Lipoproteins Transport Lipids Around The Body
Lipoproteins are transport vehicles for moving water-insoluble lipids around the body. There are different types of lipoproteins that do different jobs. However, all are made up of the same four basic components: cholesterol, triglycerides, phospholipids, and proteins.
The interior of a lipoproteincalled the lipid corecarries the triglycerides and cholesterol esters, both of which are insoluble in water. Cholesterol esters are cholesterol molecules with a fatty acid attached. The exterior of lipoproteinscalled the surface coatis made up of components that are at least partially soluble in water: proteins , phospholipids, and unesterified cholesterol. The phospholipids are oriented so that their water-soluble heads are pointed to the exterior, and their fat-soluble tails are pointed towards the interior of the lipoprotein. Apoliproteins are similarly amphipathic , a property that makes them useful for aiding in the transport of lipids in the blood.
Figure 5.24. Basic structure of all lipoproteins. Note the orientation of phospholipids on the surface coat.
While all lipoproteins have this same basic structure and contain the same four components, different types of lipoproteins vary in the relative amounts of the four components, in their overall size, and in their functions. These are summarized in the graph and table below, and the following sections give more details on the role of each type of lipoprotein.
Figure 5.25. Comparison of composition of lipoproteins.
Transport Of Cholesterol Between The Liver And Peripheral Tissues
The liver synthesizes cholesterol from acetyl-CoA . The cholesterol pool in liver cells also receives the dietary cholesterol, which is contained in the chylomicron remnants that are formed through the extraction of triacylglycerol from chylomicrons by lipoprotein lipase .
Liver cells package esterified cholesterol, together with triacylglycerol, into particles of very low density lipoprotein . Like chylomicrons, VLDL interacts with lipoprotein lipase and thereby turns into intermediate and then low density lipoprotein .
LDL is taken up by cells in the periphery through endocytosis, which is mediated by the LDL receptor.71 Excess cholesterol is exported from the cell by an active transporter and delivered to high density lipoprotein , which then carries it back to the liver. Cholesterol transport by HDL is facilitated by lecithin-cholesterol acyltransferase .
Cholesterol Esters Can Be Stored Inside Lipoprotein Particles
Cholesterol is amphiphilic and tends to accumulate at lipid/water interfaces, with the OH group exposed to the aqueous phase. Free cholesterol can therefore be transported only within the outermost layer of lipid molecules of a lipoprotein particle. In contrast, cholesterol esters are entirely hydrophobic and readily partition into the interior of lipoprotein particles. The LCAT reaction therefore greatly increases the transport capacity of HDL particles for cholesterol.
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What Treatments Are Available For High Cholesterol
Treatment may include:
Addressing risk factors. Some risk factors that can be changed include lack of exercise and poor eating habits.
Cholesterol-lowering medicines. Medicines are used to lower fats in the blood, particularly LDL cholesterol. Statins are a group of medicines that can do this. The two most effective types are atorvastatin and rosuvastatin. Other medicines that lower cholesterol levels are ezetimibe and PCSK9 inhibitors.
Vldl Ldl And Cholesterol Metabolism
Cholesterol has a vital role in life and is essential for the normal functioning of cells both as a cell membrane constituent and as a precursor of steroid hormones and other key metabolites.In the lumen of the small intestine, free cholesterol from the diet and from biliary secretion is solubilized in mixed micelles containing bile acids and phospholipids before it is absorbed by the enterocytes by a mechanism for which the apical protein Niemann-Pick C1-like 1 is crucial. Within the enterocyte, the metabolic fate of the absorbed cholesterol involves an integrated network of many different proteins. Most of it is transported to the endoplasmic reticulum where it is converted to cholesterol esters by the enzyme acyl-CoA:cholesterol acyltransferase 2 and is selectively packaged into chylomicron particles, a process that requires a specific microsomal transfer protein and apoprotein B48, for transport out of the enterocyte into the lymphatic system and subsequently to the liver for uptake at the basolateral side of the hepatocytes as described above for triacylglycerols.Regulation of intestinal cholesterol uptake and secretion is mediated by the nuclear receptor Liver X Receptor .
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Structures Of Abc Transporters In The Inward
Both ABCA5/8 and ABCA1 are members of the ATP-binding cassette or ABC family of transporters. These have a common structural organization. Several ABC transporters have been crystallized in the inward- and outward open conformations , and the two structures provide a glimpse of how they work.
