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Background: Beyond the hepatobiliary pathway, studies have demonstrated that direct transintestinal cholesterol efflux (TICE) of plasma-derived cholesterol may contribute to reverse cholesterol transport. The clinical evidence of TICE in human remains challenged because of the difficulty to discriminate the hepatobiliary and transintestinal routes in vivo., Objective: To provide the first proof of concept that TICE exists in vivo in humans by demonstrating that plasma labeled cholesterol can be excreted in the feces of patients with complete bile duct obstruction., Methods: Plasma, bile, and fecal cholesterol excretion was measured by mass spectrometry 24, 48, and 72 hours after intravenous injection of D7-cholesterol in two patients presenting cholangiocarcinomas with a total obstruction of their primary bile duct., Results: No trace of bile acids was detected in the feces of the two patients. Despite this, a significant amount of plasma D7-cholesterol was quantified in the feces of the two patients 48 hours and 72 hours after the intravenous injection., Conclusion: Our data bring a direct proof that TICE is an active pathway in humans., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Gas chromatography-mass spectrometry (GC-MS) was compared with gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) for measurements of cholesterol (13)C enrichment after infusion of labeled precursor ([(13)C1,2]acetate). Paired results were significantly correlated, although GC-MS was less accurate than GC-C-IRMS for higher enrichments. Nevertheless, only GC-MS was able to provide information on isotopologue distribution, bringing new insights to lipid metabolism. Therefore, we assessed the isotopologue distribution of cholesterol in humans and dogs known to present contrasted cholesterol metabolic pathways. The labeled tracer incorporation was different in both species, highlighting the subsidiarity of GC-MS and GC-C-IRMS to analyze in vivo stable isotope studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The aim of this study was to investigate macrophage reverse cholesterol transport (RCT) in hamster, a CETP-expressing species, fed omega 3 fatty acids (ω3PUFA) supplemented high fat diet (HFD). Three groups of hamsters (n = 6/group) were studied for 20 weeks: 1) control diet: Control, 2) HFD group: HF and 3) HFD group supplemented with ω3PUFA (EPA and DHA): HFω3. In vivo macrophage-to-feces RCT was assessed after an intraperitoneal injection of (3)H-cholesterol-labelled hamster primary macrophages. Compared to Control, HF presented significant (p<0.05) increase in body weight, plasma TG (p<0.01) and cholesterol (p<0.001) with an increase in VLDL TG and in VLDL and LDL cholesterol (p<0.001). Compared to HF, HFω3 presented significant decrease in body weight. HFω3 showed less plasma TG (p<0.001) and cholesterol (p<0.001) related to a decrease in VLDL TG and HDL cholesterol respectively and higher LCAT activity (p<0.05) compared to HF. HFω3 showed a higher fecal bile acid excretion (p<0.05) compared to Control and HF groups and higher fecal cholesterol excretion (p<0.05) compared to HF. This increase was related to higher gene expression of ABCG5, ABCA1 and SR-B1 in HFω3 compared to Control and HF groups (<0.05) and in ABCG1 and CYP7A1 compared to HF group (p<0.05). A higher plasma efflux capacity was also measured in HFω3 using (3)H- cholesterol labeled Fu5AH cells. In conclusion, EPA and DHA supplementation improved macrophage to feces reverse cholesterol transport in hamster fed HFD. This change was related to the higher cholesterol and fecal bile acids excretion and to the activation of major genes involved in RCT.

Background: Plant sterols are an established non-pharmacological means to reduce total and LDL blood cholesterol concentrations and are therefore recommended for cholesterol management by worldwide-renown health care institutions. Their efficacy has been proven in many types of foods with the majority of trials conducted in spreads or dairy products. As an alternative to dairy products, soy based foods are common throughout the world. Yet, there is little evidence supporting the efficacy of plant sterols in soy-based foods. The objective of this study was to investigate the effect of a soy drink enriched with plant sterols on blood lipid profiles in moderately hypercholesterolemic subjects., Methods: In a randomized, placebo-controlled double-blind mono-centric study, 50 subjects were assigned to 200 ml of soy drink either enriched with 2.6 g plant sterol esters (1.6 g/d free plant sterol equivalents) or without plant sterols (control) for 8 weeks. Subjects were instructed to maintain stable diet pattern and physical activity. Plasma concentrations of lipids were measured at initial visit, after 4 weeks and after 8 weeks. The primary measurement was the change in LDL cholesterol (LDL-C). Secondary measurements were changes in total cholesterol (TC), non-HDL cholesterol (non-HDL-C), HDL cholesterol (HDL-C) and triglycerides., Results: Regular consumption of the soy drink enriched with plant sterols for 8 weeks significantly reduced LDL- C by 0.29 mmol/l or 7% compared to baseline (p < 0.05). TC and non-HDL-C concentrations decreased by 0.26 mmol/l and 0.31 mmol/l (each p < 0.05), respectively. Mean reductions in total, LDL and non-HDL cholesterol were significantly greater than in the placebo group (p < 0.05). HDL-C and triglycerides were not affected. Compliance was very high (>96%), and products were well tolerated., Conclusion: Daily consumption of a plant sterol-enriched soy drink significantly decreased total, non-HDL and LDL cholesterol and is therefore an interesting and convenient aid in managing mild to moderate hypercholesterolemia.

