Management of Hypercholesterolemia Through Dietary ß-glucans–Insights From a Zebrafish Model

Consumption of lipid-rich foods can increase the blood cholesterol content. β-glucans have hypocholesterolemic effect. However, subtle changes in their molecular branching can influence bioactivity. Therefore, a comparative investigation of the cholesterol-lowering potential of two β-glucans with different branching patterns and a cholesterol-lowering drug, namely simvastatin was undertaken employing the zebrafish (Danio rerio) model of diet-induced hypercholesterolemia. Fish were allocated to 5 dietary treatments; a control group, a high cholesterol group, two β-glucan groups, and a simvastatin group. We investigated plasma total cholesterol, LDL and HDL cholesterol levels, histological changes in the tissues, and explored intestinal transcriptomic changes induced by the experimental diets. Dietary cholesterol likely caused the suppression of endogenous cholesterol biosynthesis, induced dysfunction of endoplasmic reticulum and mitochondria, and altered the histomorphology of the intestine. The two β-glucans and simvastatin significantly abated the rise in plasma cholesterol levels and restored the expression of specific genes to alleviate the endoplasmic reticulum-related effects induced by the dietary cholesterol. Furthermore, the distinct patterns of transcriptomic changes in the intestine elicited by the oat and microalga β-glucans impacted processes such as fatty acid metabolism, protein catabolic processes, and nuclear division. Oat and microalgal β-glucans also altered the pattern of lipid deposition in the liver. Our study provides insights into the effectiveness of different β-glucans to alleviate dysfunctions in lipid metabolism caused by dietary cholesterol.

Wnt5a Promotes Lysosomal Cholesterol Egress and Protects Against Atherosclerosis

Background: Impairment of cellular cholesterol trafficking is at the heart of atherosclerotic lesions formation. This involves egress of cholesterol from the lysosomes and two lysosomal proteins, the Niemann-Pick C1 (NPC1) and NPC2 that promotes cholesterol trafficking. However, movement of cholesterol out the lysosome and how disrupted cholesterol trafficking leads to atherosclerosis is unclear. As the Wnt ligand, Wnt5a inhibits the intracellular accumulation of cholesterol in multiple cell types, we tested whether Wnt5a interacts with the lysosomal cholesterol export machinery and studied its role in atherosclerotic lesions formation. Methods: We generated mice deleted for the Wnt5a gene in vascular smooth muscle cells (VSMCs). To establish whether Wnt5a also protects against cholesterol accumulation in human VSMCs, we used a CRISPR/Cas9 guided nuclease approach to generate human VSMCs knockout for Wnt5a. Results: We show that Wnt5a is a crucial component of the lysosomal cholesterol export machinery. By increasing lysosomal acid lipase expression, decreasing metabolic signaling by the mTORC1 kinase, and through binding to NPC1 and NPC2, Wnt5a senses changes in dietary cholesterol supply and promotes lysosomal cholesterol egress to the endoplasmic reticulum (ER). Consequently, loss of Wnt5a decoupled mTORC1 from variations in lysosomal sterol levels, disrupted lysosomal function, decreased cholesterol content in the ER, and promoted atherosclerosis. Conclusions: These results reveal an unexpected function of the Wnt5a pathway as essential for maintaining cholesterol homeostasis in vivo.

Egg Consumption and 4-Year Change in Cognitive Function: The Rancho Bernardo Study

