Increased Serum Triglyceride Levels Research Articles

Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels

The metabolic syndrome, a common disorder including glucose intolerance and dyslipidemia, poses a major public health issue. Patients with high blood lipids, such as triglycerides, are at high risk in developing atherosclerotic cardiovascular diseases. To identify genes involved in metabolism, we performed RNA-seq experiments on the liver and fat in mice treated with a high-fat diet or fasting, and identified Gm6484 (named Lipasin) as a novel nutritionally regulated gene. Human LIPASIN is liver specific, while the mouse one is enriched in the liver and fat, including both brown and white adipose tissues. Obesity increases liver Lipasin, whereas fasting reduces its expression in fat. ANGPTL3 (Angiopoietin-like 3) and ANGPTL4 are critical regulators of blood lipids. LIPASIN shares homology with ANGPTL3’s N-terminal domain that is needed for lipid regulation, and with ANGPTL4’s N-terminal segment that mediates lipoprotein lipase (LPL) binding. Lipasin overexpression by adenoviruses in mice increases serum triglyceride levels, and a recombinant Lipasin inhibits LPL activity. Therefore, a potential mechanism for Lipasin-mediated triglyceride elevation is through reduced triglyceride clearance by LPL inhibition. Lipasin is thus a novel nutritionally-regulated liver-enriched factor that plays a role in lipid metabolism.

Psoriasis: it's more than just the skin

Journal of Lipid Research Volume 53, 2012 1427 Psoriasis is a skin disease that is accompanied by systemic infl ammation and is one of the most common infl ammatory disorders, estimated to effect between 1 and 3% of the population ( 1 ). It is characterized by epidermal hyperproliferation and dermal infl ammation. The etiology of psoriasis is unknown but genetic factors play a role. Psoriasis may begin at any age but has two peak periods of onset: between 15 and 25 and between 50 to 60 years of age. In many patients, psoriasis affects only a small area of the skin (<2% of body surface area) whereas in other patients, the disease can be quite severe, affecting a large portion of the skin. The cutaneous manifestations lead to considerable morbidity and the emotional burden of severe psoriasis has been shown to be similar to that seen in patients with cancer, diabetes, and heart disease. However, it is important to recognize that psoriasis is associated with systemic metabolic disorders including an increased prevalence of the metabolic syndrome, obesity, diabetes, dyslipidemia, and cardiovascular disease (CVD) ( 2 ‐ 4 ). The increased risk of CVD in patients with psoriasis was fi rst reported by McDonald and Calabresi in 1978 ( 5 ). They observed that patients with psoriasis had a 2.2-fold increase in CVD compared with controls. Since then, a large number of additional epidemiological studies have also shown that the risk of CVD is increased in patients with psoriasis [see Tobin et al. ( 4 ) for an excellent review of the literature] ( 2 ‐ 5 ). Of note psoriasis still conferred an increased risk even when the studies controlled for the usual CVD risk factors such as age, sex, diabetes, hypertension, hyperlipidemia, smoking, and obesity, implying that psoriasis causes abnormalities that increase the risk of CVD that are not dependent on the usual risk factors ( 2 ‐ 4 ). Moreover, studies have suggested that the more severe the psoriasis the greater the risk of CVD. Further, supporting the link of psoriasis with atherosclerosis are studies showing that patients with psoriasis have an increase in coronary artery calcium measured by CT and carotid intima media thickness measured by ultrasound ( 6 ‐ 8 ). A very large number of studies have compared serum lipid levels in patients with psoriasis to control subjects ( 2 ‐ 4 ). Most of these reports included only a small number

Effect of Calcium-vitamin D Supplementation on Metabolic Profiles in Pregnant Women at Risk for Pre-eclampsia: A Randomized Placebo-controlled Trial

