Transintestinal Cholesterol Efflux: A New Therapeutic Target
Many cholesterol lowering therapies under development are aimed at increasing cholesterol excretion by stimulation of RCT. Recent studies in mice have now confirmed the presence of direct cholesterol secretion via the intestine. The contribution of TICE in mice to cholesterol excretion is even more prominent than that of the biliary cholesterol secretion. Of course, these observations do not constitute the existence and relevance of TICE in humans. However, by the late sixties Simmonds et al had already observed cholesterol secretion in the small intestine after performing intestine perfusions in humans. Our group recently estimated that in humans TICE might amount to around one-third of biliary cholesterol secretion, based on average dietary cholesterol intake, biliary cholesterol secretion, and cholesterol excretion in humans. Nonetheless, the exact contribution of TICE in humans still needs to be quantified. Interestingly, it has been documented that the identified and aforementioned stimulators of TICE in mice also have a positive effect on cholesterol excretion in humans. In mice, the secretion of cholesterol by the intestine could be induced by high fat diets and regulated by the phospholipid content in the intestinal lumen. Several studies in men have shown that diets enriched with polyunsaturated fatty acids increase fecal sterol excretion. Furthermore, the supplementation of phospholipids strongly stimulated the excretion of sterols in the feces in humans.
Postfeeding Fecal Sterols At Wk 9
Fecal neutral sterol excretion was higher in the groups fed the fruiting body and mycelium diets than in the controls . In all of the diet groups, the bacterial metabolite, coprostanol, was the major component of fecal neutral sterols . The mushroom fruiting body and mycelium diets resulted in lower proportions of fecal coprostanol and higher proportions of fecal cholesterol. There were no significant differences in fecal total bile acid excretion among the groups . However, there was a greater percentage of primary bile acids in hamsters fed the fruiting body diet, which was largely due to a significantly greater proportion of cholic acid and a significantly smaller proportion of deoxycholic acid .
Fecal weights, total neutral sterols and total bile acid levels in hamsters after consumption of the control or mushroom diets for 4 wk,
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Host Health Implications Of Microbial Bile Metabolism
The microbial-mediated transformations of BAs at the intestinal level have been shown to be essential for intestinal and systemic health maintenance as the intestinal BAs and the gut microbiota mutually influence each other and, accordingly, BA-microbiota crosstalk disruption has been associated with several gastrointestinal, metabolic and inflammatory disorders, including those associated with aging-related decline , as summarized below.
BAs Metabolism and Inflammation
BAs Metabolism and Colorectal Cancer
The relation between diet, microbial metabolism of BAs and human disorders, including colorectal cancer risk , is further supported by the fact that dietary fat increases biliary hepatic synthesis and, thus, the quantity of BAs that reach the colon, providing substrate for the synthesis of secondary BAs. These have been described as proinflammatory and their increase may contribute to the pathogenesis of several gastrointestinal diseases, having been associated with colon polyps and CRC . Indeed, fecal secondary BAs and microbial genes encoding for 7-dehydroxylases were more common in African Americans who had a high risk of suffering CRC as compared with rural native Africans .
BAs Metabolism and Liver Diseases
Gut Microbiota Shifts in Aging Impact BAs Metabolism and Signaling
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Cholesteryl Ester Transfer Protein Facilitates Transfer Of Cholesteryl Ester From Hdl To Other Lipoproteins
Cholesteryl ester transfer protein, associated with HDL, is found in plasma of humans and many other species. It facilitates transfer of cholesteryl ester from HDL to VLDL, IDL, and LDL in exchange for triacylglycerol, relieving product inhibition of the LCAT activity in HDL. Thus, in humans, much of the cholesteryl ester formed by LCAT finds its way to the liver via VLDL remnants or LDL . The triacylglycerol-enriched HDL2 delivers its cholesterol to the liver in the HDL cycle .
Cholesterol is excreted from the body via the bile either in the unesterified form or after conversion into bile acids in the liver. Coprostanol is the principal sterol in the feces it is formed from cholesterol by the bacteria in the lower intestine.
