjects with the MetSyn and insulin resistance, were assessed at baseline and post-intervention. RESULTS: Because there were no significant differences between the carnitine and the placebo groups for all measured parameters, participants were grouped together for all analysis. Subjects decreased total energy (-26.6%, p < 0.01) and energy from carbohydrate (-17.3%, p < 0.01) and increased energy from protein by 67% (p < 0.01) and number of steps/day (42.6%, p < 0.01). Body weight (-4.6%, p < 0.001), body mass index (-4.5%, p < 0.01), waist circumference (-6.5%, p < 0.01), total fat mass (-1.7%, p < 0.01), trunk fat mass (-2.0%, p < 0.01), insulin (- 17.9%, p < 0.01) and leptin (-5.9%, p < 0.05) decreased after the intervention. Ten of 19 participants with insulin resistance became insulin sensitive and 7 of 8 participants with the MetSyn no longer had the syndrome after the intervention. CONCLUSION: Moderate increases in physical activity and a hypocaloric/high protein diet resulted in multiple beneficial effects on body anthropometrics and insulin sensitivity. Realistic dietary and physical activity goals must be the focus of intervention strategies for overweight and obese individuals.

Cardioprotective effects of dietary polyphenols.

Dietary polyphenols have been shown to possess cardioprotective effects. For example, the most noted role of grape polyphenols is in the French Paradox, in which a diet high in saturated fat accompanied by regular consumption of red wine is associated with a low risk of coronary heart disease (CHD). Initially, the paradox was thought to be driven by the postulated major action of grape polyphenols in inhibiting LDL oxidation. Although many studies have shown inhibitory effects of polyphenols on LDL oxidation, there have been an equal number of studies that showed a null effect on this variable. Although there are contrasting viewpoints on the effects of polyphenols on LDL oxidation variables, there is increasing evidence that these compounds possess additional cardioprotective functions including altering hepatic cholesterol absorption, triglyceride assembly and secretion, the processing of lipoproteins in plasma, and inflammation. It is the purpose of this review to examine recent information on the multiple functions of dietary polyphenols, with an emphasis on grape polyphenols, in decreasing the risk of CHD by improving plasma lipid profiles and reducing inflammation.

JTT-130, a microsomal triglyceride transfer protein (MTP) inhibitor lowers plasma triglycerides and LDL cholesterol concentrations without increasing hepatic triglycerides in guinea pigs.

BACKGROUND: Microsomal transfer protein inhibitors (MTPi) have the potential to be used as a drug to lower plasma lipids, mainly plasma triglycerides (TG). However, studies with animal models have indicated that MTPi treatment results in the accumulation of hepatic TG. The purpose of this study was to evaluate whether JTT-130, a unique MTPi, targeted to the intestine, would effectively reduce plasma lipids without inducing a fatty liver. METHODS: Male guinea pigs (n = 10 per group) were used for this experiment. Initially all guinea pigs were fed a hypercholesterolemic diet containing 0.08 g/100 g dietary cholesterol for 3 wk. After this period, animals were randomly assigned to diets containing 0 (control), 0.0005 or 0.0015 g/100 g of MTPi for 4 wk. A diet containing 0.05 g/100 g of atorvastatin, an HMG-CoA reductase inhibitor was used as the positive control. At the end of the 7th week, guinea pigs were sacrificed to assess drug effects on plasma and hepatic lipids, composition of LDL and VLDL, hepatic cholesterol and lipoprotein metabolism. RESULTS: Plasma LDL cholesterol and TG were 25 and 30% lower in guinea pigs treated with MTPi compared to controls (P < 0.05). Atorvastatin had the most pronounced hypolipidemic effects with a 35% reduction in LDL cholesterol and 40% reduction in TG. JTT-130 did not induce hepatic lipid accumulation compared to controls. Cholesteryl ester transfer protein (CETP) activity was reduced in a dose dependent manner by increasing doses of MTPi and guinea pigs treated with atorvastatin had the lowest CETP activity (P < 0.01). In addition the number of molecules of cholesteryl ester in LDL and LDL diameter were lower in guinea pigs treated with atorvastatin. In contrast, hepatic enzymes involved in maintaining cholesterol homeostasis were not affected by drug treatment. CONCLUSION: These results suggest that JTT-130 could have potential clinical applications due to its plasma lipid lowering effects with no alterations in hepatic lipid concentrations.

Grape polyphenols exert a cardioprotective effect in pre- and postmenopausal women by lowering plasma lipids and reducing oxidative stress.

To evaluate the effects of grape polyphenols on plasma lipids, inflammatory cytokines, and oxidative stress, 24 pre- and 20 postmenopausal women were randomly assigned to consume 36 g of a lyophilized grape powder (LGP) or a placebo for 4 wk. The LGP consisted of 92% carbohydrate and was rich in flavans, anthocyanins, quercetin, myricetin, kaempferol, and resveratrol. After a 3-wk washout period, subjects were assigned to the alternate treatment for an additional 4 wk. The placebo consisted of an equal ratio of fructose and dextrose and was similar in appearance and energy content (554 kJ) to LGP. Plasma triglyceride concentrations were reduced by 15 and 6% in pre- and postmenopausal women, respectively (P < 0.01) after LGP supplementation. In addition, plasma LDL cholesterol and apolipoproteins B and E were lower due to LGP treatment (P < 0.05). Further, cholesterol ester transfer protein activity was decreased by approximately 15% with intake of LGP (P < 0.05). In contrast to these beneficial effects on plasma lipids, LDL oxidation was not modified by LGP treatment. However, whole-body oxidative stress as measured by urinary F(2)-isoprostanes was significantly reduced after LGP supplementation. LGP also decreased the levels of plasma tumor necrosis factor-alpha, which plays a major role in the inflammation process. Through alterations in lipoprotein metabolism, oxidative stress, and inflammatory markers, LGP intake beneficially affected key risk factors for coronary heart disease in both pre- and postmenopausal women.