The role of dietary cholesterol in cognitive decline is unclear. Eggs are a rich source of nutrients and dietary cholesterol. This study examines the association of egg consumption with 4-year change in cognitive function in 890 older, community-dwelling adults. Participants were 357 men and 533 women aged □55y (means=70.1□8.4 and 71.5□8.8, respectively, p=0.016), from the Rancho Bernardo Cohort who attended a 1988-91 clinic visit. Egg intake was obtained with a food frequency questionnaire. Cognitive function was assessed with the Mini-Mental Status Exam (MMSE), Trails B and category fluency, and reassessed in 1992-96. In this sample, rates of egg consumption ranged from never (14.0% of men, 16.5% of women) to □5/week (7.0% of men, 3.8% of women; p=0.0013). Mean 1988-91 cognitive function scores for men vs. women were 27.5 vs. 27.7 on the MMSE (p=0.08), 105.9 vs. 121.6 on Trails B (p<0.0001), and 20.2 vs. 18.2 on category fluency (p<0.0001). Sex-specific regression analyses examined associations of egg consumption with change in cognitive function. In women, after adjustment for age and education, egg intake was associated with less decline over time in category fluency (beta=-.10, p=0.01), which remained significant after adjustment for smoking, alcohol, exercise, cholesterol, calorie intake, and protein intake (p=0.02). No other associations were found in women, and no associations were observed in men before and after adjustment for covariates. Results suggest that while high in dietary cholesterol, egg consumption is not associated with decline in cognitive function. For women, there may be a small beneficial effect for verbal memory.

Mutants of the white ABCG Transporter in Drosophila melanogaster Have Deficient Olfactory Learning and Cholesterol Homeostasis

Drosophila’s white gene encodes an ATP-binding cassette G-subfamily (ABCG) half-transporter. White is closely related to mammalian ABCG family members that function in cholesterol efflux. Mutants of white have several behavioral phenotypes that are independent of visual defects. This study characterizes a novel defect of white mutants in the acquisition of olfactory memory using the aversive olfactory conditioning paradigm. The w1118 mutants learned slower than wildtype controls, yet with additional training, they reached wildtype levels of performance. The w1118 learning phenotype is also found in the wapricot and wcoral alleles, is dominant, and is rescued by genomic white and mini-white transgenes. Reducing dietary cholesterol strongly impaired olfactory learning for wildtype controls, while w1118 mutants were resistant to this deficit. The w1118 mutants displayed higher levels of cholesterol and cholesterol esters than wildtype under this low-cholesterol diet. Increasing levels of serotonin, dopamine, or both in the white mutants significantly improved w1118 learning. However, serotonin levels were not lower in the heads of the w1118 mutants than in wildtype controls. There were also no significant differences found in synapse numbers within the w1118 brain. We propose that the w1118 learning defect may be due to inefficient biogenic amine signaling brought about by altered cholesterol homeostasis.

The Influence of Plants from the Alliaceae Family on Morphological Parameters of the Intestine in Atherogenic Rats

Bulbs from the Alliaceae family have been well-known and valued spices for thousands of years, not only for their unique flavor and aroma features, but also for their high nutritional and health-promoting values. Long-term or excessive consumption of these vegetables, especially raw garlic, can have side effects in the body (including in the digestive tract), causing a number of pathological changes in the intestinal wall; these changes lead, in turn, to its damage, dysfunction, and disorder development. Therefore, the aim of this study was to investigate the effect of the addition of freeze-dried vegetables from the Alliaceae family, i.e., garlic (Allium sativum L.), white onion, and red onion (Allium cepa L.) on the morphometric parameters (intestinal villi length, crypt depth, thickness of tunica mucosa, and the thickness of tunica muscle) of the jejunum of rats fed a semi-synthetic atherogenic diet (1% dietary cholesterol). In freeze-dried vegetables administered to rats, the contents of selected bioactive ingredients and their antioxidant potentials were determined. The effect of the onion vegetable supplements on growth parameters, serum lipid profile, plasma antioxidant potential, and the intestinal morphological parameters of rats loaded with cholesterol was determined. In an animal experiment, 30 male Wistar rats were divided into 5 diet groups, diet consumption and FER were studied. Supplementation of the atherogenic diet with vegetables improved the blood plasma lipid profiles and atherogenic indices, in a manner that was dependent on the type of supplementation used, with the best hypolipidemic and anti-atherosclerotic effects found in garlic use. The atherogenic diet, as well as the supplementation of this diet with the tested vegetables from the Alliaceae family, influenced the histological changes in the epithelium of the jejunum of rats. The damage to the intestinal mucosa was the greatest in animals fed an atherogenic diet supplemented with garlic. Bearing in mind that the desired beneficial therapeutic or prophylactic effects of onion vegetables (in particular garlic) in the course of various metabolic ailments (including atherosclerosis) are achieved during long-term supplementation, it is important to remember their possible cytotoxic effects (e.g., on the digestive tract) in order to achieve real benefits related to the supplementation with vegetables from the Alliaceae family.