Cholesterol Metabolism By Intestinal Bacteria
Cholesterol is a terpenoid lipid with a carbon skeleton formed by four fused alicyclic rings. It is an essential component of the mammalian cell membranes and precursor of steroid hormones, vitamin D, and primary BAs . Following its GIT passage, most cholesterol is absorbed in the duodenum and proximal jejunum by a passive diffusion process. Reabsorbed cholesterol is incorporated with triglycerides and lipoproteins into transportable complexes called chylomicrons, which return to the liver through the enterohepatic circulation. The cholesterol escaping this re-absorption reaches the colon, where it can be metabolized by the intestinal microbiota and/or excreted with feces .
Figure 2. Phylogenetic analysis of bile salt hydrolases and cholesterol oxidases . The construction of the phylogenetic trees and the clustering methods are described in detail in Supplementary Figure 1. The edition of the phylogenetic trees was performed with FigTree v1.3.1 . The trees were divided into groups, depending on the grouping at phylum level.
Several cholesterol-reducing strains have been isolated from the intestine and feces of mammals . The first described cholesterol-reducing isolate of human origin was the Bacteroides sp. strain D8 . Otherwise, only a few cholesterol-reducing intestinal bacteria have been identified, most of them belonging to the genus Eubacterium, although the genes or enzymes involved in this metabolism have not been well characterized yet.
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Parenteral Administration Of Full
ApoA-I mimetic peptides are also of substantial therapeutic interest.93 ApoA-I has 10 amphipathic helices that are adapted to bind lipids on one face and interact with the aqueous environment on the other. Small amphipathic peptides of 18 to 22 amino acids based loosely on the apoA-I amphipathic helical sequence have similar properties to apoA-I, including the ability to promote cellular cholesterol efflux as well as to activate LCAT. Repeated injection of the peptide L-5F reduced the progression of atherosclerosis in mice.94 The apoA-I mimetic peptide ETC-642 promotes LCAT activation and is also in clinical development. Several other apoA-I mimetic peptides have been developed and tested in cell and animal models.93 There is some hope that parenterally adminisistered apoA-I mimetic peptides may prove to be an effective method of treating acute coronary syndromes in humans.
P. Jungsuwadee, M.E. Vore, in, 2010
Bile Acid Synthesis Is Regulated At The Cyp7a1 Step
The principal rate-limiting step in the biosynthesis of bile acids is at the CYP7A1 reaction . The activity of the enzyme is feedback regulated via the nuclear bile acid-binding receptor, farnesoid X receptor . When the size of the bile acid pool in the enterohepatic circulation increases, FXR is activated, and transcription of the CYP7A1 gene is suppressed. Chenodeoxycholic acid is particularly important in activating FXR. CYP7A1 activity is also enhanced by cholesterol of endogenous and dietary origin and regulated by insulin, glucagon, glucocorticoids, and thyroid hormone.
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Origins Of Neutral Sterols In Human Feces Studied By Stable Isotope Labeling Existence Of An External Secretion Of Cholesterol
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Liver Lipid Levels And Intestinal Uptake Of Cholesterol
Linear regression analysis was carried out in order to determine whether there was any relationship between liver lipid levels and the distribution of intragastrically-administered cholesterol between the liver and feces of diet-fed animals. Results for PLRDME-supplemented mice are shown in Figure , and those for PC-700-supplemented mice are shown in Figure . In both cases, a strong positive correlation was found between liver cholesterol and triglyceride levels and the hepatic accumulation of intragastrically-administered cholesterol. At the same time, a negative correlation was found between liver cholesterol and triglyceride levels and fecal excretion of intragastrically-administered cholesterol.
Figure 1
Relationship between liver lipids and intragastrically-administered cholesterol in the liver and feces of mice fed the high-fat diet alone or the high-fat diet supplemented with milk phospholipids: PLRDME or PC-700. Data points represent individual animals after 3 or 5 weeks of diet feeding. Open circles represent high-fat-fed mice filled circles represent milk phospholipid-supplemented animals . A correlation coefficient is shown in each panel together with its level of statistical significance.