Increased metabolic profiles during pregnancy are associated with an increased risk of maternal and neonatal morbidity and remain a significant medical challenge. To our knowledge, no reports are available indicating the effects of calcium-vitamin D supplementation on metabolic profiles among pregnant women at risk for pre-eclampsia. This study was designed to determine the effects of consumption calcium-vitamin D supplements on metabolic profiles among Iranian pregnant women at risk for pre-eclampsia. This randomized single-blind controlled clinical trial was performed among 49 pregnant women at risk for pre-eclampsia, primigravida, aged 18-35 year old who were carrying singleton pregnancy at their third trimester. Subjects were randomly assigned to consume the placebo (n = 25) or calcium-vitamin D supplements (n = 24) for 9 weeks. Calcium-vitamin D supplements were containing 500 mg carbonate calcium plus 200 IU vitamin D3. Fasting blood samples were taken at baseline and after 9 week intervention to measures of Fasting Plasma Glucose (FPG) and serum lipid profiles. Consumption of calcium-vitamin D supplements resulted in decreased FPG and serum triglycerides levels as compared to the placebo (-9.1 vs. 0.5 mg dL(-1); p = 0.03, -11.7 vs. 49.9 mg dL(-1); p = 0.001, respectively). No significant differences were found comparing calcium-vitamin D supplements and the placebo in terms of their effect on serum total-, HDL-, LDL-cholesterol levels. Within-group differences in the placebo group revealed a significant increase in serum triglycerides levels (+49.9 mg dL(-1), p < 0.0001). In conclusion, consumption of calcium-vitamin D supplements for 9 weeks during pregnancy among pregnant women at risk for pre-eclampsia resulted in decreased FPG and serum triglycerides levels as compared to the placebo group, but could not affect serum total-, HDL-, LDL-cholesterol levels.

The Relationship between Serum Lipids and Breast Cancer in Libya

Background: Carcinoma breast is one of the major surgical problems in Libya, particularly in younger female subjects. Since it is a commonly encountered health risk, it is important to know the etiology and associated related factors of breast cancer in Libya. There are conflicting reports regarding the association between the dietary lipids and serum lipid profiles and breast cancer. It is a fact that local dietary habits, environmental factors along with genetic predisposition play a role in the evolution of breast cancer. The present study was undertaken to identify whether there is such an association between alterations in lipid profile in carcinoma breast in a local Libyan subjects. Material and methods: A total of 40 patients with various stages of breast cancer who were being treated at the department of surgery, 7th October hospital, Benghazi, Libya during 2009 and 2010 were recruited in the present study. Twenty one healthy volunteers were included as controls. These patients were categorized according to age, pre or post menopausal status and body mass index with their respective controls. Serum lipid profile was performed in all the cases and control groups using fasting blood samples. Total cholesterol, HDL-cholesterol and Triglycerides were measured by standard kit methods and LDL cholesterol was calculated using Fried Wald’s formula. Results: Serum total cholesterol and HDL cholesterol have been observed to be significantly elevated in patients with carcinoma breast when compared with those of controls (p=0.0046 and 0.004 respectively). However, the serum levels of LDL cholesterol and triglycerides did not show any significant alteration between that of the cases studied and the controls (p=0.42 and 0.092 respectively). In the case of premenopausal women, there is a significant rise of total cholesterol (p=0.0186) and HDL cholesterol (p=0.0031) whereas serum triglycerides (p=0.335) and LDL cholesterol (p=0.2617) had not shown any statistically significant variation. Furthermore, in the postmenopausal group, there is a significant elevation of serum triglycerides (p=0.0094), total cholesterol (p=0.0238) and HDL cholesterol (p=0.0457) but LDL cholesterol had not shown any significant variation. There is a significant variation between the triglyceride levels of postmenopausal women and the premenopausal women (p=0.0298). Conclusion: This preliminary study has shown a significant alteration in serum lipid profile of breast cancer patients in the local Libyan female population. The interesting observation of high levels of HDL cholesterol in the patients needs further evaluation by extending the investigation further on and also extending the study on larger study group. Postmenopausal women have shown an increase in serum triglycerides levels, with an increase observed in serum total cholesterol and HDL cholesterol levels when compared to that of premenopausal women

Association of Serum 25-Hydroxyvitamin D Levels with Markers for Metabolic Syndrome in the Elderly: A Repeated Measure Analysis

The purpose of current study was to investigate associations of serum 25-hydroxyvitamin D (OHVD) levels with markers for metabolic syndrome in elderly Koreans. We conducted a panel study on 301 individuals over 60 yr old in Seoul, Korea, and repeatedly measured serum OHVD, glucose, insulin, and lipid levels. Mixed effect model and generalized estimating equations were used to investigate relationships between serum OHVD levels with marker levels for metabolic syndrome and each of its categories. Of all subjects, 76.6% were vitamin D deficient (< 50 nM) and 16.9% were insufficient (< 75 nM). Inverse association was demonstrated between serum OHVD levels and insulin (P = 0.004), triglyceride (P = 0.023) and blood pressure (systolic blood pressure: P = 0.002; diastolic blood pressure: P < 0.001). Vitamin D deficiency was found to increase risk of 'hypertriglyceridemia' category of metabolic syndrome (odds ratio: 1.73, 95% confidence interval: 1.13-2.66). In conclusion, we found from our repeated measure analysis that decreasing serum OHVD levels are associated with increasing insulin resistance, increasing serum triglyceride levels and increasing blood pressure in elderly Koreans, and confirmed on the risk of 'hypertriglyceridemia' in vitamin D deficient subjects.

