The low-density lipoprotein receptor (LDLR) plays a pivotal role in clearing atherogenic circulating low-density lipoprotein (LDL) cholesterol. Here we show that the COMMD/CCDC22/CCDC93 (CCC) and the Wiskott–Aldrich syndrome protein and SCAR homologue (WASH) complexes are both crucial for endosomal sorting of LDLR and for its function. We find that patients with X-linked intellectual disability caused by mutations in CCDC22 are hypercholesterolaemic, and that COMMD1-deficient dogs and liver-specific Commd1 knockout mice have elevated plasma LDL cholesterol levels. Furthermore, Commd1 depletion results in mislocalization of LDLR, accompanied by decreased LDL uptake. Increased total plasma cholesterol levels are also seen in hepatic COMMD9-deficient mice. Inactivation of the CCC-associated WASH complex causes LDLR mislocalization, increased lysosomal degradation of LDLR and impaired LDL uptake. Furthermore, a mutation in the WASH component KIAA0196 (strumpellin) is associated with hypercholesterolaemia in humans. Altogether, this study provides valuable insights into the mechanisms regulating cholesterol homeostasis and LDLR trafficking.

Bile acids (BAs) are essential for fat absorption and appear to modulate glucose and energy metabolism. Colesevelam, a BA sequestrant, improves glycemic control in type 2 diabetes mellitus (T2DM). We aimed to characterize the alterations in BA metabolism associated with T2DM and colesevelam treatment and to establish whether metabolic consequences of T2DM and colesevelam are related to changes in BA metabolism. Male subjects with T2DM (n 5 16) and controls (n 5 12) were matched for age and body mass index. BA pool sizes and synthesis/input rates were determined before and after 2 and 8 weeks of colesevelam treatment. T2DM subjects had higher cholic acid (CA) synthesis rate, higher deoxycholic acid (DCA) input rate, and enlarged DCA pool size. Colesevelam resulted in a preferential increase in CA synthesis in both groups. CA pool size was increased whereas chenodeoxycholic acid and DCA pool sizes were decreased upon treatment. Fasting and postprandial fibroblast growth factor 19 (FGF19) levels did not differ between controls and diabetics, but were decreased by treatment in both groups. Colesevelam treatment reduced hemoglobin A1C by 0.7% (P < 0.01) in diabetics. Yet, no relationships between BA kinetic parameters and changes in glucose metabolism were found in T2DM or with colesevelam treatment. Conclusion: Our results reveal significant changes in BA metabolism in T2DM, particularly affecting CA and DCA. Colesevelam treatment reduced FGF19 signaling associated with increased BA synthesis, particularly of CA, and resulted in a more hydrophilic BA pool without altering total BA pool size. However, these changes could not be related to the improved

No abstract

On the basis of the high fat content of nuts, they are traditionally considered as foods that provide a high amount of energy. However, epidemiologic and clinical observations do not indicate an association between nut intake and increased BMI. There is a notorious variability in macronutrient composition among nuts, although they have some consistent patterns. Nuts contain all major macronutrients: protein, carbohydrate, and fat. The total protein content is relatively high, which makes them a good source of plant protein (especially for vegetarians). Although nuts contain low amounts of some essential amino acids, this is not a nutritional concern due to the complement of protein. In addition, nuts have a low lysine:arginine ratio, which is inversely associated with the risk of developing hypercholesterolemia and atherosclerosis. Carbohydrates are the second highest macronutrient in nuts in terms of total calories provided. The fat fraction is characterized by a high amount of unsaturated fatty acids and a low content of saturated fatty acids. In conclusion, the high content in unsaturated fatty acids, the low lysine:arginine ratio, and the presence of other bioactive molecules (such as fibre, phytosterols, vitamin and other antioxidants, and minerals) make the addition of nuts to healthy diets a useful tool for the prevention of cardiovascular heart diseases.As we define them today, tree nuts (almonds, Brazil nuts, cashew, hazelnuts, macadamia nuts, pecans, pine nuts, pistachios and walnuts) originate from Anatolia. From there, the cultivation of tree nuts was introduced in Greece, then in Italy during the Roman Empire, and finally it was extended to all of Europe during the Middle Ages. The growing of tree nuts was introduced in America in the 16th century (Lemoine, 1998). Nuts are part of the Mediterranean diet, although their per capita consumption is relatively low (2-9 kg/year). Traditional Mediterranean nuts include almonds, hazelnuts, walnuts, peanuts and pistachios. Typically in Mediterranean diets, nuts are incorporated into many dishes, such as snacks (roasted and salted almonds, hazelnuts, and pistachios), sauces ('romesco' and 'pesto'), cold soups, such as 'ajoblanco' in Spain, cakes, pastries, and cookies ('turrón', 'nougat', walnut cakes, 'menjar blanc', 'amaretti'). Because of their high-energy content, nuts have been introduced into sports snacks and supplements.With today's busy lifestyles, nuts are a convenient, tasty and easy snack that contributes to a healthy lifestyle. In addition to their tastiness, tree nuts and peanuts are both cholesterol-free and rich in important nutrients, including vegetable protein, fibre and unsaturated fatty acids. They also contain relevant micronutrients, such as folic acid, niacin and vitamins E and B 6 , and minerals such as magnesium, copper, zinc, selenium, phosphorus and potassium.Nuts are part of the US Food Guide Pyramid and Mediterranean Diet Pyramids. Experts recommend eating a variety of foods from the five food groups every day in order to obtain ...

