The Cholesterol Biosynthesis Metabolic Pathway
The 27 carbon cholesterol molecule is synthesized in a series of approximately 30 enzymatic reactions with all of the carbon atoms originally derived from acetate . The first sterol intermediate, lanosterol, is formed by the condensation of the 30 carbon isoprenoid squalene , and subsequent enzymatic reactions define the post-squalene half of the pathway . The conversion of lanosterol to cholesterol involves the reduction of the C-24 double bond, removal of three methyl groups at the C-14 and C-4 positions, and migration of the C-8 double bond . Some of the enzymatic reactions must occur in sequence for example, 87 isomerization cannot precede C-14 demethylation. The saturation of the C-24 double bond of lanosterol can occur at multiple points in the pathway, creating two immediate precursors for cholesterol, desmosterol and 7-dehydrocholesterol , whose relative abundance may vary among different tissues. Desmosterol, in particular, appears to be abundant in the developing mammalian brain .
Treatment Of Slo Syndrome With Cholesterol
Before the biochemical basis of SLO syndrome was understood, it was well recognised that a significant proportion of infants with SLO syndrome had a major feeding problem associated with marked failure to thrive and irritability. Some of these infants showed an improvement in weight gain when the calorie density of their feeds was increased others showed remarkable catch up weight gain after nasogastric or gastrostomy feeds were begun. When fed adequately, these infants were less irritable. The fact that such improvements can be achieved by correcting malnutrition must be borne in mind when assessing the results obtained with other dietary manipulations.
Not all children show a positive response to cholesterol supplementation some show no change, and we have observed one infant whose parents requested that we stop the treatment because he was more irritable . It is clear that carefully constructed trials are required to delineate what benefits can really be expected when children of different ages and with different severity scores are treated with oral cholesterol.
How A Triglyceride Is Synthesised
Synthesis of Triglycerides The major building block for the synthesis of TGs, in tissues other than adipose tissue, is glycerol. Glycerol-3-phosphate acyltransferase then esterifies a fatty acid to glycerol 3-phosphate, generating the monoacylglycerol phosphate structure called lysophosphatidic acid.
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Intracellular Transport Of Cholesterol
The transport of cholesterol involves both the transport of endogenous cholesterol from the liver to the tissues of the body for use and the transport of cholesterol back to the liver for catabolism.
Cholesterol is transported in the blood as a lipoprotein. Cholesterol combines with apolipoprotein in the blood to form various forms of lipoprotein, such as chylomicron, very-low-density lipoprotein , low-density lipoprotein , and high-density lipoprotein . LDL is mediated by the LDLR into cells. HDL is mediated by scavenger receptor . SR-B1 is related to cholesterol entering and leaving cells and plays an important role in the main signaling pathway of human steroid-producing cells.
Chylomicron: It is responsible for the transport of triglycerides, phospholipids, and cholesterol absorbed by the intestine.
High-density lipoprotein : It is also known as “good” cholesterol because it mainly transfers cholesterol from tissues other than the liver to the liver for catabolism. Many studies have shown that HDL is a unique type of lipoprotein that “sucks” cholesterol out of the walls of atherosclerotic blood vessels and transports it to the liver for metabolic clearance. Therefore, HDL is honored as”anti-atherosclerotic lipoprotein”.
Very-low-density lipoprotein : Some people also call VLDL “bad” cholesterol because it causes plaque to accumulates in arteries too. Differently, VLDL carries triglycerides, LDL transports cholesterol.
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.
11.5.3
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Absorption Transport And Storage
Cholesterol absorption
Cholesterol in the intestinal lumen typically consists of one third dietary cholesterol and two-thirds biliary cholesterol. The average daily diet contains 300500 mg of cholesterol obtained from animal products. The bile provides an additional 8001200 mg of cholesterol throughout each day as gallbladder contractions provide a flow of bile acids, cholesterol, and phospholipids to facilitate lipid digestion and absorption. Dietary cholesterol is a mixture of free and esterified cholesterol whereas biliary cholesterol is nonesterified and is introduced into the small intestine as a cholesterolbile saltphospholipid water-soluble complex. The only other source of intraluminal cholesterol is mucosal cell cholesterol, derived from either sloughed mucosal cells or cholesterol secreted by the mucosal cells into the intestinal lumen. Measurements of exogenous and endogenous cholesterol absorption in humans indicate that there is probably very little direct secretion of newly synthesized cholesterol from mucosal cells into the intraluminal contents.
Exogenous Cholesterol Transport
Tissue Uptake and Storage
What Is True Lipogenesis
Lipogenesis, or fatty acid synthesis, occurs in several cycles. The reactions of lipogenesis include, but are not limited to, two reductions and a dehydration. Malonyl CoA adds a two-carbon group to the growing fatty acid chain with each cycle. The growing fatty acid chain is bound to an acyl carrier protein .