Reduction of Insulin Signaling Upregulates Angiopoietin-like Protein 4 Through Elevated Free Fatty Acids in Diabetic Mice

Angiopoietin-like protein 4 (Angptl4) is thought to cause an increase in serum triglyceride levels. In the present study, we elucidated Angptl4 expression in the mouse models of type 1 and type 2 diabetes mellitus, and investigated the possible mechanisms involved. Type 1 diabetes was induced in C57BL/6 J mice by treating them with streptozotocin (STZ). Type 2 diabetes was induced by feeding the mice a high-fat diet (HFD) for 18 weeks. The levels of Angptl4 mRNA expression in liver, white adipose tissue (WAT), and brown adipose tissue (BAT) were found to increase in the STZ diabetic mice relative to control mice. This effect was attenuated by insulin administration. In the HFD diabetic mice, the Angptl4 mRNA expression levels were increased in liver, WAT, and BAT. Treatment with metformin for 4 weeks attenuated the increased levels of Angptl4 mRNA. Fatty acids (FAs) such as palmitate and linoleate induced Angptl4 mRNA expression in H4IIE hepatoma cells and 3T3-L1 adipocytes. Treatment with insulin but not metformin attenuated FA-induced Angptl4 mRNA expression in H4IIE. Both insulin and metformin did not influence the effect of FAs in 3T3-L1 cells. These observations demonstrated that Angptl4 mRNA expression was increased through the elevated free FAs in diabetic mice.

Metabolic Effects of the Ingestion of Different Fructose Sources in Rats

Fructose is a simple carbohydrate that should be ingested in a restricted manner. However, current data suggest increased daily consumption of fructose which may lead to an increased incidence of diseases such as obesity, diabetes and co-morbidities associated with excess weight. Thus, the objective of the present study was to assess the effect of the ingestion of different fructose sources on weight gain, glycemia and serum triglyceride levels in rats. The study was conducted on male Wistar rats divided into 5 groups according to the source and concentration of fructuse (ingested AD LIBITUM in liquid form). Drink intake was increased and chow consumption was reduced in all groups compared to control ( P<0.05). The animals of the groups receiving 10 and 20% fructose solutions showed increased triglyceride levels and the 20% group also showed weight gain. The exaggerate consumption of fructose promotes a reduced consumption of chow, an increase in serum triglyceride levels, and weight gain in some animals.

Early antenatal serum lipid levels and the risk of pre-eclampsia in Trinidad and Tobago

Objective: To determine the lipid levels in early pregnancy and the risk for pre-eclampsia in a Trinidad population.Methods: Prospective cohort study comprised 156 pregnant women attending antenatal clinic visits prior to 20 weeks at an average of 14 weeks. Blood samples were analysed for lipid levels. Of which 102 participants were followed until delivery and were monitored for pre-eclampsia. Data was analysed using univariate linear and stepwise logistic regression analysis.Results: In the study 11 women developed pre-eclampsia and 91 remained normal. Mean triglyceride levels were found significantly higher in the pre-eclampsia group (p = 0.001). Mean HDL levels were low and LDL/HDL ratios were high in pre-eclampsia group. Women with triglycerides above 130 mg/dL had increased risk of pre-eclampsia (adjusted OR 14.046; 95% CI 1.254–157.334) compared with those with triglycerides levels 91 mg/dL or less.Conclusion: Increased serum triglyceride levels in early pregnancy before 20 weeks are associated with pre-eclampsia.

