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Steroids and Fat Soluble Vitamins
Terms in this set (11)
Steroids are a special group of lipids of considerable importance. They function as components of cell membranes, as emulsifiers of dietary fat and as hormones. Steroids with methyl groups at positions 10 and 13, a hydroxyl group at position 3 and an aliphatic side chain of 8‑10 carbons at position 17 are called sterols, such as cholesterol. In cholesterol, the structure around carbon 7 is important in both vitamin D and bile salts.
Functions - The most abundant sterol in animal tissues is cholesterol. It is an important component of biological membranes in which it intercalates (with its hydroxyl group facing outwards) in between phospholipids on either side of the membrane monolayer. By filling in the gaps formed by the 2C unsaturated FAs of the phospholipids it serves to reduce the fluidity of the membrane, decreasing the thermal motion of other membrane components and membrane permeability. It also tends to cluster in "rafts" on the membrane surface, where it can be present at a ratio of 1 cholesterol/ 1 phospholipid. These relatively non-fluid membrane rafts appear to play important roles in the functioning of certain membrane proteins and the traffic of membrane vesicles. Derivatives of cholesterol also have important functions (as steroid hormones, bile acids and vitamin D). Cholesterol can come from the diet, but is not an essential nutrient, since the body can synthesize sufficient cholesterol de novo
Dietary Cholesterol - Dietary Cholesterol comes from animal fats. As there is no cholesterol in plants, all plant
products are naturally "cholesterol free" (instead plants have another class of sterols, called sitosterols, which we cannot make use of). Dietary cholesterol esters are hydrolyzed to cholesterol and free FAs by a pancreatic cholesterol esterase. This released cholesterol is absorbed through the intestinal wall, re-packaged as cholesterol esters into chylomicrons, and transferred to the blood stream by way of the lacteals. The liver ultimately takes up dietary cholesterol through LRP-mediated endocytosis of chylomicron fragments.
Important derivatives of cholesterol and its synthetic intermediates includes bile salts, steroid hormones, Vitamin D, coenzyme Q, etc.
The liver is the main site of cholesterol synthesis, but other tissues such as intestines, skin and kidneys can contribute significant amounts of cholesterol. The biosynthesis of cholesterol occurs in both the cytoplasm and the endoplasmic reticulum. Under conditions of high energy charge, acetyl CoA is transported from the mitochondria to the cytoplasm via citrate. Once there it can be used to form fatty acids or can be used for the synthesis of cholesterol. The first step in cholesterol synthesis is the formation of cytoplasmic 3-hydroxy-3-methylglutaryl CoA (HMG CoA). The cytoplasmic reactions, catalyzed by thiolase to form acetoacetyl CoA from 2 acetyl CoA's, and HMG CoA synthase to form HMG-CoA from acetyl-CoA and acetoacetyl-CoA. Note that these reactions are essentially identical to those used to form HMG-CoA for ketone body synthesis in the mitochondria (although separate enzymes, isozymes, are used in these separate compartments).
The fate of HMG-CoA in the cytoplasm is quite different
from that in the mitochondria, where HMG-CoA lyase produces the ketone body acetoacetate. Cytoplasmic HMG-CoA is instead acted upon by the enzyme HMG-CoA reductase, located on the endoplasmic reticulum. HMG-CoA reductase uses two molecules of NADPH to reduce HMG CoA and form a six carbon branched-chain acid which is no longer linked to CoA, called mevalonic acid (mevalonate). HMG CoA reductase is the most important regulatory step in cholesterol synthesis. Its activity is decreased by high levels of free cholesterol. It can also be inhibited by phosphorylation performed by an AMPK kinase that is activated by cAMP-dependent protein kinase (thus glucagon and epinephrine inhibit HMG CoA reductase). Removal of these phosphates by action of a phosphatase can reactivate it. In addition, the enzyme has a t1/2 of only 3 hours and its concentration is controlled by the rate of its own synthesis and degradation. Specific competitive inhibitors of HMG CoA reductase, the statins (such as pravastatin) are commonly used to reduce cholesterol levels of patients at risk of heart disease since they closely resemble the cholesterol substrate. By blocking the ability of HMG-CoA to bind to the enzyme the statins can result in decreased production of cholesterol and a 20-40% drop in the levels of circulating cholesterol on LDL.