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Lipoproteins As Delivery Vehicles In Cancer Therapeutics
Lipoproteins share a common structural configuration of a phospholipid monolayer stabilized by a protein meshwork, creating a stable, sealed inner hydrophobic core. Based on this architecture, lipoproteins are ideally suited to accommodate and transport lipophilic compounds, including anti-cancer drugs. This capability of natural and synthetic lipoprotein structures is a major advantage for drug delivery, as it allows a stable hydrophobic environment to accommodate anti-cancer agents and protect them from rapid removal from the blood circulation .
The rHDL delivery of anti-cancer drugs has another potential advantage associated with the selective uptake mechanism of the SR-B1 receptor that facilitates the cytoplasmic delivery of rHDL core components without internalization of the lipoprotein particle . This mechanism may be of particular interest as it avoids the lysozomal environment, characteristic of the endocytotic pathway, frequent cause of drug inactivation .
Biosynthesis Of Cholesterol And Its Regulation
- Cholesterol levels in the body originate from its biosynthesis and diet.
- Most of the cholesterol used by active adults is produced in the liver, which produces ~70% of daily cholesterol demand .
- The other 30% originates from dietary absorption.
- Biosynthesis of cholesterol commonly happens in the endoplasmic reticulum of hepatic cells.
- It starts with acetyl-CoA, which is basically taken from an oxidation response in the mitochondria.
- In spite of that, acetyl-CoA can be taken from the cytoplasmic oxidation of ethanol by acetyl-CoA synthetase.
- Acetyl-CoA and acetoacetyl-CoA are transformed into 3-hydroxy-3-methylglutaryl-CoA by HMG-CoA synthase.
The following products should be synthesized first before leading to the biosynthesis of cholesterol:
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Cholesterol From Dietary Sources
Before releasing dietary triglycerides and cholesterol into the circulation system as Very low-density lipoproteins , they are packaged together with Apo proteins in the liver. The VLDL that is circulated in our body contains cholesterol, triglycerides, and phospholipids. Smaller low-density lipoproteins , rich in cholesterol, ars formed by the degradation of triglycerides.
The LDLs travel through the bloodstreams and reach the peripheral tissues. On the cell membrane, the LDL was recognized by the LDL receptors and were endocytosed through receptor-mediated endocytosis. HDL, on the other hand, get rid of the excess cholesterol by carrying it from the peripheral tissue to the liver in a reverse transport mechanism.
Since we produce enough cholesterol in our body, we dont need to consume it from dietary sources. The lipids present in those food items can produce LDL and cause damage to our body. Therefore, one must take care of certain facts while consuming food.
One must pay attention to the levels of added sugar, the saturated, and trans fat present in the food before eating it. Consumption of a lesser amount of fats can keep your body healthy.
One can replace saturated fats with more healthy and saturated fats. For example, butter can be replaced with extra virgin olive oil in cooking or nuts, and seeds can replace processed snack foods.
The Biosynthesis Of Hmg
The synthesis of HMG-CoA takes place in the following steps:
- 2 acetyl CoA molecules combine to form acetoacetyl- CoA, in the presence of enzyme thiolase.
- The 3rd molecule of acetyl CoA is added to form 3-Hydroxy-3-Methylglutaryl CoA . This takes place in the presence of enzyme HMG-CoA synthase. It is a cytosolic enzyme.
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Hormone Regulation Of Cholesterol Synthesis
Cholesterol is the chief source of the biogenesis of steroid hormones. As a result, several hormones exert acute effects on cholesterol synthesis or metabolism. When this occurs through the direct impact of the hormones upon regulating the expression or activity of HMG-CoA reductase SREBP-1c or LDLr, it is known as the hormone regulation of cholesterol synthesis.
Medical Guidelines And Recommendations
In 2015, the United States Department of Agriculture Dietary Guidelines Advisory Committee recommended that Americans eat as little dietary cholesterol as possible, because most foods that are rich in cholesterol are also high in saturated fat and thereby may increase the risk of cardiovascular disease. For over 2 decades, the Dietary Guidelines for Americans recommended that dietary cholesterol be no more than 300 mg per day. In a 2014 draft, DGAC dropped this recommendation because evidence showed no appreciable relationship between dietary and serum cholesterol. This caught the eye of the Physicians Committee for Responsible Medicine , which sued DGAC due to concerns of conflicts of interest which prompted the final draft to recommend eating “as little dietary cholesterol as possible”. A 2013 report by the American Heart Association and the American College of Cardiology recommended to instead focus on healthy dietary patterns rather than cholesterol limits as they are hard for clinicians and consumers to implement. They recommend the DASH and Mediterranean diet, which are low in cholesterol. A 2017 review by the American Heart Association recommends switching saturated fats for polyunsaturated fats to reduce cardiovascular disease risk.
| > 6.2 | High risk |
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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.
11.2.5
The Utilization Of Cholesterol
Cholesterol is transported in the plasma predominantly as cholesteryl esters associated with lipoproteins. Dietary cholesterol is transported from the small intestine to the liver within chylomicrons. Cholesterol synthesized by the liver, as well as any dietary cholesterol in the liver that exceeds hepatic needs, is transported in the serum within LDL. The liver synthesizes VLDL and these are converted to LDL through the action of endothelial cell-associated lipoprotein lipase. Cholesterol found in plasma membranes can be extracted by HDL and esterified by the HDL-associated enzyme lecithin-cholesterol acyltransferase, LCAT. The cholesterol acquired from peripheral tissues by HDL can then be transferred to VLDL and LDL via the action of cholesteryl ester transfer protein which is associated with HDL. Reverse cholesterol transport allows peripheral cholesterol to be returned to the liver in LDL. Ultimately, cholesterol is excreted in the bile as free cholesterol or as bile salts following conversion to bile acids in the liver.
