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Which one of the following sequences places the lipoproteins in the order of most dense to least dense? They act mainly as “local” hormones generic estradiol 1 mg without prescription, affecting the cells that produce them or neighboring cells of a different type safe 1mg estradiol. Eicosanoids participate in many processes in the body discount 1 mg estradiol visa, particularly the inflam- matory response that occurs after infection or injury order 1 mg estradiol amex. The inflammatory response is the sum of the body’s efforts to destroy invading organisms and to repair dam- age. It includes the control of bleeding through the formation of blood clots. In the process of protecting the body from a variety of insults, the inflammatory response can produce symptoms such as pain, swelling, and fever. An exaggerated or inap- propriate expression of the normal inflammatory response may occur in individuals who have allergic or hypersensitivity reactions. In addition to participating in the inflammatory response, eicosanoids also regu- late smooth muscle contraction (particularly in the intestine and uterus). They increase water and sodium excretion by the kidney and are involved in regulating blood pressure. They frequently serve as modulators; some eicosanoids stimulate and others inhibit the same process. For example, some serve as constrictors and others as dilators of blood vessels. They are also involved in regulating bronchoconstriction and bronchodilation. Eicosanoids are derived from polyunsaturated fatty acids containing 20 carbon atoms, which are found in cell membranes esterified to membrane phospholipids. Arachidonic acid, derived from the diet or synthesized from linoleate, is the com- pound from which most of the eicosanoids are produced in the body. Compounds that serve as signals for eicosanoid production bind to cell membrane receptors and activate phospholipases that cleave the polyunsaturated fatty acids from cell membrane phospholipids (Fig. Arachidonic acid is enzymatically metabolized by three major pathways. The two pathways that have been most thoroughly studied are the cyclooxygenase pathway (which produces prostaglandins and thromboxanes) and the lipoxygenase pathway (which produces leukotrienes). The cytochrome P450 pathway generates eicosanoids with less well-defined physiologic functions. Isoprostanes are a relatively new class of eicosanoids derived from nonenzymatic free radical–catalyzed reactions. The isoprostanes are similar to prostaglandins in structure and may play a role in inflammatory responses and free radical–mediated tissue injury. In brain tissue, arachidonic acid can be coupled to ethanolamine to generate anandamide. This compound can bind and activate cannabinoid receptors with actions similar to those of ∆9- tetrahydrocannabinol (THC). Many eicosanoids have very short half-lives, in the range of a few minutes or less. Eicosanoids are produced from fatty acids released from membrane phospholipids. In humans, arachidonic acid is the major precursor of the eicosanoids, which include the prostaglandins, leukotrienes, and thromboxanes. THE WAITING ROOM Since her admission to the hospital for an acute myocardial infarction, Ann Jeina has been taking the bile salt sequestrant cholestyramine and the HMG-CoA reductase inhibitor pravastatin to lower her blood cholesterol levels (see Chapter 34). She also takes 160 mg acetylsalicylic acid (ASA; aspirin) each day. At her most recent visit to her cardiologist, she asked whether she should 656 SECTION SIX / LIPID METABOLISM continue to take aspirin because she no longer has any chest pain. She was told that the use of aspirin in her case was not to alleviate pain but to reduce the risk of a sec- ond heart attack and that she should continue to take this drug for the remainder of her life unless a complication, such as gastrointestinal bleeding, occurred as a result “Eicosa” is the Greek word for the of its use. Eicosanoids are syn- thesized from polyunsaturated Emma Wheezer has done well with regard to her respiratory function fatty acids with 20 carbon atoms. She has been maintained on two puffs of triamcinolone acetonide, a potent inhaled cor- ticosteroid, three times per day, and has not required systemic steroids for months.