Purpose: We recently reported that direct and maternal supplementation with n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) alleviates the metabolic disturbances in adult hamster pups fed with a high-fat diet (HFD). In this study, we hypothesized that these results involved a perinatal modulating effect of sphingolipids by n-3 LC-PUFA. Methods: We studied the effect of direct and maternal n-3 LC-PUFA supplementation on sphingolipid contents in liver and muscle, hepatic triglycerides (TG) secretion and glucose tolerance. Offspring male hamsters born from supplemented (Cω) or unsupplemented (C) mothers were subjected after weaning to a HFD during 16 weeks, without (Cω-HF or C-HF) or with direct supplementation with n-3 LC-PUFA (C-HFω). Results: Direct supplementation decreased sphingosine, sphinganine and ceramides in liver and decreased sphingosine, sphinganine, sphingosine-1-phosphate (S1P) and ceramides in muscle in C-HFω compared to C-HF ( p < 0.05). Maternal supplementation decreased C20 ceramide and lactosylceramide in liver and sphinganine, S1P and lactosylceramide in muscle ( p < 0.05). This supplementation tended to decrease glucosylceramide in liver ( p < 0.06) and muscle ( p < 0.07) in Cω-HF compared to C-HF. Direct supplementation increased glucose tolerance and decreased hepatic TG secretion and hepatic gene expression levels of diacylglycerol O-acyltransferase 2 (DGAT2), sterol regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase, stearoyl-CoA desaturase-1 (SCD1) and tumor necrosis factor α (TNFα). Maternal supplementation decreased basal glycemia and hepatic TG secretion. We observed a positive correlation between hepatic TG secretion and hepatic ceramide ( p = 0.0059), and between basal glycemia and hepatic ceramide ( p = 0.04) or muscle lactosylceramide contents ( p = 0.001). Conclusion: We observed an improvement of lipids and glucose metabolism in hamster with n-3 LC-PUFA direct supplementation and a decrease in glycemia and hepatic TG secretion with maternal supplementation. These results are probably related to a decrease in both lipogenesis and sphingolipid contents in liver and muscle. [ABSTRACT FROM AUTHOR]

Aim: Nicotinic acid (NA) treatment decreases plasma triglycerides and increases HDL cholesterol, but the mechanisms involved in these change are not fully understood. A reduction in cholesteryl ester transfer protein (CETP) activity has been advanced to explain most lipid-modulating effects of NA. However, due to the central role of CETP in reverse cholesterol transport in humans, other effects of NA may have been hidden. As dogs have no CETP activity, we conducted this study to examine the specific effects of extended-release niacin (NA) on lipids and high-density lipoprotein (HDL) cholesteryl ester (CE) turnover in obese Insulin-Resistant dogs with increase plasma triglycerides. Methods: HDL kinetics were assessed in fasting dogs before and four weeks after NA treatment through endogenous labeling of cholesterol and apolipoprotein AI by simultaneous infusion of [1,2 13C2] acetate and [5,5,5 2H3] leucine for 8 h. Kinetic data were analyzed by compartmental modeling. In vitro cell cholesterol efflux of serum from NA-treated dogs was also measured. Results: NA reduced plasma total cholesterol, low-density lipoprotein cholesterol, HDL cholesterol, triglycerides (TG), and very-low-density lipoprotein TG concentrations (p < 0.05). The kinetic study also showed a higher cholesterol esterification rate (p < 0.05). HDL-CE turnover was accelerated (p < 0.05) via HDL removal through endocytosis and selective CE uptake (p < 0.05). We measured an elevated in vitro cell cholesterol efflux (p < 0.05) with NA treatment in accordance with a higher cholesterol esterification. Conclusion: NA decreased HDL cholesterol but promoted cholesterol efflux and esterification, leading to improved reverse cholesterol transport. These results highlight the CETP-independent effects of NA in changes of plasma lipid profile. [ABSTRACT FROM AUTHOR]

Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity, metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction Initiative (R3i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk, especially in insulinresistant conditions. As part of its mission to improve awareness and clinical management of atherogenic dyslipidaemia, the R3i has identified three key priorities for action: i) to improve recognition of atherogenic dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic dyslipidaemia. The R3i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging treatments may offer promise. These include the next generation peroxisome proliferator-activated receptorα agonists, cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R3i believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk. [ABSTRACT FROM AUTHOR]