Egg and Dietary Cholesterol Consumption and Mortality Among Hypertensive Patients: Results From a Population-Based Nationwide Study

Background: Hypertensive patients are sensitive to the amount of dietary cholesterol intake, especially cholesterol from the whole eggs. Whether whole egg and dietary cholesterol consumption are suitable for hypertensive patients is still controversial.Aim: The objective of the study was to examine the associations of intake of eggs as well as the dietary cholesterol with total mortality in a Chinese nationwide cohort.Methods: We utilized data from the China Health and Nutrition Survey (CHNS) from the year of 1991 to 2015. Cumulative averages of egg and cholesterol intake were calculated to represent the consumption of the long-term diet of the participants in each available round of the survey. Cox regression models were employed to estimate the effects of eggs and dietary cholesterol from the different sources on mortality among hypertensive patients.Results: A total of 8,095 participants were included in the final analysis and followed up for a mean of 11.4 years. Finally, 927 cases of death were detected. After adjustment for the multivariate factors, consuming more than seven eggs per week was related to 29% lower mortality among the hypertensive patients compared with the consumers with not more than two eggs per week [hazard ratio (HR): 0.71; 95% CI: 0.59–0.85; P < 0.001]. Similarly, the egg-sourced cholesterol intake was inversely associated with mortality (P = 0.002) whereas intake of the dietary cholesterol from the non-egg sources was significantly related to the higher mortality (P < 0.001). However, total cholesterol intake was not related to mortality among hypertensive patients. Substituting eggs for an equivalent amount of non-egg-sourced protein-abundant foods was also associated with lower mortality.Conclusion: Higher consumption of eggs and egg-sourced dietary cholesterol was associated with lower mortality among the enrolled Chinese hypertensive patients but non-egg-sourced cholesterol intake was related to higher mortality. Therefore, our findings do not support the view that hypertensive patients should avoid whole egg consumption for the purpose of restricting dietary cholesterol intake.

Off-Target Effect of Lovastatin Disrupts Dietary Lipid Uptake and Dissemination through Pro-Drug Inhibition of the Mesenteric Lymphatic Smooth Muscle Cell Contractile Apparatus

Previously published, off-target effects of statins on skeletal smooth muscle function have linked structural characteristics within this drug class to myopathic effects. However, the effect of these drugs on lymphatic vascular smooth muscle cell function, and by proxy dietary cholesterol uptake, by the intestinal lymphatic network has not been investigated. Several of the most widely prescribed statins (Atorvastatin, Pravastatin, Lovastatin, and Simvastatin) were tested for their in-situ effects on smooth muscle contractility in rat mesenteric collecting lymphatic vessels. Lovastatin and Simvastatin had a concentration-dependent effect of initially increasing vessel contraction frequency before flatlining the vessel, a phenomenon which was found to be a lactone-ring dependent phenomenon and could be ameliorated through use of Lovastatin- or Simvastatin-hydroxyacid (HA). Simvastatin treatment further resulted in mitochondrial depolymerization within primary-isolated rat lymphatic smooth muscle cells (LMCs) while Lovastatin was found to be acting in a mitochondrial-independent manner, increasing the function of RhoKinase. Lovastatin’s effect on RhoKinase was investigated through pharmacological testing and in vitro analysis of increased MLC and MYPT1 phosphorylation within primary isolated LMCs. Finally, acute in vivo treatment of rats with Lovastatin, but not Lovastatin-HA, resulted in a significantly decreased dietary lipid absorption in vivo through induced disfunction of mesenteric lymph uptake and trafficking.