CHAPTER 47 / METABOLISM OF MUSCLE AT REST AND DURING EXERCISE 877 free fatty acids depends on mitochondria and oxidative phosphorylation trusted 1mg estradiol, long-dis- tance running uses muscles that are principally slow-twitch oxidative fibers estradiol 2mg low cost, such as the gastrocnemius discount estradiol 1mg visa. It is also important to realize that resting skeletal muscle uses free fatty acids as a principle fuel generic estradiol 2 mg with visa. At almost anytime except the postprandial state (right after eating), free fatty acids are the preferred fuel for skeletal muscle. The preferential utilization of fatty acids over glucose as a fuel in skeletal mus- cle depends on the following factors: 1. The availability of free fatty acids in the blood, which depends on their release from adipose tissue triacylglycerols by hormone-sensitive lipase. During pro- longed exercise, the small decrease of insulin, and increases of glucagon, epi- nephrine and norepinephrine, cortisol, and possibly growth hormone all activate adipocyte tissue lipolysis. Inhibition of glycolysis by products of fatty acid oxidation. Pyruvate dehydroge- nase activity is inhibited by acetyl CoA, NADH, and ATP, all of which are ele- vated as fatty acid oxidation proceeds. As AMP levels drop, and ATP levels rise, PFK-1 activity is decreased (see Chapter 22). Glucose transport may be reduced during long-term exercise. Glucose transport into skeletal muscles via the GLUT 4 transporter is greatly activated by either insulin or exercise. During long-term exercise, the effect of falling insulin levels or increased fatty acid levels may counteract the stimulation of glucose transport by the exercise itself. Ketone body oxidation also increases during exercise. Their utilization as a fuel is dependent on their rate of production by the liver. Ketone bodies are, however, never a major fuel for skeletal muscle (muscles prefer free fatty acids). Acetyl-CoA carboxylase (isozyme ACC-2) must be inactivated for the muscle to use fatty acids. This occurs as the AMP-PK is activated and phosphorylates ACC-2, rendering it inactive. Branched-Chain Amino Acids Branched-chain amino acid oxidation has been estimated to supply a maximum of 20% of the ATP supply of resting muscle. Oxidation of branched-chain amino acids in muscle serves two functions. The first is the generation of ATP, and the second is the synthesis of glutamine, which effluxes from the muscle. The highest rates of branched-chain amino acid oxidation occur under conditions of acidosis, in which there is a higher demand for glutamine to transfer ammonia to the kidney and to buffer the urine as ammonium ion during proton excretion. Recall that glutamine synthesis occurs from the carbon skeletons of branched-chain amino acid oxidation (valine and isoleucine) after the initial five steps of the oxidative pathway. The Purine Nucleotide Cycle Exercise increases the activity of the purine nucleotide cycle, which converts aspar- tate to fumarate plus ammonia (see Fig. The ammonia is used to buffer the proton production and lactate production from glycolysis, and the fumarate is recy- cled and can form glutamine. Acetate Acetate is an excellent fuel for skeletal muscle. It is treated by the muscle as a very- short-chain fatty acid. It is activated to acetyl CoA in the cytosol and then trans- ferred into the mitochondria via acetylcarnitine transferase, an isozyme of carnitine palmitoyl transferase. Sources of acetate include the diet (vinegar is acetic acid) and acetate produced in the liver from alcohol metabolism.
She has been gaining weight buy estradiol 2mg online, The multienzyme complex MEOS (microsomal and is now back to 99 lb from a low of 85 lb safe estradiol 1mg. Her blood glucose is still ethanol oxidizing system) buy estradiol 2mg amex, which is also called below normal (fasting blood glucose of 72 mg/dL cheap 2mg estradiol with amex, compared with a normal range cytochrome P450-2E1, provides an additional of 80-100 mg/dL). She complains to her physician that she feels tired when she route for ethanol oxidation to acetaldehyde in jogs, and she is concerned that the “extra weight” she has gained is slowing her the liver. Although the regulation of metabolic pathways is an exceedingly complex sub- ject, dealt with in most of the subsequent chapters of this text, a number of com- mon themes are involved. Physiologic regulation of a metabolic pathway depends on the ability to alter flux through the pathway by activating the enzyme catalyzing the rate-limiting step in the pathway (see Fig. The type of regulation employed always reflects the function of the pathway and the need for that path- way in a particular tissue or cell type. Pathways producing a necessary product are usually feedback-regulated through a mechanism directly or indirectly involving the concentration of product (e. The concentration of product signals when enough of the product has been synthesized. Storage and toxic disposal pathways are usually regulated directly or indirectly through a feedforward mechanism reflecting the availability of precursor. Regulatory enzymes are often tissue-specific isozymes whose properties reflect the different functions of a pathway in particular tissues. Pathways are also regulated through compartmen- tation, collection of enzymes with a common function within a particular organelle or at a specific site in the cell. The mechanisms employed to regulate enzymes have been organized into three general categories: regulation by compounds that bind reversibly in the active site (including dependence of velocity on substrate concentration and product levels); regulation by changing the conformation of the active site (including allosteric reg- ulators, covalent modification, protein–protein interactions, and zymogen cleav- age); and regulation by changing the concentration of enzyme (enzyme synthesis and degradation). Glucose 6-P is metabolized in the pathway of glycolysis to gen- erate ATP. This pathway is feedback regulated, so that as her muscles use ATP, the rate of glycolysis will increase to generate more ATP. Glycogen Glycogen Glycogenolysis synthesis Glucose Glucose-6-P hexokinase glucokinase Glycolysis Energy, ATP When she is resting, her muscles and liver will convert glucose 6-phosphate to glycogen (a fuel storage pathway, shown in blue). Glyco- gen synthesis is feed-forward regulated by the supply of glucose and by insulin and other hormones that signal glucose availability. Glycogenolysis (glycogen degradation) is activated during exercise to supply additional glucose 6-P for glycolysis. Unless Ann consumes sufficient calories, her glycogen stores will not be replenished after exercise, and she will tire easily. REGULATION BY SUBSTRATE AND PRODUCT CONCENTRATION A. Velocity and Substrate Concentration The velocity of all enzymes is dependent on the concentration of substrate. This dependence is reflected in conditions such as starvation, in which a number of pathways are deprived of substrate. In the following sections, relates the initial velocity of the we use the Michaelis-Menten equation to describe the response of an enzyme to reaction (v ) to the concentration ofi changes in substrate concentration and use glucokinase to illustrate the role of sub- enzyme substrate complexes (ES). This strate supply in regulation of enzyme activity. MICHAELIS-MENTEN EQUATION to form ES with the rate constant of k1. The The equations of enzyme kinetics provide a quantitative way of describing the depend- complex dissociates with the rate constant ence of enzyme rate on substrate concentration. The simplest of these equations, the of k2, or is converted to P with the rate con- Michaelis-Menten equation, relates the initial velocity (v ) to the concentration of sub-i stant k3. Under conditions in which [S] >> strate [S] and the two parameters Km and Vmax (Equation 9. The concentration of and the Km of the enzyme for a substrate is the concentration of substrate required to i 3 reach 1⁄2 V. The Michaelis-Menten model of enzyme kinetics applies to a simple ES is a fraction of ET, the total amount of max enzyme present as ES and E. The initial velocity of prod- uct formation, v , is proportionate to the concentration of enzyme–substrate complexesi k3[ET][S] [ES]. As substrate concentration is increased, the concentration of enzyme–substrate vi k3[ES] Km [S] complexes increases, and the reaction rate increases proportionately.