Carbohydrate intake is correlated with biomarkers for coronary heart disease in a population of overweight premenopausal women.

The associations between macronutrient intake and plasma parameters associated with increased risk for coronary heart disease (CHD) were evaluated in 80 overweight premenopausal women. We hypothesized that higher carbohydrate intake would be associated with a more detrimental plasma lipid profile. Dietary data were collected using a validated food frequency questionnaire (FFQ). Plasma total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were determined from two fasting blood samples. In addition, selected apolipoproteins (apo) and LDL peak size were measured. Values for TC, TG and HDL were not in the range of risk classification; however, the mean values of LDL-C, 2.7 +/- 0.7 mmol/L, were higher than the current recommendations. Carbohydrate intake was positively associated with TG and apo C-III (P < .01) concentrations, and negatively associated with LDL diameter (P < .01). Participants were divided into low (<53% of energy) or high (> or = 53% energy) carbohydrate intake groups. Individuals in the <53% carbohydrate group consumed more cholesterol and total fat, but also had higher intake of polyunsaturated and monounsaturated fatty acids (SFAs). In contrast, subjects in the > or =53% group consumed higher concentrations of glucose and fructose than those in the low-carbohydrate (LC) group. In addition, subjects consuming <53% carbohydrate had lower concentrations of LDL-C and apo B (P < .01) and a larger LDL diameter (P < .05) than the > or =53% group. These results suggest that the lower LDL-C in the LC group may be related to both the amount of carbohydrate and the type of fatty acids consumed by these subjects.

SC-435, an ileal apical sodium co-dependent bile acid transporter (ASBT) inhibitor lowers plasma cholesterol and reduces atherosclerosis in guinea pigs.

Male Hartley guinea pigs were randomly allocated to one of four treatments, 10 guinea pigs per group, for 12 weeks. The control diet contained no ASBT inhibitor (ASBTi) or simvastatin. Low ASBTi (LowASBTi) and high ASBTi (HighASBTi) were monotherapies containing 0.03 g/100 g and 0.1 g/100 g of the ASBTi SC-435. Combination therapy (COMBO) was a combination therapy consisting of 0.03 g/100 g ASBTi and 0.05 g/100 g simvastatin. Based on food consumption, guinea pigs received 17.2 and 47.8 mg/kg per day ASBTi in the ASBTi groups or 13.7 mg/kg per day ASBTi and 21.4 mg/kg per day simvastatin in the COMBO group. The amount of cholesterol in each diet was 0.25 g/100 g. LDL cholesterol was 40 and 70% lower with the HighASBTi and COMBO treatments compared to controls. Plasma triglycerides (TG) were 70% lower with COMBO therapy while HDL cholesterol was 43-47% higher with all treatments. Hepatic free cholesterol was reduced 60-80% with all treatments. Cholesterol content in the aortic arch was reduced by 25 and 42% in the HighASBTi and COMBO groups. Fecal bile acids were increased by 2.5- and 4-fold with HighASBTi and COMBO treatments. These data suggest that the interruption in the enterohepatic circulation of bile acids by ASBTi and statin co-administration therapy cause a significant reduction in plasma cholesterol concentrations and attenuate the progression of atherosclerosis in guinea pigs.

Grape polyphenols decrease plasma triglycerides and cholesterol accumulation in the aorta of ovariectomized guinea pigs.

Female ovariectomized guinea pigs, a model for menopausal women, were fed either a control diet or a diet containing 10 g/100 g of a lyophilized grape preparation for 12 wk. The macronutrient composition of the grape preparation was: simple carbohydrates, 90 g/100 g; protein, 4 g/100 g; and dietary fiber, 6 g/100 g. Control and grape diets had the same composition except for the percentage of macronutrients provided by the grape preparation. Polyphenols were present in the grape preparation at 0.58 g/100 g and included flavans, anthocyanins, quercetin, myricetin, kaempferol and resveratrol. Dietary cholesterol was 0.33 g/100 g to raise plasma cholesterol concentrations and ensure the development of atherosclerosis. Plasma LDL cholesterol concentrations did not differ between groups, whereas plasma triglycerides and VLDL cholesterol were 39 and 50% lower, respectively in guinea pigs fed the grape diet compared with controls (P < 0.05). Significant modifications in LDL particles included 58 and 30% lower triglycerides and phospholipids, respectively (P < 0.0001). Hepatic acyl CoA:cholesteryl acyltransferase activity was 27% lower (P < 0.05) in the grape diet-fed group compared with controls. In addition, concentrations of cholesterol in the aorta were 33% lower (P < 0.05) in guinea pigs fed the grape diet. These results suggest that grape intake in ovariectomized guinea pigs alters hepatic cholesterol metabolism, which may affect VLDL secretion rates and result in less accumulation of cholesterol in the aorta.