In the next step of cholesterol synthesis, mevalonic acid is decarboxylated and phosphorylated in a series of reactions involving the utilization of three molecules of ATP to ultimately form a five-carbon alcohol pyrophosphate, 3-isopentenyl pyrophosphate (IPP). Isopentenyl pyrophosphate is an isoprene compound, and steroids are built up of multiple condensations of 5-carbon isoprene units. The first condensation reaction in sterol biosynthesis is the effective "head to tail" condensation (PP-end to alkyl end) of two molecules of IPP. The reaction forms a 10-carbon compound, geranyl pyrophosphate. The latter compound condenses with another molecule of IPP to yield a 15-carbon pyrophosphate, farnesyl pyrophosphate (FPP). Both of these reactions are catalyzed by a single enzyme. Farnesyl groups can be attached to proteins to anchor them in membranes. In addition to cholesterol, farnesyl-PP is the precursor in the formation of several other important isoprenoids, such as dolichol (see the lectures on Carbohydrate Metabolism) which carries sugars for protein glycosylation, and ubiquinone (coenzyme Q, see the lectures on Mitochondria) which is the electron carrier between complexes I or II and complex III in the respiratory chain. The final condensation in sterol biosynthesis is a reaction involving two molecules of farnesyl pyrophosphate that condense using NADPH as a reductant, and forming the 30-carbon hydrocarbon, squalene.
Squalene is oxidized by squalene monooxygenase (a mixed-function oxidase), utilizing both NADPH and O2 to
form squalene-2,3-epoxide. This molecule undergoes cyclization, catalyzed by squalene-2,3,-oxide cyclase to form the first steroid product, lanosterol. Lanosterol (a 30-carbon compound) can then undergo a series of demethylation and rearrangement reactions using either NADH or NADPH to form cholesterol. Total of 18 ATP and 14 NADPH's used!
Cellular Control of Cholesterol Levels
The maintenance of precise cholesterol levels is important for membrane functions of the cell. Accordingly, levels of free cholesterol must be carefully regulated. This is accomplished by the following mechanisms:
1. HMG CoA reductase - As detailed above, de novo cholesterol synthesis is largely controlled via reducing or
increasing the levels or activity of cytoplasmic HMG CoA reductase. High levels of cholesterol result in the inhibition of HMG CoA reductase. Occurs in liver, skin, and intestines; provides source of cholesterol
2. Import control - In addition to synthesizing cholesterol, cells can get free cholesterol by endocytosing LDL and hydrolyzing the cholesterol esters within. High levels of free cholesterol down-regulate the number of LDL receptors on the cell surface, resulting in less LDL being taken in. Another source of cholesterol.
3. Formation of intracellular cholesterol esters - High levels of free cholesterol stimulates the activity of acyl cholesterol acyl transferase (ACAT), which forms cholesterol esters from cholesterol and acyl-CoA. These CEs can be stored inside cells as lipid droplets and released by esterase action when needed.
4. Export of excess cholesterol - Instead of forming lipid droplets, CEs formed by ACAT can be packaged into lipoproteins for export from the cell (chylomicrons in the intestine and VLDL in the liver). In addition, serum HDL can pick up excess free cholesterol from the surface of cells by stimulating the action of serum lecithin cholesterol acyl transferase (LCAT).
5. Use in membranes - New sources of cholesterol are required to replace that lost from membranes by oxidation
or turnover, and to generate new membranes.
6. Conversion to cholesterol derivatives - cholesterol is modified in the liver to form the bile salts required for lipid emulsification. In addition, in steroidogenic tissues, free cholesterol is converted to steroid hormones.
**Each cell in the body needs to maintain a proper balance of cholesterol inputs, uses and outputs. Defects in this process can have wide-ranging, deleterious effects. For instance, a defective LDL receptor greatly decreases the ability of cells to take in circulating cholesterol, and results in continuous high levels of circulating LDL and the development of atherosclerotic plaques (Familial Hypercholesterolemia). By contrast, in Wolman's Syndrome or Cholesterol Ester Storage Disease, the uptake of LDL is normal, but a defect in a lysosomal esterase prevents the hydrolysis of cholesterol esters, resulting in the accumulation of large amounts of cholesterol esters within cells.
The steroid ring of cholesterol cannot be effectively broken down in humans. The pool recycling of bile acids through
enterohepatic circulation of cholesterol in the body is determined by the rate of input (from diet and synthesis) versus the rate of use or removal (from excretion, conversion to cholesterol derivatives, and growth of new tissue). The major route of cholesterol removal from the body pool is via metabolism in the liver to bile acids (bile salts). The rate limiting step for bile acid synthesis is 7α-hydroxylase, which converts cholesterol to 7α-hydroxycholesterol. 7th position gets modified to become hydrophilic which is good for emulsification. A series of reactions involving mixed function oxidases then further oxidize and modify 7α-hydroxycholesterol to a variety of bile acids such as cholic acid (which differ depending on the nature of the R- side chain on the terminal carboxylic acid moiety).