No abstract

Diabetes is characterized by high blood glucose levels and dyslipidemia. Bile salt sequestration has been found to improve both plasma glycemic control and cholesterol profiles in diabetic patients. Yet bile salt sequestration is also known to affect triglyceride (TG) metabolism, possibly through signaling pathways involving farnesoid X receptor (FXR) and liver X receptor ␣ (LXR␣). We quantitatively assessed kinetic parameters of bile salt metabolism in lean C57Bl/6J and in obese, diabetic db/db mice upon bile salt sequestration using colesevelam HCl (2% wt/wt in diet) and related these to quantitative changes in hepatic lipid metabolism. As expected, bile salt sequestration reduced intestinal bile salt reabsorption. Importantly, bile salt pool size and biliary bile salt secretion remained unchanged upon sequestrant treatment due to compensation by de novo bile salt synthesis in both models. Nevertheless, lean and db/db mice showed increased, mainly periportally confined, hepatic TG contents, increased expression of lipogenic genes, and increased fractional contributions of newly synthesized fatty acids. D iabetes is a multifactorial disease characterized by increased fasting blood glucose levels and dyslipidemia-that is, high plasma triglyceride (TG) and low-density lipoprotein cholesterol levels. Controlling blood glucose and cholesterol levels in diabetic patients is critical for delaying the progression of clinical complications such as neuropathy and cardiovascular disease. An efficient way to reduce plasma cholesterol levels is to induce cholesterol secretion in bile, either as bile salt or as free cholesterol. Bile is secreted into the ileum to facilitate absorption of lipids and lipid-soluble vitamins. About 95% of secreted bile salts are reabsorbed in the terminal ileum and transported back to the liver through the portal vein (enterohepatic circulation). In addition to their function in the absorption of dietary fats, bile salts are signaling molecules that play an important role in the regulation of lipid metabolism. 1 Interestingly, bile salt metabolism is affected in diabetes, which might contribute to the altered lipid profile observed in diabetic patients. 2 Knowledge of potential disturbances in bile salt metabolism in type 2 diabetic humans and animal models is still very limited, however. 3 Increasing fecal bile salt loss by preventing their intestinal reabsorption (sequestration) increases bile salt synthesis and, hence, hepatic cholesterol turnover. As a consequence, low-density lipoprotein cholesterol levels

The small intestine plays a significant role in the regulation of body cholesterol homeostasis. Active processes control both absorption and excretion of the sterol and the pathways involved are being elucidated. TICE might provide an attractive target for therapy aiming at reduction of atherosclerosis.

We evaluated the effects of 2 commonly available strategies (plant stanol ester drink and 10 mg simvastatin) on coronary heart disease (CHD) risk variables in participants with metabolic syndrome. Metabolic syndrome patients are at increased risk to develop CHD, partly due to high triacylglycerol (TAG) and low HDL cholesterol (HDL-C) concentrations and a low-grade inflammatory profile. Effects of plant stanol esters on TAG concentrations in these participants are unknown. After a 3-wk run-in period in which individuals consumed placebo yogurt drinks and placebo capsules, participants were randomly divided into 4 groups: placebo (n = 9), simvastatin + placebo drink (n = 10), placebo + stanol drink (n = 9), and simvastatin + stanol drink (n = 8). After 9 wk, we evaluated the effects on serum lipids, low-grade inflammation, and endothelial dysfunction markers. In metabolic syndrome patients, stanol esters (2.0 g/d), simvastatin, or the combination lowered non-HDL-C by 12.8% (P = 0.011), 30.7% (P < 0.001), and 35.4% (P < 0.001), respectively, compared with placebo. TAG were lowered by 27.5% (P = 0.044), 21.7% (P = 0.034), and 32.7% (P < 0.01), respectively. The total-:HDL-C ratio was significantly lowered in all 3 intervention groups. We found no treatment effects on the apolipoprotein CII:CIII ratio, cholesterol ester transfer protein mass, FFA concentrations, and markers for low-grade inflammation or endothelial dysfunction. This study shows that in metabolic syndrome patients, plant stanol esters lower not only non-HDL-C, but also TAG. Effects on TAG were also present in combination with statin treatment, illustrating an additional benefit of stanol esters in this CHD risk population.