Perfil hematólogico e características das fezes de equinos consumindo dietas hiperlipidêmicas

Objetivou-se avaliar os parâmetros sanguíneos, o consumo de matéria seca e as características fecais de equinos alimentados com dietas hiperlipidêmicas. Foram utilizados 15 equinos em delineamento experimental inteiramente casualizado, com três tratamentos e cinco repetições. As dietas utilizadas foram: dieta sem inclusão de óleo de soja (controle); dieta com inclusão de 8,5% de óleo de soja; dieta com inclusão de 19,5% de óleo de soja. O ensaio teve duração de 34 dias, sendo 30 dias de adaptação dos equinos às dietas e quatro dias de coleta de amostras. As amostras sanguíneas para avaliação hematológica e bioquímica foram coletadas no 34° dia, as características das fezes foram avaliadas no 33° e no 34° dia do ensaio e, a partir do 30° dia, o consumo de matéria seca (CMS) foi avaliado. Os equinos alimentados com as dietas hiperlipidêmicas apresentaram aumento no número de eritrócitos e redução no volume corpuscular médio (P&lt;0,05). O nível de hemoglobina dos equinos avaliados diferiu (P&lt;0,05) somente entre os animais que consumiram as dietas de controle e com inclusão de 8,5% de óleo de soja, com menor valor na dieta de controle de 9,5d dL-1. A inclusão de 19,5% de óleo de soja na dieta elevou os níveis séricos de triglicerídios nos equinos. Houve redução no CMS diário de 1,9 e 2,8kg, nos equinos alimentados com as dietas com 8,5 e 19,5% de óleo de soja em relação à dieta de controle de 9,0kg MS. A produção fecal diária reduziu em 0,7 e 1,1kg MS, nos equinos alimentados com as dietas com 8,5 e 19,5% de óleo de soja, respectivamente, em relação à dieta de controle de 3,4kg MS. A utilização de dietas hiperlipidêmicas para equinos com inclusão de óleo de soja possibilita a redução do consumo dietético e o aumento da disponibilidade plasmática de triglicerídeos sem a ocorrência de diarreias ou alteração das características das fezes.

Akt2 Is Required for Hepatic Lipid Accumulation in Models of Insulin Resistance

Insulin drives the global anabolic response to nutrient ingestion, regulating both carbohydrate and lipid metabolism. Previous studies have demonstrated that Akt2/protein kinase B is critical to insulin's control of glucose metabolism, but its role in lipid metabolism has remained controversial. Here, we show that Akt2 is required for hepatic lipid accumulation in obese, insulin-resistant states induced by either leptin deficiency or high-fat diet feeding. Lep(ob/ob) mice lacking hepatic Akt2 failed to amass triglycerides in their livers, associated with and most likely due to a decrease in lipogenic gene expression and de novo lipogenesis. However, Akt2 is also required for steatotic pathways unrelated to fatty acid synthesis, as mice fed high-fat diet had reduced liver triglycerides in the absence of hepatic Akt2 but did not exhibit changes in lipogenesis. These data demonstrate that Akt2 is a requisite component of the insulin-dependent regulation of lipid metabolism during insulin resistance.

The Metabolic Syndrome

The metabolic syndrome (MS) is a cluster of metabolic derangements that are associated with primary disturbances in adipose tissue. Abnormal visceral fat accumulates from physical inactivity and excess calories in genetically susceptible individuals. This increased adipocyte mass acts as an endocrine organ and communicates with other organ systems via increases in inflammatory cytokines. The resulting disorders define MS as increased waist circumference, decreased serum high-density lipoprotein, and increased serum triglyceride levels, hypertension, and insulin resistance. MS accounts for the majority of cardiovascular disease risk in the U.S. population. Dietary interventions, such as the Mediterranean diet, have been shown to improve these metabolic derangements. Many substances found in these diets are being investigated as specific therapies for MS, and when scientific substantiation is lacking, they may be considered as part of complementary and alternative medicine (CAM). However, as scientific evidence accumulates, these CAM treatments may become part of conventional medicine. This review will scrutinize the emerging evidence behind many, though not all, CAM treatments currently thought to target the various derangements found in MS.

