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An because of the high venous pressure within orthopedic surgeon was consulted regarding the compound fracture of his right these varices in addition to the adverse forearm effective tadacip 20mg erectile dysfunction treatment in sri lanka. Jean Ann Tonich’s signs and symptoms tadacip 20mg on-line impotence zinc, as well as her laboratory profile, were consistent with the presence of mild reversible alcohol-induced hepatocellular inflammation (alcohol-induced hepatitis) superimposed on a degree of irreversible scarring of liver tissues known as chronic alcoholic (Laennec’s) cirrhosis of the liver. The chronic inflammatory process associated with long-term ethanol abuse in patients such as Jean Ann Tonich is accompanied by increases in the levels of serum alanine aminotrans- ferase (ALT) and aspartate aminotransferase (AST). Her elevated bilirubin and alkaline phosphatase were consistent with hepatic damage. Her values for ALT and CHAPTER 25 / METABOLISM OF ETHANOL 469 AST were significantly below those seen in acute viral hepatitis. In addition, the Although the full spectrum of alco- ratio of the absolute values for serum ALT and AST often differ in the two diseases, hol-induced liver disease may be tending to be greater than 1 in acute viral hepatitis and less than 1 in chronic alco- present in a well-nourished individ- ual, the presence of nutritional deficiencies hol-induced cirrhosis. The reason for the difference in ratio of enzyme activities enhances the progression of the disease. The ingestion of logic tests for viral hepatitis were nonreactive. Her serum folate, vitamin B12, and ethanol reduces the gastrointestinal absorp- iron levels were also slightly suppressed, indicating impaired nutritional status. In addition, Jean Ann was referred to the hos- essential amino acids. For example, ethanol pital drug and alcohol rehabilitation unit for appropriate psychological therapy and interferes with absorption of folate, thi- supportive social counseling. The physician also arranged for a follow-up office amine, and other nutrients. Changes in the level of trans- port proteins produced by the liver also Fibrosis in Chronic Alcohol-Induced Liver Disease Fibrosis is strongly affect nutrient status. In the liver, it is a frequent event following a repeated or chronic insult of sufficient intensity (such as chronic ethanol intoxication or infection by a hepatitis virus) to trig- ger a “wound healing–like” reaction. Regardless of the insult, the events are similar: an overproduction of extracellular matrix components occurs, with the tendency to progress into sclerosis, accompanied by a degenerative alteration in the composition of matrix components. The development of hepatic fibrosis after ethanol consumption is related to stimu- lation of the mitogenic development of stellate (Ito) cells into myofibroblasts, and stim- ulation of the production of collagen type I and fibronectin by these cells. The stellate cells are perisinusoidal cells lodged in the space of Disse that produce extracellular matrix protein. Normally the space of Disse contains basement membrane–-like colla- gen (collagen type IV) and laminin. As the stellate cells are activated, they change from a resting cell filled with lipids and vitamin A to one that proliferates, loses its vitamin A content, and secretes large quantities of extracellular matrix components. One of the initial events in the activation and proliferation of stellate cells is the activation of Kupffer cells, which are macrophages resident in the liver sinusoids Table 25. Hepatic Injury Stage of Injury Main Features Fibrosis: Increase of connective tissue Accumulation of both fibrillar and basement membrane–like collagens Increase of laminen and fibronectin Thickening of connective tissue septae Capillarization of the sinusoids Sclerosis: Aging of fibrotic tissue Decrease of hyaluronic acid and heparan sulfate proteoglycans Increase of chondroitin sulfate proteoglycans Progressive fragmentation and disappearance of elastic fibers Distortion of sinusoidal architecture and parenchymal damage Cirrhosis: End-stage process of liver fibrotic degeneration Whole liver heavily distorted by thick bands of collagen surrounding nodules of hepatocytes with regenerative foci 470 SECTION FOUR / FUEL OXIDATION AND THE GENERATION OF ATP Hepatocyte Acetaldehyde Kupffer Actived cell Kupffer Acetaldehyde- cell protein adducts Respiratory burst Lipid peroxidation ROS products NO TGF-β Stimulated Stellate cell stellate cell (Vitamin A) Extracellular matrix Metallo Collagen Proteases FIBROSIS Fig. Proposed model for the development of hepatic fibrosis involving hepatocytes, Kupffer cells, and stellate (Ito) cells. ROS, reactive oxygen species; NO, nitric oxide: TGF 1, transforming growth factor 1. The Kupffer cells are probably activated by a product of the damaged hepatocytes, such as necrotic debris, iron, ROS, acetaldehyde, or aldehyde products of lipid peroxidation. Kupffer cells also may produce acetaldehyde from ethanol internally through their own MEOS pathway. Activated Kupffer cells produce a number of products that contribute to activation of stellate cells. They generate additional ROS through NADPH oxidase during the Cytokines are proteins produced oxidative burst and NOS through inducible NO synthase (see Chapter 24). In addition, by inflammatory cells that serve as communicators with other cells. The cytokine transforming growth factor duced by inflammatory cells that promote 1 (TGF 1), produced by both Kupffer cells and sinusoidal endothelial cells, is a migration of other inflammatory cells (e.