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Proteolytic Cleavage In The Golgi Releases Srebp
Once SREBP reaches the Golgi, it is ambushed and cleaved by two specific proteases . Cleavage releases the DNA-binding domain of the protein from the membrane. This fragment then moves across the cytosol and enters the nucleus, where it binds to SRE sequence elements that increase the expression of HMG-CoA reductase and also of various other enzymes from the cholesterol synthesis pathway .
Another protein that is upregulated by SREBP and SRE is the LDL receptor, a membrane protein that mediates endocytosis of low density lipoprotein . In cells that do not synthesize cholesterol themselves, SREBP upregulates transcription of the LDL receptor,
Like SREBP and SCAP, HMG-CoA reductase is anchored in the ER membrane. This does not seem necessary for the chemistry it performs. Instead, this location facilitates the negative feedback regulation imposed on it by cholesterol. Indeed, the enzyme contains a sterol-sensing domain that is homologous to the one found in SCAP .
11.4
How Is The Biosynthesis Of Cholesterol Regulated
The amount of cholesterol that is synthesized in the liver is tightly regulated by dietary cholesterol levels. When dietary intake of cholesterol is high, synthesis is decreased and when dietary intake is low, synthesis is increased. However, cholesterol produced in other tissues is under no such feedback control.
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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.
| 11.5.4 |
When Cholesterol Is Low Srebp Is Sorted To The Golgi Apparatus
At low cholesterol concentrations, SCAP binds to another membrane protein that recruits it into nascent vesicles, and it takes SREBP along for the ride. When these vesicles bud off from the ER membrane, they travel to the Golgi apparatus and fuse with its membrane. The Golgi is a cellular organelle that performs many types of posttranslational protein modification, such as glycosylation, lipid modification, and proteolytic processing.
11.3.3
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Targeting Cholesterol Pathways As Cancer Therapy
Accumulating evidence suggests that cholesterol plays an important role in cancer progression and development. Accordingly, several strategies involving regulatory factors that impact cell and blood cholesterol levels have been studied. The inhibition of the mevalonate pathway using statin drugs or biophosphonates result in inhibition of tumor growth and proliferation . Parallel to the statins and bisphosphonates, isoprenoids and particularly tocotrienols suppress tumor growth in vitro and in vivo consequent to mevalonate deprivation.
Similarly, a drug , known to inhibit cholesterol absorption by blocking NPC1L1 gut transporters, was shown to interfere with carcinogenesis . In this study the administration of ezitimibe significantly decreased tumor-associated blood vessel development, apparently via increased levels of TSP-1, a potent inhibitor of angiogenesis . These and other findings suggest that decreasing plasma cholesterol levels may be a plausible therapeutic approach to cancer therapy. Alternate therapeutic strategies have also been proposed attempting to take advantage of the high cholesterol requirements of cancer cells. This strategy relies on Trojan horse approach to deliver anti-cancer agents to cancer cells and tumors via receptor-mediated mechanism as discussed below.
Plasma Transport And Regulation Of Absorption
As an isolated molecule, cholesterol is only minimally soluble in water, or hydrophilic. Because of this, it dissolves in blood at exceedingly small concentrations. To be transported effectively, cholesterol is instead packaged within lipoproteins, complex discoidal particles with exterior amphiphilic proteins and lipids, whose outward-facing surfaces are water-soluble and inward-facing surfaces are lipid-soluble. This allows it to travel through the blood via emulsification. Unbound cholesterol, being amphipathic, is transported in the monolayer surface of the lipoprotein particle along with phospholipids and proteins. Cholesterol esters bound to fatty acid, on the other hand, are transported within the fatty hydrophilic core of the lipoprotein, along with triglyceride.
There are several types of lipoproteins in the blood. In order of increasing density, they are chylomicrons, very-low-density lipoprotein , intermediate-density lipoprotein , low-density lipoprotein , and high-density lipoprotein . Lower protein/lipid ratios make for less dense lipoproteins. Cholesterol within different lipoproteins is identical, although some is carried as its native “free” alcohol form , while others as fatty acyl esters, known also as cholesterol esters, within the particles.
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Formation Of A C10 Intermediate
The next stage begins with the conversion of one molecule of isopentenyl-pyrophosphate to dimethylallyl-pyrophosphate, catalyzed by the isopentenyl-pyrophosphate isomerase. The product is condensed with another molecule of isopentenyl-pyrophosphate to yield geranyl-pyrophosphate. In this reaction, catalyzed by geranyl-pyrophosphate synthase, the pyrophosphate of the first substrate serves as a leaving group. The resulting carbocation reacts with the double bond of the second substrate.
11.2.4
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.
11.4.6
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