Dietary Patterns Are Associated with Metabolic Syndrome in Adult Samoans ,

The prevalence of metabolic syndrome has reached epidemic levels in the Samoan Islands. In this cross-sectional study conducted in 2002–2003, dietary patterns were described among American Samoan (n = 723) and Samoan (n = 785) adults (≥18 y) to identify neo-traditional and modern eating patterns and to relate these patterns to the presence of metabolic syndrome using Adult Treatment Panel III criteria. The neo-traditional dietary pattern, similar across both polities, was characterized by high intake of local foods, including crab/lobster, coconut products, and taro, and low intake of processed foods, including potato chips and soda. The modern pattern, also similar across both polities, was characterized by high intake of processed foods such as rice, potato chips, cake, and pancakes and low intake of local foods. The neo-traditional dietary pattern was associated with significantly higher serum HDL-cholesterol in American Samoa (P-trend = 0.05) and a decrease in abdominal circumference in American Samoa and Samoa (P-trend = 0.004 and 0.01, respectively). An inverse association was found with metabolic syndrome, although it did not reach significance (P = 0.23 in American Samoa; P = 0.13 in Samoa). The modern pattern was significantly positively associated with metabolic syndrome in Samoa (prevalence ratio = 1.21 for the fifth compared with first quintile; 95% CI: 0.93.1.57; P-trend = 0.05) and with increased serum triglyceride levels in both polities (P < 0.05). Reduced intake of processed foods high in refined grains and adherence to a neo-traditional eating pattern characterized by plant-based fiber, seafood, and coconut products may help to prevent growth in the prevalence of metabolic syndrome in the Samoan islands.

Hiperglicerolemia, una seudohipertrigliceridemia: A propósito de un niño de 6 años de edad

Recent recommendations from the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults, considered that an increase in serum triglyceride levels is an independent risk factor for coronary heart disease. Most enzymatic methods used in routine laboratories do not involve a glycerol blank and determine both glycerol and triglycerides. Patients with glycerol-kinase deficiency or decreased ability to oxidize glycerol may be diagnosed with a pseudo-hypertriglyceridemia. We report a case of a child with a pseudo hypertriglyceridemia (falsely elevated triglycerides) due to a hyperglycerolemia.

The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress

The nuclear receptor constitutive androstane receptor (CAR) (NR1I3) regulates hepatic genes involved in xenobiotic detoxification as well as genes involved in energy homeostasis. We provide data that extend the role of CAR to regulation of serum triglyceride levels under conditions of metabolic/nutritional stress. The typically high serum triglyceride levels of ob/ob mice were completely normalized when crossed onto a Car(-/-) (mice deficient for the Car gene) genetic background. Moreover, increases in serum triglycerides observed after a high-fat diet (HFD) regime were not observed in Car(-/-) animals. Conversely, pharmacological induction of CAR activity using the selective mouse CAR agonist TCPOBOP during HFD feeding resulted in a CAR-dependent increase in serum triglyceride levels. A major regulator of hepatic fatty oxidation is the nuclear receptor PPARalpha (NR1C1). The expression of peroxisome proliferator-activated receptor alpha (PPARalpha) target genes was inversely related to the activity of CAR. Consistent with these observations, Car(-/-) animals exhibited increased hepatic fatty acid oxidation. Treatment of mice with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) significantly decreased expression of PPARalpha mRNA as well as Cyp4a14, CPT1alpha, and cytosolic Acyl-CoA thioesterase (CTE) in the liver. These data have implications in disease therapy such as for diabetes and nonalcoholic steatohepatitis (NASH).

Apolipoprotein E4 allele influences the response of plasma triglyceride levels to tamoxifen in breast cancer patients

Background Apolipoprotein E4 (APOE4) allele is an important risk factor for breast cancer and affects clearance of chylomicron remnants. Tamoxifen therapy increases serum triglyceride levels and sometimes inducing severe hypertriglyceridemia in breast cancer patients. Methods Thirty-three women with breast cancer were recruited to examine the APOE polymorphism and fasting plasma lipid profiles before and after tamoxifen treatment for 6 months. Results We found that plasma lipid profiles changed in accordance with the APOE4 allele after tamoxifen treatment for 6 months. Especially plasma triglyceride levels significantly decreased in the APOE4-positive patients ( p = 0.025), while there was no change in APOE4-negative patients ( p = 0.189). The total plasma cholesterol levels were reduced in APOE-4 positive patients after 6-month tamoxifen treatment ( p = 0.014). The levels of plasma low density lipoprotein cholesterol and high density lipoprotein cholesterol significantly decreased in both APOE4-negative and APOE4-positive patients. Conclusions These findings indicate that the effects of tamoxifen on plasma triglyceride levels are modified by APOE polymorphism. Breast cancer patients with APOE4 allele have low plasma triglyceride levels when receiving tamoxifen therapy. Therefore, we suggest that APOE gene polymorphism is a critical validation before tamoxifen treatment in breast cancer patients.

