desmosterol and Atherosclerosis

Topics: Animals; Atherosclerosis; Cholesterol; Coronary Vessels; Desmosterol; Foam Cells; Humans; Inflammasomes; Inflammation; Lipid Metabolism; Liver X Receptors; Macrophage Activation; Macrophages; Male; Mice; Nerve Tissue Proteins; Oxidoreductases Acting on CH-CH Group Donors; Plaque, Atherosclerotic; Sterols

It is controversial whether atherosclerosis is linked to increased intestinal cholesterol absorption or synthesis in humans. The aim of the present study was to relate atherosclerosis to the measurements of plasma markers of cholesterol synthesis (desmosterol, lathosterol) and absorption (campesterol, sitosterol). In healthy male (n=344), non-obese, non-diabetics, belonging to the city of São Paulo branch of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), we measured in plasma these non-cholesterol sterol markers, together with their anthropometric, dietary parameters, traditional atherosclerotic risk factors, and blood chemistry, coronary arterial calcium score (CAC), and ultrasonographically measured common carotid artery intima-media thickness (CCA-IMT). Cases with CAC>zero had the following parameters higher than cases with CAC = zero: age, waist circumference (WC), plasma total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), and non-high density lipoprotein-cholesterol (non HDL-C). Plasma desmosterol and campesterol, duly corrected for TC, age, body mass index (BMI), waist circumference (WC), hypertension, smoking, and the homeostasis model assessment-insulin resistance (HOMA-IR) correlated with CAC, but not with CCA-IMT. The latter related to increased age, BMI, waist circumference (WC), and systolic blood pressure (SBP). Plasma HDL-C concentrations did not define CAC or CCA-IMT degrees, although in relation to the lower tertile of HDL-C in plasma the higher tertile of HDL-C had lower HOMA-IR and concentration of a cholesterol synthesis marker (desmosterol). Present work indicated that increased cholesterol synthesis and absorption represent primary causes of CAD, but not of the common carotid artery atherosclerosis.

Topics: Adult; Aged; Atherosclerosis; Biomarkers; Body Mass Index; Brazil; Calcium; Carotid Artery, Common; Carotid Intima-Media Thickness; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Coronary Vessels; Cross-Sectional Studies; Desmosterol; Female; Humans; Intestinal Absorption; Intestinal Mucosa; Longitudinal Studies; Male; Middle Aged; Phytosterols; Prospective Studies; Sitosterols; Tomography, X-Ray Computed; Ultrasonography

Intestinal microbiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). We demonstrate here that metabolism by intestinal microbiota of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis in mice. Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism. The presence of specific bacterial taxa in human feces was associated with both plasma TMAO concentration and dietary status. Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predicted increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (myocardial infarction, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary L-carnitine supplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis, but this did not occur if intestinal microbiota was concurrently suppressed. In mice with an intact intestinal microbiota, dietary supplementation with TMAO or either carnitine or choline reduced in vivo reverse cholesterol transport. Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk.

Topics: Animals; Atherosclerosis; Carnitine; Cholesterol; Choline; Desmosterol; Female; Humans; Intestines; Macrophages; Mass Spectrometry; Meat; Metagenome; Methylamines; Mice; Mice, Knockout; RNA; Time Factors

Euterpe Oleracea (açai) is a fruit from the Amazon region whose chemical composition may be beneficial for individuals with atherosclerosis. We hypothesized that consumption of Euterpe Oleracea would reduce atherosclerosis development by decreasing cholesterol absorption and synthesis.. Male New Zealand rabbits were fed a cholesterol-enriched diet (0.5%) for 12 weeks, when they were randomized to receive Euterpe Oleracea extract (n = 15) or water (n = 12) plus a 0.05% cholesterol-enriched diet for an additional 12 weeks. Plasma phytosterols and desmosterol were determined by ultra-performance liquid chromatography and mass spectrometry. Atherosclerotic lesions were estimated by computerized planimetry and histomorphometry.. At sacrifice, animals treated with Euterpe Oleracea had lower levels of total cholesterol (p =0.03), non-HDL-cholesterol (p = 0.03) and triglycerides (p = 0.02) than controls. These animals had smaller atherosclerotic plaque area in their aortas (p = 0.001) and a smaller intima/media ratio (p = 0.002) than controls, without differences in plaque composition. At the end of the study, campesterol, β-sitosterol, and desmosterol plasma levels did not differ between groups; however, animals treated with Euterpe Oleracea showed lower desmosterol/campesterol (p = 0.026) and desmosterol/ β-sitosterol (p =0.006) ratios than controls.. Consumption of Euterpe Oleracea extract markedly improved the lipid profile and attenuated atherosclerosis. These effects were related in part to a better balance in the synthesis and absorption of sterols.