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Enjoy Lots Of Fruits And Vegetables
Eating fruits and vegetables is an easy way to lower LDL cholesterol levels.
Studies show that adults who consume at least four servings of fruits and vegetables each day have roughly 6% lower LDL cholesterol levels than people who eat fewer than two servings per day .
Fruits and vegetables also contain high numbers of antioxidants, which prevent LDL cholesterol from oxidizing and forming plaques in your arteries .
Together, these cholesterol-lowering and antioxidant effects can reduce your risk of heart disease.
Research has found that people who eat the most fruits and vegetables have a 17% lower risk of developing heart disease over 10 years compared to those who eat the fewest .
Summary Eating at least four servings of fruits and vegetables daily can lower LDL cholesterol levels and reduce LDL oxidation, which may reduce your risk of heart disease.
What Is The Major Site Of Cholesterol Synthesis And Storage
Biosynthesis of cholesterol generally takes place in the endoplasmic reticulum of hepatic cells and begins with acetyl- CoA, which is mainly derived from an oxidation reaction in the mitochondria.
Where in the body is cholesterol synthesized?
the liverThe majority of cholesterol utilized by healthy adults is synthesized in the liver, which produces ~70% of the total daily cholesterol requirement . The other 30% comes from dietary intake.
Is cholesterol excreted in urine?
Small amounts of cholesterol, mainly nonesterified, are present in normal urine , whereas elevated levels have been reported in patients with benign and malignant diseases of the kidney and the urogenital tract .
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Farnesyl Diphosphate Gives Rise To Dolichol & Ubiquinone
The polyisoprenoids dolichol and ubiquinone are formed from farnesyl diphosphate by the further addition of up to 16 or 37 isopentenyl diphosphate residues . Some GTP-binding proteins in the cell membrane are prenylated with farnesyl or geranylgeranyl residues. Protein prenylation is believed to facilitate the anchoring of proteins into lipoid membranes and may also be involved in protein-protein interactions and membrane-associated protein trafficking.
FIGURE 264
Possible mechanisms in the regulation of cholesterol synthesis by HMG-CoA reductase. Insulin has a dominant role compared with glucagon. *See Figure 186.
In tissues, cholesterol balance is regulated as follows : An increase in cell cholesterol is caused by uptake of cholesterol-containing lipoproteins by receptors, for example, the LDL receptor or the scavenger receptor, uptake of free cholesterol from cholesterol-rich lipoproteins to the cell membrane, cholesterol synthesis, and hydrolysis of cholesteryl esters by the enzyme cholesteryl ester hydrolase. A decrease is due to efflux of cholesterol from the membrane to HDL via the ABCA1, ABCG1, or SR-B1 esterification of cholesterol by ACAT and utilization of cholesterol for synthesis of other steroids, such as hormones, or bile acids in the liver.
FIGURE 265
Metabolic Effects Of Pc
In order to confirm the effect of milk PL on intestinal cholesterol and plant sterol uptake, a second milk PL preparation was investigated . This commercially-available milk PL concentrate contained more total fat and more PL than PLRDME. Less PC-700 was therefore added to the HF diet, to ensure that the HFPL diets contained comparable amounts of milk PL . The PC-700 and the PLRDME had a similar PL composition and a similar fatty acid composition .
Mice were fed the HF diet and the HF diet containing PC-700 . They were studied in the same way as in the first experiment. Metabolic parameters for these animals are given in Table . Two mice had to be excluded from the analysis since they did not react well to the intragastric gavage. Addition of PC-700 to the HF diet had no significant effect on any of the parameters. The tendency of PLRDME to reduce liver weight was not evident in mice supplemented with PC-700.
Table 3 Body weight, liver weight, food intake, and fecal excretion of mice fed the high-fat diet alone or the high-fat diet supplemented with milk phospholipids in the form of commercially-prepared PC-700Table 4 Effect of dietary milk phospholipids in the form of commercially-prepared PC-700 on liver and fecal lipid parameters in mice given an intragastric gavage of radioactively-labelled cholesterol and sitostanol after 3 or 5 weeks on high-fat diet.