ABC transporters often have rather broad substrate specificity and mediate the membrane translocation of many metabolites and xenobiotics. In addition to cholesterol and other membrane lipids, important examples are bile acids , conjugated bilirubin , drugs, and drug metabolites . Cancer cells often overexpress ABC transporters, which renders them resistant to multiple anticancer drugs.
Reverse Cholesterol Transport: Molecular Mechanisms And The Non
- 1Exercise and Immunometabolism Research Group, Department of Physical Education, Universidade Estadual Paulista, Presidente Prudente, Brazil
- 2Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- 3Immunometabolism of Skeletal Muscle and Exercise Research Group, Department of Physical Education, Federal University of Piauí, Teresina, Brazil
- 4Human Movement Laboratory, Universidade São Judas Tadeu, São Paulo, Brazil
- 5Department of Biosciences, Universidade Federal de São Paulo, Santos, Brazil
Estimation Of Ldl Particles Via Cholesterol Content
Chemical measures of lipid concentration have long been the most-used clinical measurement, not because they have the best correlation with individual outcome, but because these lab methods are less expensive and more widely available.
The lipid profile does not measure LDL particles. It only estimates them using the Friedewald equationby subtracting the amount of cholesterol associated with other particles, such as HDL and VLDL, assuming a prolonged fasting state, etc.:
- L T
- where H is HDL cholesterol, L is LDL cholesterol, C is total cholesterol, T are triglycerides, and k is 0.20 if the quantities are measured in mg/dl and 0.45 if in mmol/l.
There are limitations to this method, most notably that samples must be obtained after a 12 to 14 h fast and that LDL-C cannot be calculated if plasma triglyceride is > 4.52 mmol/L . Even at triglyceride levels 2.5 to 4.5 mmol/L, this formula is considered inaccurate. If both total cholesterol and triglyceride levels are elevated then a modified formula, with quantities in mg/dl, may be used
- L T
This formula provides an approximation with fair accuracy for most people, assuming the blood was drawn after fasting for about 14 hours or longer, but does not reveal the actual LDL particle concentration because the percentage of fat molecules within the LDL particles which are cholesterol varies, as much as 8:1 variation.
The Role Of Hdl In Protection From Oxidation
In addition to the role of HDL in cholesterol transport, recent research indicates that some HDL species have a second, probably independent role. Two enzymes implicated in protection of lipids and cells against oxidation circulate as complexes with specific HDL subspecies. These are platelet activating factor hydrolase and paraoxonase. Both enzymes have been implicated in catabolizing the oxidized fatty acids which accumulate in phospholipids exposed to cellular peroxidases. Without degradation, these oxidized lipids accumulate in the tissues and may be an important element in the inflammatory reaction occurring at the artery wall in atherosclerosis. The apolipoprotein composition of these specialized HDL fractions has not yet been defined.
Teresita Bellido, Kathleen M. Hill Gallant, in, 2014
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Transport Of Lipids In The Body Fluids
Transport of Triglycerides and Other Lipids from the Gastrointestinal Tract by LymphThe Chylomicrons
As explained in Chapter 65, almost all the fats in the diet, with the principal exception of a few short-chain fatty acids, are absorbed from the intestines into the intestinal lymph. During digestion, most triglycerides are split into monoglycerides and fatty acids. Then, while passing through the intestinal epithelial cells, the mono-glycerides and fatty acids are resynthesized into new molecules of triglycerides that enter the lymph as minute, dispersed droplets called chylomicrons, whose diameters are between 0.08 and 0.6 micron. A small amount of apoprotein B is adsorbed to the outer surfaces of the chylomicrons. This leaves the remainder of the protein molecules projecting into the surrounding water and thereby increases the suspension stability of the chylomicrons in the lymph fluid and prevents their adherence to the lymphatic vessel walls.
Most of the cholesterol and phospholipids absorbed from the gastrointestinal tract enter the chylomicrons. Thus, although the chylomicrons are composed principally of triglycerides, they also contain about 9 per cent phospholipids, 3 per cent cholesterol, and 1 per cent apoprotein B. The chylomicrons are then transported upward through the thoracic duct and emptied into the circulating venous blood at the juncture of the jugular and subclavian veins.