Therefore order 20 mg tadacip with visa xarelto impotence, compared with the glycoconjugates purchase tadacip 20 mg with visa erectile dysfunction specialist, an even greater percentage of the molecules of these conjugates are ionized in the lumen of the gut (Fig. FATE OF THE BILE SALTS The bile salts are produced in the liver and secreted into the bile (Fig. Intestinal bacteria deconjugate and dehydroxylate the bile salts, removing the glycine and taurine residues and the hydroxyl group at position 7. The bile salts that lack a hydroxyl group at position 7 are called secondary bile salts. The deconjugated and dehydroxylated bile salts are less soluble and, therefore, less readily resorbed from the intestinal lumen than the bile salts that have not been subjected to bacterial 630 SECTION SIX / LIPID METABOLISM Cholic acid ATP CoASH AMP + Pi O C SCoA OH CH3 CH3 HO OH Cholyl CoA pK˜6 + – + – H3N CH2 CH2 SO3 H3N CH2 COO Taurine Glycine O O C SO– C 3 HO N HO N – COO H H CH3 CH3 CH3 CH3 HO OH HO OH Taurocholic acid Glycocholic acid pK˜2 pK˜4 Fig. Conjugation lowers the pK of the bile salts, making them better detergents; i. The reactions are the same for the chenocholic acid series of bile salts. CHAPTER 34 / CHOLESTEROL ABSORPTION, SYNTHESIS, METABOLISM, AND FATE 631 action (Fig. Lithocholic acid, a secondary bile salt that has a hydroxyl group Primary bile salts only at position 3, is the least soluble bile salt. The second- OH CH3 ary bile salts may be reconjugated in the liver, but they are not rehydroxylated. The 12 bile salts are recycled by the liver, which secretes them into the bile. This entero- CH3 hepatic recirculation of bile salts is extremely efficient. Less than 5% of the bile salts entering the gut are excreted in the feces each day. Because the steroid nucleus 3 7 cannot be degraded in the body, the excretion of bile salts serves as a major route for removal of the steroid nucleus and, thus, of cholesterol from the body. TRANSPORT OF CHOLESTEROL BY THE BLOOD – LIPOPROTEINS COO Because they are hydrophobic and essentially insoluble in the water of the blood, CH3 cholesterol and cholesterol esters, like triacylglycerols and phospholipids, must be 12 transported through the bloodstream packaged as lipoproteins. Each lipoprotein particle is composed of a core of hydropho- bic lipids such as cholesterol esters and triacylglycerols surrounded by a shell of 3 7 polar lipids (the phospholipids), which allows a hydration shell to form around the HO OH lipoprotein (see Fig. This occurs when the positive charge of the nitrogen atom Chenocholic acid of the phospholipid (phosphatidylcholine, phosphatidylethanolamine, or phos- phatidylserine) forms an ionic bond with the negatively charged hydroxyl ion of the environment. In addition, the shell contains a variety of apoproteins that also increase the water solubility of the lipoprotein. Free cholesterol molecules are dispersed Secondary bile salts throughout the lipoprotein shell to stabilize it in a way that allows it to maintain its – COO spherical shape. The major carriers of lipids are chylomicrons (see Chapter 32), OH VLDL, and HDL. Metabolism of CH3 chylomicrons leads to chylomicron remnant formation. The apoproteins 3 7 (“apo” describes the protein within the shell of the particle in its lipid-free form) not HO only add to the hydrophilicity and structural stability of the particle but have other Deoxycholic acid functions as well: (1) they activate certain enzymes required for normal lipoprotein metabolism and (2) they act as ligands on the surface of the lipoprotein that target specific receptors on peripheral tissues that require lipoprotein delivery for their COO– innate cellular function. Their tissue source, molecu- CH3 12 lar mass, distribution within lipoproteins, and metabolic functions are shown in Table 34. CH3 The lipoproteins themselves are distributed among eight major classes. Some of their characteristics are shown in Table 34. Each class of lipoprotein has a specific 3 7 function determined by its apolipoprotein content, its tissue of origin, and the pro- HO portion of the macromolecule made up of triacylglycerols, cholesterol esters, free Lithocholic acid cholesterol, and phospholipids (see Tables 34. Structures of the primary and sec- ondary bile salts. The Chylomicrons jugates with taurine or glycine in the liver. After secretion into the intestine, they may be Chylomicrons are the largest of the lipoproteins and the least dense because of their deconjugated and dehydroxylated by the bac- rich triacylglycerol content. They are synthesized from dietary lipids (the “exoge- terial flora, forming secondary bile salts. Note nous” lipoprotein pathway) within the epithelial cells of the small intestine and then that dehydroxylation occurs at position 7, secreted into the lymphatic vessels draining the gut (see Fig.