Glucose intolerance and dyslipidaemia are independent risk factors for endothelium dysfunction and CVD. The aim of the present study was to analyse the preventive effect of n-3 PUFA (EPA and DHA) on lipid and carbohydrate disturbances and endothelial dysfunction. Three groups of adult hamsters were studied for 20 weeks: (1) control diet (Control); (2) high-fat diet (HF); (3) high-fat diet enriched with n-3 PUFA (HFn-3) groups. The increase in body weight and fat mass in the HF compared to the Control group (P < 0·05) was not found in the HFn-3 group. Muscle TAG content was similar in the Control and HF groups, but significantly lower in the HFn-3 group (P = 0·008). Glucose tolerance was impaired in the HF compared to the Control group, but this impairment was prevented by n-3 PUFA in the HFn-3 group (P < 0·001). Plasma TAG and cholesterol were higher in the HF group compared to the Control group (P < 0·001), but lower in the HFn-3 group compared to the HF group (P < 0·001). HDL-cholesterol was lower in the HFn-3 group compared to the Control and HF groups (P < 0·0005). Hepatic secretion of TAG was lower in the HFn-3 group compared to the HF group (P < 0·005), but did not differ from the Control group. Hepatic gene expression of sterol regulatory element-binding protein-1c, diacylglycerol O-acyltransferase 2 and stearyl CoA desaturase 1 was lower in the HFn-3 group, whereas carnitine palmitoyl transferase 1 and scavenger receptor class B type 1 expression was higher (P < 0·05). In adipocytes and adipose macrophages, PPARγ and TNFα expression was higher in the HF and HFn-3 groups compared to the Control group. Endothelium relaxation was higher in the HFn-3 (P < 0·001) than in the HF and Control groups, and was correlated with glucose intolerance (P = 0·03) and cholesterol (P = 0·0003). In conclusion, n-3 PUFA prevent some metabolic disturbances induced by high-fat diet and improve endothelial function in hamsters. [ABSTRACT FROM PUBLISHER]

Gain-of-function mutations within proprotein convertase subtilisin kexin type 9 (PCSK9) are linked to familial autosomal dominant hypercholesterolaemia, a disease characterized by elevated plasma concentrations of cholesterol associated with low-density lipoproteins (LDLs). Conversely, PCSK9 loss-of-function mutations result in low levels of LDL cholesterol (LDLC) and protect against coronary heart disease. Although compelling evidence indicates that PCSK9 impairs the LDLR pathway, its role in cholesterol metabolism remains incompletely defined. In the past two years, several new biochemical findings, including the PCSK9 crystal structure and the identification of several transcriptional repressors, were reported. Moreover, new clinical and epidemiological data have revealed the correlation between plasma PCSK9 concentrations and LDLC levels. [Copyright &y& Elsevier]

Amongst the processes involved in the reverse cholesterol transport (RCT) from organs to liver, including high density lipoproteins-apolipoprotein AI (HDL-apoAI) dependent tissue uptake and cholesteryl ester transfer protein (CETP)-mediated transfers, the selective uptake of cholesteryl ester (CE) is of increasing interest through its antiatherogenic role. The purpose of this report is to develop a simple protocol allowing study of this process in an animal model with easier quantification of CE selective uptake. The dog was chosen essentially because this animal has a low CETP activity and an appropriate size to conduce a kinetic study. Tracer kinetics were performed to estimate in vivo the contributions of the pathways involved in HDL-CE turnover in dogs. Stable isotopes, 13C-acetate and D3-leucine as labeled precursors of CE and apoAI, were infused to fasting dogs. Isotopic enrichments were monitored in plasma unesterified cholesterol and in HDL-CE and apoAI by mass spectrometry. Kinetics were analyzed using compartmental modeling. Results concerned the measurement of the activity of cholesterol esterification (0.13±0.032 h-1), rate of HDL-apoAI catabolism (0.024±0.012 h-1), HDL-CE turnover (0.062±0.010 h-1) and CE selective uptake (0.038±0.014 h-1). Our results show that CE in dogs is mainly eliminated by selective uptake of HDL-CE (60% of HDL-CE turnover), unlike in other species studied by similar methods in our laboratory. This study shows that among species used to analyze cholesterol metabolism, the dog appears to be the animal in whom HDL-CE selective uptake represents the largest part of HDL-CE turnover. [Copyright &y& Elsevier]

Abstract: PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) is a proprotein convertase that plays a key role in cholesterol homeostasis by decreasing hepatic low-density lipoprotein receptor (LDLR) protein expression. Here, we investigated the expression and the function of PCSK9 in pancreatic islets. Immunohistochemistry analysis showed that PCSK9 co-localized specifically with somatostatin in human pancreatic δ-cells, with no expression in α- and β-cells. PCSK9 seems not to be secreted by mouse isolated islets maintained in culture. Pcsk9-deficiency led to a 200% increase in LDLR protein content in mouse isolated islets, mainly in β-cells. Conversely, incubation of islets with recombinant PCSK9 almost abolished LDLR expression. However, Pcsk9-deficiency did not alter cholesterol content nor glucose-stimulated insulin secretion in mouse islets. Finally, in vivo glucose tolerance was similar in Pcsk9 +/+ and Pcsk9 −/− mice under basal conditions and following streptozotocin treatment. These results suggest, at least in mice, that PCSK9 does not alter insulin secretion. [Copyright &y& Elsevier]