The Relationship Between Nontraditional Risk Factors and Outcomes in Individuals With Stage 3 to 4 CKD

Chronic kidney disease is associated with increased risk for cardiovascular disease and mortality. Both traditional and nontraditional cardiovascular disease risk factors may contribute. Cohort. Community-based adult population of the Atherosclerosis Risk in Communities and Cardiovascular Health Studies with estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m(2). Nontraditional cardiovascular disease risk factors, including body mass index, diastolic blood pressure, and triglyceride, albumin, uric acid, fibrinogen, C-reactive protein, and hemoglobin levels. Composite of myocardial infarction, stroke, and all-cause mortality. Secondary outcomes included individual components of the composite. Of 1,678 individuals with decreased eGFR (mean, 51.1 +/- 8.5 mL/min/1.73 m(2)), 891 (53%) reached the composite end point during a median follow-up of 108 months; 23% had a cardiac event, 45% died, and 14% experienced a stroke. Serum albumin level less than 3.9 g/dL (hazard ratio, 0.68 for every 0.3-g/dL decrease; 95% confidence interval, 0.60 to 0.77), increased serum triglyceride level (hazard ratio, 1.07 for every 50-mg/dL increase; 95% confidence interval, 1.02 to 1.12), C-reactive protein level (hazard ratio, 1.15 per log-unit increase; 95% confidence interval, 1.07 to 1.24), and fibrinogen level (hazard ratio, 1.12 per 50-mg/dL increase; 95% confidence interval, 1.07 to 1.18) independently predicted composite events. Both decreased (<14.5 g/dL) and increased (>14.5 g/dL) hemoglobin levels predicted composite events. Serum albumin level less than 3.9 g/dL and increased serum fibrinogen level independently predicted cardiac events. For serum albumin and hemoglobin levels, the relationship with composite and mortality outcomes was nonlinear (P < 0.001). Single assessment of eGFR. No albuminuria data. Several nontraditional cardiovascular disease risk factors predict adverse outcomes in individuals with stage 3 to 4 chronic kidney disease. The relationship between risk factors and outcomes is often nonlinear.

Bicyclol, a synthetic dibenzocyclooctadiene derivative, decreases hepatic lipids but increases serum triglyceride level in normal and hypercholesterolaemic mice

Bicyclol is used for the treatment of chronic hepatitis B in China. In this study, the effects of bicyclol (100 or 300 mg kg(-1), p.o.) on serum and liver lipid contents were investigated in both normal and experimentally induced hypercholesterolaemic mice. Hypercholesterolaemia was induced by either oral administration of cholesterol/bile salt or feeding a diet containing lard/cholesterol. Daily administration of bicyclol for 7 days dose-dependently increased the serum triglyceride level (29-80%) but slightly decreased the hepatic total cholesterol level (12-17%) in normal mice. Co-administration of bicyclol with cholesterol/bile salt decreased the hepatic triglyceride and total cholesterol levels (7-15% and 25-31%, respectively), when compared with the drug-untreated and cholesterol/bile salt-treated group. Bicyclol treatment for 7 days decreased hepatic triglyceride (5-76%) and total cholesterol (5-48%) levels in mice fed with high-fat/cholesterol diet. In contrast, bicyclol treatment increased the serum triglyceride level (18-77%) in mice treated with cholesterol/bile salt or fed with high-fat/cholesterol diet. Bicyclol treatment also caused an increase in hepatic index of normal and hypercholesterolaemic mice (3-32%). The results indicate that bicyclol treatment can invariably decrease hepatic lipid levels and increase serum triglyceride levels in normal and hypercholesterolaemic mice.

The Cholesterol-Raising Factor from Coffee Beans, Cafestol, as an Agonist Ligand for the Farnesoid and Pregnane X Receptors