Bile acids are stored in the gall bladder, and secreted through the bile into the small intestine to facilitate lipid absorption. Bile acids are then actively reabsorbed (in an energy requiring process) in the small intestine and are shuttled back to the gall bladder for reuse, in a process known as enterohepatic circulation. While some bile acids are still lost in the stool, this active reabsorption reduces the body's overall need for cholesterol biosynthesis
**When cholesterol is too abundant, levels of circulating LDL increase, which is a root cause of atherosclerosis. LDL levels can be controlled by:
Ensuring proper LDL uptake by LDL-Receptors
Decreasing synthesis (HMG-CoA reductase inhibitors)
Decreasing dietary cholesterol
Promoting excretion of excess cholesterol (as bile salts)
Oats bind bile acids enough that they get excreted a little bit
Cholesterol is also the precursor for the steroid hormones including the adrenal cortical hormones and male and female sex hormones. These are synthesized from cholesterol in the adrenal cortex and gonads, respectively. Much of this cholesterol enters these cells via the LDL pathway, and potentially also from internalization of HDL. Pregnenolone is first precursor to the rest of the steroid hormones.
In general, the steroid hormones function as intercellular signaling molecules. They tend to have enough polar groups (generally hydroxyls) to be soluble in aqueous media such as the blood and the cytoplasm of cells. They are also hydrophobic enough to readily pass through cell (and nuclear) membranes. When a hormone (e.g. estradiol from the ovaries) is released, it travels through the blood and enters cells. Once inside it can bind to specific members of a class of steroid hormone receptor proteins in the nucleus (e.g. the estrogen receptor, ER). The steroid receptors are sequence-specific DNA-binding transcription factors which, when bound by hormone, generally result in increased transcription of specific target genes. The tissues that harbor the appropriate steroid receptor, and the specific genes activated when that receptor binds hormone dictate the body's response to each hormone. The structures for aldosterone and estradiol lack the aliphatic tail and often have additional polar groups. This gives
them the important characteristic of being moderately soluble in aqueous medium, but also capable of crossing
1. Aldosterone = from adrenal cortex, regulate electrolyte and water resorption in kidney.
2. Cortisol = from adrenal cortex, involved in carbohydrate, protein & fat metabolism, also suppresses immune response & inflammation.
3. Corticosterone = from adrenal cortex, similar to cortisol and aldosterone but less potent
4. Estradiol (estrogen) = from ovary, chief female sex hormone responsible for development of secondary sexual characteristics and reproductive cycle
5. Pregnenolone = from many tissues, initial precursor for all other steroid hormones
6. Progesterone = from corpus luteum, placenta, and adrenal cortex. Chief hormone of pregnancy, maintains pregnancy.
7. Testosterone = from testes, chief male sex hormone and is precursor to estradiol
Fat Soluble Vitamins
Certain isoprene-based lipids required as cofactors or signaling molecules cannot be synthesized by humans, and must be derived from the diet. These are the fat-soluble vitamins A, E, and K. Vitamin D is included in this class, although it can be synthesized de novo under the appropriate conditions but further supplementation may be needed. Fat soluble vitamins are generally transported by the lipoproteins or specific transport proteins (vit A and D).
Not soluble in water- cannot be easily excreted. Great excess (>10x RDA) can be toxic, especially for vitamins D & A.
Vitamin A plays an important role in vision, growth, differentiation, and maintenance of normal epithelial tissue functions. The term Vitamin A refers to three separate but closely related molecules, retinal, retinol and retinoic acid (in which the terminal carbon is an aldehyde [−CH=O], hydroxyl group [−CH2−OH] or carboxylic acid (COOH), respectively).
Dietary vitamin A comes from animal fat and products, such as milk, cheese and liver, along with some fruits and vegetables (in beta-carotene plant version of Vitamin A). Alternatively, Vitamin A can be formed by the cleavage and processing of certain 40-carbon plant pigments known as provitamin A, or carotenoids (which look essentially like 2 molecules of retinal, connected through their tails). Vitamin A is stored in the liver and transported to tissues where it is needed via VLDL. Because it is not water soluble it is possible for Vitamin A to build up in tissues to levels where it becomes toxic. This is generally not possible with a normal diet, but can occur with vitamin supplements.