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Serum Cholesterol Is Correlated With The Incidence Of Atherosclerosis & Coronary Heart Disease
Atherosclerosis is an inflammatory disease characterized by the deposition of cholesterol and cholesteryl ester from the plasma lipoproteins into the artery wall and is a major cause of heart disease. Elevated plasma cholesterol levels are one of the most important factors in promoting atherosclerosis, but it is now recognized that elevated blood triacylglycerol is also an independent risk factor. Diseases in which there is a prolonged elevation of levels of VLDL, IDL, chylomicron remnants, or LDL in the blood are often accompanied by premature or more severe atherosclerosis. There is also an inverse relationship between HDL concentrations and coronary heart disease, making the LDL:HDL cholesterol ratio a good predictive parameter. This is consistent with the function of HDL in reverse cholesterol transport. Susceptibility to atherosclerosis varies widely among species, and humans are one of the few in which the disease can be induced by diets high in cholesterol.
Tips To Lower Cholesterol With Your Diet
Cholesterol is a waxy substance produced by your liver and obtained by eating animal products such as meat, dairy and eggs.
Your liver will produce less cholesterol if you consume a lot of this substance from food, so dietary cholesterol rarely has a great impact on total cholesterol levels.
However, eating large amounts of saturated fat, trans fat and sugars can raise cholesterol levels.
Bear in mind that there are different types of cholesterol.
While good HDL cholesterol may be beneficial for your health, high levels of bad LDL cholesterol, particularly when oxidized, have been linked to an increased risk of heart disease, heart attack and stroke .
Thats because oxidized LDL cholesterol is more likely to stick to the walls of your arteries and form plaques, which clog these blood vessels.
Here are 10 tips to lower cholesterol with your diet and help reduce your risk of heart disease.
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Postfeeding Plasma And Hepatic Lipid Concentrations At Wk 9
Although the plasma total cholesterol concentration in the group fed the mushroom fruiting body was 40% lower than that in the control group, there were no significant differences between the hamsters fed the mycelium diet and the control group . The plasma HDL cholesterol concentration was also significantly lower only in the group fed the fruiting body diet when compared with the control group. The combined plasma VLDL + LDL cholesterol level of the group fed the fruiting body was 43% lower than that of the control group, which did not differ from hamsters fed the mycelium diet. There were no significant differences in the plasma triacylglycerol among the three groups . Hamsters fed both the fruiting body and mycelium diets had lower liver cholesterol concentrations and contents and liver weights compared with the control group .
Plasma lipid concentrations in hamsters after consumption of the control or mushroom diets for 4 wk,
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Assessment Of Intestinal Cholesterol Absorption
Blood was allowed to clot and serum was separated by centrifugation . Sera were aliquoted and stored frozen until analysis. Livers were immediately excised, weighed and divided into small pieces for storage at -80°C . Fecal samples collected for each animal over 4 days were combined and were dried in an oven at 60°C for 24 h. Dried feces were ground to a fine powder using a mortar and pestle. In order to extract total lipid, 100 mg aliquots of the powder and triplicate 10 l aliquots of the original dosing mixture were added to 1.2 ml of chloroform:methanol . Nitrogen-dried lipid extract was ‘saponified’ in 1 ml of 2N NaOH : methanol and incubated at 60°C for 1 h. Labelled sterols were then extracted into 2 ml of diethyl ether. Duplicate 500 l aliquots of the organic phase were transferred into scintillation vials and dried. Scintillation fluid was added and radioactivity was counted. Total liver and fecal lipids were determined gravimetrically after extraction with chloroform:methanol. Individual hepatic and fecal lipids were quantitated enzymatically after solubilization in isopropanol. Triglyceride and total cholesterol concentrations were measured by using GPO-PAP and CHOD-PAP kits , respectively.
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Plasma Lcat Is Responsible For Virtually All Plasma Cholesteryl Ester In Humans
Lecithin: cholesterol acyltransferase activity is associated with HDL containing apo A-I. As cholesterol in HDL becomes esterified, it creates a concentration gradient and draws in cholesterol from tissues and from other lipoproteins , thus enabling HDL to function in reverse cholesterol transport .