Removal of the Chylomicrons from the Blood
mg/dl of plasma
Structure And Function Of Cetp
CETP acts as a medium between lipoproteins for elevating plasma LDL-C level and lowering HDL-C level . A series of CETP inhibitors have been investigated in clinical, such as torcetrapib, dalcetrapib, evacetrapib, and anacetrapib . However, current inhibitors represent the turbulent beginning of CETP inhibition and an increased mortality rate related to off-target effects and lack of efficacy . Accompanying adverse effects call for a deeper exploration of the mechanism for CETP-mediated lipid transfer.
The crystal structure of CETP and three-dimensional density maps of CETP binging lipoproteins. Atom figure of CETP. Secondary structure of CETP. Ternary complexes of HDL-CETP-LDL in cryo-EM micrographs. ~ the CETP insert into HDL, VLDL, LDL respectively in cryo-EM micrographs. the tunnel model of CETP-mediated lipid transfer .
However, there are some discrepancies with the tunnel model mentioned above. Matthias et al. used the experiments which involve three monoclonal antibodies to demonstrate that the antibodies binding on both ends of CETP do not inhibit CETPs function of transshipment cholesterol esters, but the antibodies on the middle does . In their research they supposed that the formation of the ternary tunnel complexes is not a mechanistic prerequisite by CETP to perform its functions. Hence, the real mechanism of CETP-mediated lipid transfer still remains to be studied and verified.
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Bile Acid Cycling Involves Multiple Transport Proteins
A variety of transport proteins enable the bile acid enterohepatic cycle. Secretion from the liver cell into the bile is driven by ABCC2, another ABC type transporter . Reuptake from the lumen of the gut is mediated by the apical sodium-coupled bile acid transporter . A similar transporter, the Na+-dependent taurocholate cotransporting polypeptide , mediates uptake from the blood back into the liver cell. At the basolateral membranes of both intestinal and liver cells, organic anion transport proteins , which have a fairly low degree of substrate specificity, participate in bile acid transport.
How Are Fats Transported In The Blood
Triglycerides and cholesteryl esters are transported in the core of plasma lipoproteins. The intestine secretes dietary fat in chylomicrons, lipoproteins that transport triglyceride to tissues for storage. Dietary cholesterol is transported to the liver by chylomicron remnants which are formed from chylomicrons.
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Formation Of C15 And C30 Intermediates
The synthesis of the C15 intermediate, farnesyl-pyrophosphate, is catalyzed by the eponymous synthase and mechanistically resembles that of geranyl-pyrophosphate. Farnesyl-pyrophosphate is used not only in sterol synthesis but also in the posttranslational modification of some membrane-associated proteins. While the amount of farnesyl-pyrophosphate used for the latter purpose is not very large, inhibition of protein farnesylation may contribute to the clinical effect of inhibitory drugs that act upstream in this pathway this includes the statins, which inhibit HMG-CoA reductase .
Two molecules of farnesyl-pyrophosphate are joined head to head in the synthesis of the final linear sterol precursor, namely, squalene the enzyme is named squalene synthase.
Lipid Transport From The Liver
The contents of chylomicron remnants, as well as other lipids in the liver, are incorporated into another type of lipoprotein called very-low-density lipoprotein . Similar to chylomicrons, the main job of VLDL is delivering triglycerides to the bodys cells, and lipoprotein lipase again helps to break down the triglycerides so that they can enter cells .
As triglycerides are removed from VLDL, they get smaller and more dense, because they now contain relatively more protein compared to triglycerides. They become intermediate-density lipoproteins and eventually low-density lipoproteins . The main job of LDL is to deliver cholesterol to the bodys cells. Cholesterol has many roles around the body, so this is an important job. However, too much LDL can increase a persons risk of cardiovascular disease, as well discuss below.
High-density lipoproteins are made in the liver and gastrointestinal tract. Theyre mostly made up of protein, so theyre very dense. Their job is to pick up cholesterol from the bodys cells and return it to the liver for disposal.
Figure 5.27. Overview of lipoprotein functions in the body.
VIDEO: Cholesterol Metabolism, LDL, HDL, and Other Lipoproteins, Animation, by Alila Medical Media, YouTube , 3:45 minutes.
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Initial Activation Steps In Cholesterol Synthesis
The reactions shown in this slide are catalyzed by thiolase , HMG-CoA synthase , HMG-CoA reductase , mevalonate kinase, phosphomevalonate kinase , and diphosphomevalonate decarboxylase, and diphosphomevalonate decarboxylase again .68 In the subsequent steps of the pathway, six molecules of isopentenyl-pyrophosphate are used for the synthesis of one cholesterol molecule.