Cafestol, a diterpene present in unfiltered coffee brews such as Scandinavian boiled, Turkish, and cafetière coffee, is the most potent cholesterol-elevating compound known in the human diet. Several genes involved in cholesterol homeostasis have previously been shown to be targets of cafestol, including cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid biosynthesis. We have examined the mechanism by which cafestol elevates serum lipid levels. Changes in several lipid parameters were observed in cafestol-treated APOE3Leiden mice, including a significant increase in serum triglyceride levels. Microarray analysis of these mice identified alterations in hepatic expression of genes involved in lipid metabolism and detoxification, many of which are regulated by the nuclear hormone receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR). Further studies demonstrate that cafestol is an agonist ligand for FXR and PXR, and that cafestol down-regulates expression of the bile acid homeostatic genes CYP7A1, sterol 12alpha-hydroxylase, and Na(+)-taurocholate cotransporting polypeptide in the liver of wild-type but not FXR null mice. Cafestol did not affect genes known to be up-regulated by FXR in the liver of wild-type mice, but did increase expression of the positive FXR-target genes intestinal bile acid-binding protein and fibroblast growth factor 15 (FGF15) in the intestine. Because FGF15 has recently been shown to function in an enterohepatic regulatory pathway to repress liver expression of bile acid homeostatic genes, its direct induction in the gut may account for indirect effects of cafestol on liver gene expression. PXR-dependent gene regulation of cytochrome P450 3A11 and other targets by cafestol was also only seen in the intestine. Using a double FXR/PXR knockout mouse model, we found that both receptors contribute to the cafestol-dependent induction of intestinal FGF15 gene expression. In conclusion, cafestol acts as an agonist ligand for both FXR and PXR, and this may contribute to its impact on cholesterol homeostasis.

Low serum testosterone in men is inversely associated with non-fasting serum triglycerides: The Tromsø study

ObjectiveTo study the relationships between endogenous testosterone, sex hormone-binding globulin (SHBG) and serum lipids in non-fasting men. MethodsWe performed a cross-sectional study in 1274 men without known cardiovascular disease who participated in a population-based study, the 1994/1995 Tromsø study. Anthropometric characteristics were measured and questionnaires regarding lifestyle and medical history were completed. Non-fasting blood samples were drawn between 08.00 and 16.00h, and total testosterone, SHBG, triglycerides (TG), total cholesterol (TC) and high-density lipoprotein (HDL) were analyzed. ResultsIn stratified analyses based on sampling time, a linear increase in serum TG levels was found in men with total testosterone levels below the 50th percentile during the day (p for trend=0.004). In contrast, serum triglycerides did not change during the day in men with testosterone levels above the 50th percentile. In regression analyses, total testosterone and SHBG were inversely and independently associated with TG (p<0.001 and p<0.001 respectively), and positively and independently associated with HDL (p=0.005 and p<0.001, respectively). Men with an unfavorable lipid profile (HDL <0.90 and TG >1.8) had significantly lower levels of total testosterone and SHBG (p=0.004 and p<0.001, respectively) in age and BMI adjusted analyses, compared to men with a normal lipid profile. ConclusionsLow serum total testosterone was associated with a linear increase in serum TG during the day, and was independently associated with an unfavorable lipid profile. Our findings may indicate that low total testosterone is associated with impaired TG metabolism in men.

Tumor necrosis factor and interleukin 1 decrease RXR α, PPAR α, PPAR γ, LXR α, and the coactivators SRC-1, PGC-1 α, and PGC-1 β in liver cells

During the acute phase response, cytokines induce marked alterations in lipid metabolism including an increase in serum triglyceride levels and a decrease in hepatic fatty acid oxidation, in bile acid synthesis, and in high-density lipoprotein levels. Here we demonstrate that tumor necrosis factor (TNF) and interleukin 1 (IL-1), but not IL-6, decrease the expression of retinoid X receptor α (RXR α), peroxisome proliferator–activated receptor α (PPAR α), PPAR γ, liver X receptor α (LXR α), and coactivators PPAR γ coactivator 1 α (PGC-1 α), PGC-1 β, and steroid receptor coactivator 1 (SRC-1) in Hep3B human hepatoma cells. In addition, treatment of mice with TNF and IL-1 also decreased RXR α, PPAR α, PPAR γ, LXR α, and PGC-1 α messenger RNA (mRNA) levels in the liver. These decreases were accompanied by reduced binding of nuclear extracts to RXR, PPAR, and LXR response elements and decreased luciferase activity driven by PPAR and LXR response elements. In addition, the mRNA levels of proteins regulated by PPAR α (carnitine palmitoyltransferase 1 α) and LXR (sterol regulatory element binding protein) were decreased in Hep3B cells treated with TNF or IL-1. Finally, using constructs of the LXR α promoter or the PGC-1 α promoter linked to luciferase, we were able to demonstrate that a decrease in transcription contributes to the reduction in mRNA levels of nuclear hormone receptors and coactivators. Thus, our results suggest that decreased expression of nuclear hormone receptors RXR α, PPAR α, PPAR γ, and LXR α, as well as coactivators PGC-1 α, PGC-1 β, and SRC-1 may contribute to the cytokine-induced alterations in hepatic lipid metabolism during the acute phase response.