For example purchase 1mg estradiol mastercard, the thyroid hormone receptor forms a heterodimer with the retinoid X receptor (RXR) that binds to thy- roid hormone response elements and to corepressors (including one with deacety- lase activity) buy estradiol 2 mg with mastercard, thereby inhibiting expression of certain genes 2 mg estradiol amex. When thyroid hormone binds order 1mg estradiol overnight delivery, the receptor dimer changes conformation, and the transactivation domain binds coactivators, thereby initiating transcription of the genes. The RXR receptor, which binds the retinoid 9-cis retinoic acid, can form het- erodimers with at least eight other nuclear receptors. Each heterodimer has a dif- ferent DNA binding specificity. This allows the RXR to participate in the regulation of a wide variety of genes, and to regulate gene expression differently, depending on the availability of other active receptors. STRUCTURE OF DNA BINDING PROTEINS Several unique structural motifs have been characterized for specific transcription factors. Each of these proteins has a distinct recognition site (DNA binding domain) that binds to the bases of a specific sequence of nucleotides in DNA. Four of the best-characterized structural motifs are zinc fingers, b-zip proteins (including leucine zippers), helix-turn-helix, and helix-loop-helix. CHAPTER 16 / REGULATION OF GENE EXPRESSION 287 To regulate gene transcription, two estrogen receptors combine to form a dimer that binds to a palindrome in the promoter region of certain genes (see TR RXR Figs. A palindrome is a sequence of bases that is identical on the antiparallel strand when read in the opposite direction. For example, the sequence Corepressor ATCGCGAT base-pairs to form the sequence TAGCGCTA, which when read in the oppo- complex site direction is ATCGCGAG. Each estrogen receptor is approximately 73 amino acids long and contains two zinc fingers. Each zinc is chelated to two cysteines in an -helix HDAC and two cysteines in a -sheet region. The position of the nucleotide recognition domain Basal sequence in an -helix keeps the sequence in a relatively rigid conformation as it fits into transcription the major groove of DNA. The zinc finger that lies closest to the carboxyl terminal is complex involved in dimerization with the second estrogen receptor, thus inverting the nucleotide recognition sequence to match the other half of the palindrome. The dimer-palindrome T 3 requirement enormously enhances the specificity of binding, and, consequently, only certain genes are affected. T3 TR RXR Zinc finger motifs (commonly found in the DNA binding domain of steroid hor- mone receptors) contain a bound zinc chelated at four positions with either histidine Coactivator or cysteine in a sequence of approximately 20 amino acids (Fig. The result complex is a relatively small, tight, autonomously-folded domain. The zinc is required to HAC maintain the tertiary structure of this domain. Eukaryotic transcription factors gen- domain erally have two to six zinc finger motifs that function independently. At least one of Basal transcription the zinc fingers forms an -helix containing a nucleotide recognition signal, a complex sequence of amino acids that specifically fits into the major groove of DNA (Fig. Activity of the thyroid hormone Leucine zippers also function as dimers to regulate gene transcription (see Fig. The leucine zipper motif is an -helix of 30 to 40 amino acid residues that the presence and absence of thyroid hormone contains a leucine every seven amino acids, positioned so that they align on the same (T3). Abbrev: HAC, histone acetylase; HDAC, side of the helix. Two helices dimerize so that the leucines of one helix align with the histone deacetylase. A wide variety of transcription factors contain the zinc finger motif, including the steroid hormone receptors, such as the estrogen and the glucocorticoid receptor. Other transcription factors that contain zinc finger motifs include Sp1 and polymerase III transcription factor TFIIIA (part of the basal transcription complex), which has nine zinc finger motifs. Leucine zipper transcription factors function as homodimers or heterodimers. For example, AP1 is a heterodimer whose subunits are encoded by the genes fos and jun.