Bile Acids Undergo Enterohepatic Cycling
In an enterohepatic cycle, a substance is secreted by the liver into the bile, passes into the intestine and is taken up again into the blood, either by passive diffusion across cell membranes or by active transport. Since blood drained from the intestines feeds into the portal vein, the substance will return to the liver, where it may be captured by liver cells and once again secreted into the bile.
Bile acids are taken up by active transport in the terminal ileum, that is, in the lowermost section of the small intestine. The efficiency of reuptake is normally > 90Ã %. Only the fraction that is not recovered needs to be replaced by de novo synthesis from cholesterol.
During their repeated passages through the intestine, some bile acids undergo modification by microbial enzymes an example is the formation of deoxycholate from cholate. Such modified molecules become part of the circulating bile acid pool.
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Only About 20% Of The Cholesterol In Your Bloodstream Comes From The Food You Eat Your Body Makes The Rest
Cholesterol has a bad reputation, thanks to its well-known role in promoting heart disease. Excess cholesterol in the bloodstream is a key contributor to artery-clogging plaque, which can accumulate and set the stage for a heart attack. However, the role of cholesterol in your body is not all negative.
To fully explain cholesterol, you need to realize that it’s also vital to your health and well-being. Although we measure cholesterol production in the blood, it’s found in every cell in the body. The Harvard Special Health Report Managing Your Cholesterol explains cholesterol as a waxy, whitish-yellow fat and a crucial building block in cell membranes. Cholesterol also is needed to make vitamin D, hormones , and fat-dissolving bile acids. In fact, cholesterol production is so important that your liver and intestines make about 80% of the cholesterol you need to stay healthy. Only about 20% comes from the foods you eat.
If you eat only 200 to 300 milligrams of cholesterol a day , your liver will produce an additional 800 milligrams per day from raw materials such as fat, sugars, and proteins.
Since cholesterol is a fat, it can’t travel alone in the bloodstream. It would end up as useless globs . To get around this problem, the body packages cholesterol and other lipids into minuscule protein-covered particles that mix easily with blood. These tiny particles, called lipoproteins , move cholesterol and other fats throughout the body.
Which Lipoprotein Transports Cholesterol To The Liver
- The most common causes of high triglycerides are obesity and poorly controlled diabetes.
- Other causes of high triglycerides include hypothyroidism, kidney disease, and certain inherited lipid disorders.
- Estrogen therapy, which may be used for menopause symptoms, may also raise triglyceride levels.
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How Do Chylomicrons Transport Cholesterol
Chylomicrons predominately transport triacylglycerols to adipose tissue and muscle as fatty acids, but also deliver dietary cholesterol taken up by enterocytes in the lumen to the liver. Once most of the triacylglycerols have been delivered to the adipose tissue and muscle, the remnants of the lipoprotein,
Can Jiggling Fat Burn Calories
Multiple studies have confirmed that fidgeting throughout the entire day can burn ten times more calories than just sitting still one study from 2005 clocked the number at 350 calories per day, enough to lose 30 to 40 pounds in one year. It makes sense: constant motion, even while sitting, is a form of cardio.
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A Familial Hypercholesterolemia: Ldlr Pathway
Familial hypercholesterolemia is one of the most common inborn errors of metabolism and the most common in the category of monogenic defects of cellular cholesterol processing . In most cases, it is an autosomal dominant disorder, with the heterozygous state affecting 1 in 500 individuals . There is a strong gene dosage effect, and the rare homozygous FH patients exhibit a very severe clinical phenotype. The majority are caused by mutations in the LDLR gene. A rarer, clinically indistinguishable phenotype is caused by mutations in apoB, the ligand for the LDLR. In the latter case, the disease is referred to as familial defective apoB-100.
A third locus underlying autosomal dominant hypercholesterolemia, PCSK9 , was recently identified . In addition to an increasing number of patient mutations, there is suggestive evidence for the involvement of PCSK9 gene variants in affecting total and LDL cholesterol levels in the population . PCSK9 is a serine protease in the secretory pathway and plays an important role in controlling LDLR levels, but the precise mechanism remains to be resolved. In principle, increased LDL cholesterol in the absence of PCSK9 function could reflect decreased clearance or increased hepatic secretion of apoB-containing lipoproteins. Both possibilities are being investigated .