Ribosomes attached to is sometimes used for processes occurring the membranes of the RER give them their “rough” appearance 20mg tadacip for sale erectile dysfunction jogging. When cells are lysed in the labora- on these ribosomes enter the lumen of the RER purchase 20 mg tadacip with amex erectile dysfunction medication risks, travel to the Golgi complex in vesi- tory, the ER is fragmented into vesicles cles, and are subsequently either secreted from the cell, sequestered within called microsomes, which can be isolated by membrane-enclosed organelles such as lysosomes, or embedded in the plasma centrifugation. Posttranslational modifications of these proteins, such as the initiation actually present in cells. In contrast, proteins encoded by the nucleus and found in the cytosol, peroxisomes, or mitochondria are synthesized on free ribosomes in the cytosol and are seldom mod- ified by the attachment of oligosaccharides. A Smooth endoplasmic reticulum (SER) Ribosomes Rough endoplasmic reticulum (RER) B Fig. GOLGI COMPLEX The Golgi complex is involved in modifying proteins produced in the RER and in sorting and distributing these proteins to the lysosomes, secretory vesicles, or the plasma membrane. It consists of a curved stack of flattened vesicles in the cyto- plasm that is generally divided into three compartments: the cis-Golgi network, which is often convex and faces the nucleus; the medial Golgi stacks; and the trans Golgi network, which often faces the plasma membrane (Fig. Proteins are transported to and from the Golgi in at least three kinds of vesicles: coatomer-coated COP I vesicles, coatomer-coated COP II vesicles, and clathrin- coated vesicles (see Fig. Proteins produced on the RER travel in COP II vesicles to an endoplasmic reticulum-Golgi intermediate compartment (ERGIC), and then to the cis-Golgi network, where they enter the lumen. Here N-linked oligosaccharide chains that were added to proteins in the RER are modified, and O-linked oligosaccharides are added. COP I vesicles recycle material from the Golgi back to the ER and possibly transfer material from the Golgi to other sites. Clathrin Trans-Golgi Medial-Golgi COPI Cis-Golgi COPI COPII ER-golgi Fusion intermediate of COPII compartment vesicles Rough ER Fig. COP II vesicles (coatomer- coated) form in the rough ER and move to the Golgi. COP I vesicles generally go from the trans to the cis Golgi to the ER. Vesicles that go to late endosomes (eventually lysosomes) from the Golgi or the plasma membrane are clathrin-coated. Vesicle transport, as well as transport of organelles and secretory proteins, occurs along microtubules (structures formed from the protein tubulin). CHAPTER 10 / RELATIONSHIP BETWEEN CELL BIOLOGY AND BIOCHEMISTRY 177 Vesicles released from the trans face of the Golgi complex travel to endosomes as clathrin-coated vesicles. COP vesicles are coated with a complex composed of coatomer proteins (COP), an Arf family monomeric G protein that mediates vesicle assembly, and other proteins (Fig. COP I vesicles contain the monomeric G protein Arf (ADP-ribosylating factor), and COP II vesicles contain the monomeric G protein Sar (another member of the Arf family). In both types of vesicles, hydrolysis of GTP causes dissociation of the G-protein and disassembly of the vesicle coat. Glycoproteins or glycolipids once anchored in the membrane of the vesicle remain in the plasma membrane when the vesicular and plasma membranes fuse. Vesicles that have lost their coats are ready to fuse with the target membrane. The monomeric G protein Arf was The vesicle membranes contain proteins called v-SNARES (vesicle-SNARES) named for its contribution to the (see Fig. Each type of v-SNARE is able to recognize and bind to its com- pathogenesis of cholera and not for its normal function in the assembly of plementary t-SNARE (target SNARE) on the target membrane, thus ensuring that COP I vesicles. However, it is also required for the transport of V. Assembly and release vesicles that subsequently merge with lyso- somes (or are transformed into lysosomes), Coatomer where the acidic pH contributes to activation ARF of the toxin. As the toxin is transported through the Golgi and ER, it is further processed and activated. Arf forms a com- plex with the A-toxin that promotes its travel between compartments. The A-toxin is actu- ally an ADP-ribosylase (an enzyme that cleaves NAD and attaches the ADP portion to a protein) (see Chapter 6, Fig. The ADP-ribosylation of pro- GDP ARF Coatomer teins regulating the CFTR chloride channel leads to Dennis Veere’s dehydration and diarrhea. Docking Rab Vesicle Rab NSF v-Snare SNAPs Rab Rab t-Snare Target Fig.
