Dietary plant stanol ester supplementation reduces peripheral symptoms in a mouse model of Niemann-Pick type C1 disease

Niemann-Pick type C1 (NPC1) disease is a rare genetic condition in which the function of the lysosomal cholesterol transporter NPC1 protein is impaired. Consequently, sphingolipids and cholesterol accumulate in lysosomes of all tissues, triggering a cascade of pathological events that culminate in severe systemic and neurological symptoms. Lysosomal cholesterol accumulation is also a key-factor in the development of atherosclerosis and non-alcoholic steatohepatitis (NASH). In these two metabolic diseases, the administration of plant stanol esters has been shown to ameliorate cellular cholesterol accumulation and inflammation. Given the overlap of pathological mechanisms among atherosclerosis, NASH and NPC1 disease, we sought to investigate whether dietary supplementation with plant stanol esters improves the peripheral features of NPC1 disease. To this end, we used an NPC1 murine model featuring an Npc1 null allele (Npc1nih), creating a dysfunctional NPC1 protein. Npc1nihmice were fed a two or six percent plant stanol esters-enriched diet over the course of 5 weeks. During this period, hepatic and blood lipid and inflammatory profiles were assessed. Npc1nihmice fed the plant stanol-enriched diet exhibited lower hepatic cholesterol accumulation, damage and inflammation than regular chow-fed Npc1nihmice. Moreover, plant stanol consumption shifted circulating T-cells and monocytes in particular towards an anti-inflammatory profile. Overall, these effects were stronger following dietary supplementation with 6% stanols, suggesting a dose-dependent effect. The findings of our study highlight the potential use of plant stanols as an affordable complementary means to ameliorate disorders in hepatic and blood lipid metabolism and reduce inflammation in NPC1 disease

Sex-opposed inflammatory effects of 27-hydroxycholesterol are mediated via differences in estrogen signaling

Despite the increased awareness of differences in the inflammatory response between men and women, only limited research has focused on the biological factors underlying these sex differences. The cholesterol derivative 27-hydroxycholesterol (27HC) has been shown to have opposite inflammatory effects in independent experiments using mouse models of atherosclerosis and non-alcoholic steatohepatitis (NASH), pathologies characterized by cholesterol-induced inflammation. As the sex of mice in these in vivo models differed, we hypothesized that 27HC exerts opposite inflammatory effects in males compared to females. To explore whether the sex-opposed inflammatory effects of 27HC translated to humans, plasma 27HC levels were measured and correlated with hepatic inflammatory parameters in obese individuals. To investigate whether 27HC exerts sex-opposed effects on inflammation, we injected 27HC into female and male Niemann–Pick disease type C1 mice (Npc1nih) that were used as an extreme model of cholesterol-induced inflammation. Finally, the involvement of estrogen signaling in this mechanism was studied in bone marrow-derived macrophages (BMDMs) that were treated with 27HC and 17β-estradiol (E2). Plasma 27HC levels showed opposite correlations with hepatic inflammatory indicators between female and male obese individuals. Likewise, hepatic 27HC levels oppositely correlated between female and male Npc1nih mice. Twenty-seven hydroxycholesterol injections reduced hepatic inflammation in female Npc1nih mice in contrast to male Npc1nih mice, which showed increased hepatic inflammation after 27HC injections. Furthermore, 27HC administration also oppositely affected inflammation in female and male BMDMs cultured in E2-enriched medium. Remarkably, female BMDMs showed higher ERα expression compared to male BMDMs. Our findings identify that the sex-opposed inflammatory effects of 27HC are E2-dependent and are potentially related to differences in ERα expression between females and males. Hence, the individual’s sex needs to be taken into account when 27HC is employed as a therapeutic tool as well as in macrophage estrogen research in general

Dietary Sargassum fusiforme improves memory and reduces amyloid plaque load in an Alzheimer's disease mouse model

Activation of liver X receptors (LXRs) by synthetic agonists was found to improve cognition in Alzheimer's disease (AD) mice. However, these LXR agonists induce hypertriglyceridemia and hepatic steatosis, hampering their use in the clinic. We hypothesized that phytosterols as LXR agonists enhance cognition in AD without affecting plasma and hepatic triglycerides. Phytosterols previously reported to activate LXRs were tested in a luciferase-based LXR reporter assay. Using this assay, we found that phytosterols commonly present in a Western type diet in physiological concentrations do not activate LXRs. However, a lipid extract of the 24(S)-Saringosterol-containing seaweed Sargassum fusiforme did potently activate LXR beta. Dietary supplementation of crude Sargassum fusiforme or a Sargassum fusiforme-derived lipid extract to AD mice significantly improved short-term memory and reduced hippocampal A beta plaque load by 81%. Notably, none of the side effects typically induced by full synthetic LXR agonists were observed. In contrast, administration of the synthetic LXRa activator, AZ876, did not improve cognition and resulted in the accumulation of lipid droplets in the liver. Administration of Sargassum fusiforme-derived 24(S)-Saringosterol to cultured neurons reduced the secretion of A beta 42. Moreover, conditioned medium from 24(S)-Saringosterol-treated astrocytes added to microglia increased phagocytosis of A beta. Our data show that Sargassum fusiforme improves cognition and alleviates AD pathology. This may be explained at least partly by 24(S)-Saringosterol-mediated LXR beta activation.</p

Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease

Peer reviewe

Fractional cholesterol absorption measurements in humans: Determinants of the blood-based dual stable isotope tracer technique

BACKGROUND: The flux of absorbed cholesterol is a controlling element in the regulation of cholesterol biosynthesis and catabolism. A review of 5 published methods to measure cholesterol absorption is presented, including 2 dual stable isotope approaches. The continuous dual isotope feeding procedure is accurate, but only suitable for small-scale studies. The blood-based dual stable isotope technique is the least invasive and complex procedure, but leads to large variations in individual (90%) and mean population values (24%-70%) for healthy subjects. The results may be partly determined by the experimental and analytical procedures. SOURCES OF MATERIAL: Fifteen blood-based dual stable isotope studies published between 1993 and 2013 have been analyzed. The results were related to the methodologies applied and evidence was sought for accordance to the test principles. FINDINGS: Seven different isotopic tracers, 3 cholesterol subcompartments in blood, and 6 mass spectrometry techniques were applied. The oral and intravenous test formulations were presented in only 1 study. Time points for blood sampling and methodologies for blood sample preparation and analysis were highly variable. No definite proofs were supplied for the fates of the oral and intravenous cholesterol tracers. Isotope enrichment measurements in free and total cholesterol in plasma and erythrocytes were never compared. Fractional cholesterol absorption rate values depend strongly on the mass spectrometry methodology. Dual-inlet isotope ratio mass spectrometry appears to be the method of choice. CONCLUSIONS: Dual stable isotope approaches require validation and standardization of administration and analysis procedures. A control group must always be included to correct for methodological differences. (C) 2015 National Lipid Association. All rights reserved

Individualized lipid-lowering therapy to further reduce residual cardiovascular risk

Hypercholesterolemia is a major risk factor for cardiovascular diseases. Serum cholesterol concentrations are regulated by enteral absorption, biliary secretion, and hepatic synthesis. Statins inhibit the rate limiting enzyme of cholesterol synthesis, HMG-CoA-reductase, and reduce serum cholesterol concentrations as well as cardiovascular morbidity and mortality. Some studies indicate that patients with high baseline cholesterol absorption may show only a small response to statin treatment in terms of cholesterol lowering. Data from genetic association studies and from the IMPROVE-IT trial show that reducing intestinal cholesterol absorption via NCP1L1 further reduces cardiovascular risk. However, some patients do not attain LDL-cholesterol targets on combination therapy. For these patients PCSK9-antibody treatment and lipid-apheresis are options to be considered. This article reviews the current literature on this issue and suggests 'individualized lipid-lowering therapy' as an approach to optimize and personalize lipid-lowering treatment of patients with hypercholesterolemia to further reduce residual cardiovascular risk. (C) 2016 Elsevier Ltd. All rights reserved

Comment on Tauriainen et al.:Serum, liver and bile sitosterol and sitostanol in obese patients with and without NAFLD

This short article provides a comment on the recent article by Tauriainen et al. [Bioscience Reports (2018) 38, BSR20171274 https://doi.org/10.1042/BSR20171274].? 2018 The Author(s)

Neutrophil-derived myeloperoxidase promotes atherogenesis and neointima formation in mice

Background: Myeloperoxidase (MPO), expressed mainly in neutrophils, is an enzyme linked to inflammation and oxidative stress. MPO is an independent prognostic marker in healthy individuals as well as in patients with coronary artery disease. In this present study we analyze the role of MPO in experimental atherogenesis and neointima formation after vascular injury in mice. Methods and results: 6-8 weeks old apolipoprotein E-deficient (ApoE(-/-)) mice were fed a high-cholesterol diet for 8 weeks with concomitant treatment with two different doses (10 mu g/mg bw vs. 20 mu g/mg bw) of 4-ABAH (MPO inhibitor). Application at lower dosage did not affect oxidative stress, endothelial function and atherosclerotic plaque development. 4-ABAH in higher dosage decreased inflammatory markers and vascular oxidative stress, consecutively improved endothelial function and reduced significantly atherosclerotic plaque development. To assess the role of circulating intracellular MPO, irradiated ApoE(-/-) mice were repopulated with bone marrow-derived cells from MPO(-/-)mice and were fed a high-cholesterol diet for 8 weeks. This MPO deficiency resulted in alleviated inflammation, reduced oxidative stress and improved endothelial function with a significant impact on plaque formation. To understand the possible role of MPO in vascular remodeling, we tested its effects on neointima formation following vascular injury in mice. MPO inhibition by 4-ABAH reduced significantly neointima formation. It was significantly reduced in MPO deficient mice, whereas transfer of spleen-derived neutrophils from WT mice enhanced it. Conclusion: Our data suggests a central role of MPO in the pathogenesis of atherogenesis and prefers pharmacological MPO inhibition as a therapeutic strategy for prevention and therapy of atherosclerosis and restenosis. (C) 2015 Elsevier Ireland Ltd. All rights reserved