Vitamin A is essential for vision, and Vitamin A deficiency leads to night blindness. The aldehyde form of vitamin A, retinal, combines with specific proteins in the retina, called opsins, to form the active light receptor proteins, the rhodopsins. The actual form of retinal that is bound is an 11-cis-retinal which acts as part of the chromophore, absorbing light and undergoing a subsequent isomerization to all-trans-retinal. This isomerization is associated with a conformational change in the protein, followed by nervous excitation and dissociation of the retinal-opsin complex. Subsequent isomerization of the trans-retinal to 11-cis-retinal allows the re-association with opsin to reform rhodopsin.
A second form of Vitamin A, retinoic acid is an important intercellular signaling molecule involved in growth and differentiation. It functions by binding to a transcription factor receptor and activating it, which is similar to the steroid hormone receptors.
Vitamin D is formed in the skin by the action of ultraviolet light on 7-dehydrocholesterol, the penultimate intermediate in cholesterol biosynthesis. once UV light hits skin it breaks double bond and leads to formation of Vitamin D3/cholecalciferol which is a calcium homeostasis important form. Thus, it is only an essential vitamin in the absence of exposure to sunlight. Note, 7-dehydrocholesterol has a double bond at the 7 position, and should not be confused with 7 α hydroxycholesterol involved in bile acid synthesis. Vitamin D3 or cholecalciferol is formed from 7-dehydrocholesterol. Cholecalciferol must then be activated by the addition of −OH groups to the 25 position (in the liver) and 1 position (in the kidney). The resulting product, 1,25-dihydroxycholecalciferol, is the most potent functional form of the vitamin, involved in increasing the intestinal absorption of Ca2+, bone formation, and the prevention of rickets (in children) or osteomalacia (in adults). It functions by binding a specific transcription factor protein, which is similar to the steroid hormone receptors. An excess of Vitamin D (greater than ten times the RDA) can lead to too much calcium retention, hypercalcinemia and a tendency to develop kidney stones. Seemingly paradoxically, excess Vitamin D can also weaken bones, since high circulating calcium levels can cause bone demineralization. VitD enters intestinal cell, binds to a cytosolic receptor; the complex travels to the nucleus; increases synthesis of a specific-calcium binding protein. Also stimulates the mobilization of calcium from bone in the presence of parathyroid hormone (PTH) to maintain plasma levels. Also has effects on renal reabsorption and excretion of calcium.
Vitamin E, or α-tocopherol, also has an isoprene‑based structure. It functions as an antioxidant, terminating the peroxidative destruction of polyunsaturated fatty acids in tissues (effectively preventing FAs from becoming rancid). The reactions involving free radicals that initiate lipid peroxidation on a polyunsaturated fatty acid is effectively terminated by Vitamin E. It targets double bonds in FAs, vitamin E can accept those electrons. It is found in many foods including vegetable oils, cereals, meat, poultry, eggs, fruits, vegetables, and wheat germ oil. Anyone diagnosed with cystic fibrosis, individuals who have had part or all of their stomach removed or who have had a gastric bypass, and individuals with malabsorptive problems such as Crohn's disease, liver disease or pancreatic insufficiency may not absorb fat (people who cannot absorb fat often pass greasy stools or have chronic diarrhea and bloating). Sometimes vitamin E is used to lessen the harmful effects of medical treatments such as dialysis and radiation. Photoreceptor outer segment membranes have a very high concentration of polyunsaturated fatty acids (PUFA's) and are potentially very susceptible to oxidative damage (the retina consumes 5-10 times more oxygen per milligram than any other tissue tested). Vitamin E is present in the outer segment and is the only well-recognized chain-breaking, lipid-soluble antioxidant in vivo.
Vitamin K is an essential cofactor for the synthesis of prothrombin and several other proteins involved in blood clotting. The vitamin functions in the reaction where protein glutamic acid residues are converted to γ-carboxyl glutamic acid, a modified amino acid essential for the function of several blood clotting proteins. Its use in this carboxylation reaction results in the formation of a Vitamin K epoxide, which must then be converted back to active Vitamin K in a series of reduction reactions. Vitamin K is abundant in nature and also made by symbiotic gut bacteria, so deficiencies are rare. Vitamin K is found in leafy vegetables, cheese and liver. It is also found in asparagus, coffee, bacon and green tea. In premature infants, however, Vitamin K deficiency can contribute to hemorrhagic disease. Vitamin K epoxide reductase inhibitors are often used as rat poisons (e.g. warfarin). At more controlled concentrations similar compounds can help control improper blood clotting⁄coagulation and are used to treat thromboses (e.g. coumarol).
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