Topics: Animals; Arecaceae; Atherosclerosis; Cholesterol; Cholesterol, Dietary; Chromatography, High Pressure Liquid; Desmosterol; Immunoenzyme Techniques; Lipids; Male; Phytosterols; Phytotherapy; Plant Extracts; Rabbits; Sitosterols; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Inflammation and macrophage foam cells are characteristic features of atherosclerotic lesions, but the mechanisms linking cholesterol accumulation to inflammation and LXR-dependent response pathways are poorly understood. To investigate this relationship, we utilized lipidomic and transcriptomic methods to evaluate the effect of diet and LDL receptor genotype on macrophage foam cell formation within the peritoneal cavities of mice. Foam cell formation was associated with significant changes in hundreds of lipid species and unexpected suppression, rather than activation, of inflammatory gene expression. We provide evidence that regulated accumulation of desmosterol underlies many of the homeostatic responses, including activation of LXR target genes, inhibition of SREBP target genes, selective reprogramming of fatty acid metabolism, and suppression of inflammatory-response genes, observed in macrophage foam cells. These observations suggest that macrophage activation in atherosclerotic lesions results from extrinsic, proinflammatory signals generated within the artery wall that suppress homeostatic and anti-inflammatory functions of desmosterol.

Topics: Animals; Atherosclerosis; Cholesterol; Desmosterol; Fatty Acids; Foam Cells; Gene Knockdown Techniques; Leukocytes, Mononuclear; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Receptors, LDL; Sterol Regulatory Element Binding Proteins; Transcriptome

Plant sterols such as sitosterol and campesterol are frequently applied as functional food in the prevention of atherosclerosis. Recently, it became clear that plasma derived plant sterols accumulate in murine brains. We questioned whether plant sterols in the brain are associated with alterations in brain cholesterol homeostasis and subsequently with brain functions. ATP binding cassette (Abc)g5-/- mice, a phytosterolemia model, were compared to Abcg5+/+ mice for serum and brain plant sterol accumulation and behavioral and cognitive performance. Serum and brain plant sterol concentrations were respectively 35-70-fold and 5-12-fold increased in Abcg5-/- mice (P<0.001). Plant sterol accumulation resulted in decreased levels of desmosterol (P<0.01) and 24(S)-hydroxycholesterol (P<0.01) in the hippocampus, the brain region important for learning and memory functions, and increased lanosterol levels (P<0.01) in the cortex. However, Abcg5-/- and Abcg5+/+ displayed no differences in memory functions or in anxiety and mood related behavior. The swimming speed of the Abcg5-/- mice was slightly higher compared to Abcg5+/+ mice (P<0.001). In conclusion, plant sterols in the brains of Abcg5-/- mice did have consequences for brain cholesterol metabolism, but did not lead to an overt phenotype of memory or anxiety related behavior. Thus, our data provide no contra-indication for nutritional intake of plant sterol enriched nutrition.

Topics: Affect; Animals; Anxiety Disorders; Atherosclerosis; ATP-Binding Cassette Transporters; Behavior, Animal; Brain; Cholesterol; Desmosterol; Diet; Hippocampus; Homeostasis; Hydroxycholesterols; Hypercholesterolemia; Intestinal Diseases; Lanosterol; Lipid Metabolism, Inborn Errors; Male; Maze Learning; Memory; Mice; Mice, Mutant Strains; Phytosterols; Sitosterols; Stigmasterol

The purpose of this study was to evaluate the effects of whole body overexpression of human ABCG1 on atherosclerosis in apoE(-/-) mice.. We generated BAC transgenic mice in which human ABCG1 is expressed from endogenous regulatory signals, leading to a 3- to 7-fold increase in ABCG1 protein across various tissues. Although the ABCG1 BAC transgene rescued lung lipid accumulation in ABCG1(-/-) mice, it did not affect plasma lipid levels, macrophage cholesterol efflux to HDL, atherosclerotic lesion area in apoE(-/-) mice, or levels of tissue cholesterol, cholesterol ester, phospholipids, or triglycerides. Subtle changes in sterol biosynthetic intermediate levels were observed in liver, with chow-fed ABCG1 BAC Tg mice showing a nonsignificant trend toward decreased levels of lathosterol, lanosterol, and desmosterol, and fat-fed mice exhibiting significantly elevated levels of each intermediate. These changes were insufficient to alter ABCA1 expression in liver.. Transgenic human ABCG1 does not influence atherosclerosis in apoE(-/-) mice but may participate in the regulation of tissue cholesterol biosynthesis.

Topics: Animals; Apolipoproteins E; Atherosclerosis; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters; Cholesterol; Desmosterol; Dietary Fats; Disease Models, Animal; Homeostasis; Humans; Lipoproteins; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Up-Regulation

Topics: Alcohols; Arteriosclerosis; Atherosclerosis; Desmosterol; Humans; Sterols

Topics: Arteriosclerosis; Atherosclerosis; Desmosterol; Humans; Sterols