Week 3 Flashcards

(145 cards)

1
Q

What is a complex polysaccharide?

A
  • Any oligosaccharide with more than one type of sugar residue
  • usually attached to proteins, protein anchors or lipids
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2
Q

What does a glycotransferases do?

A
  • Transfers a monosaccaride from a donor to an acceptor
    • Donor - UDP, GDP, CMP, Dolichol
    • Acceptor - protein, lipid, non-reducing end of another sugar
  • glycotransferases are VERY specific for every aspect of the binding
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3
Q

What does glycosidases do?

A
  • Removes a specific sugar reisdues with the help of H20
  • Specific for the bond hydrolyzed
  • Important for
    • Producing final carbohydrate struture
    • degrading carb structures in lysosome
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4
Q

Describe a N-Linked glycoprotein

A
  • GlcNAc attached to a Asn
    • specific site: Asn-X-Thr/Ser
  • Common core: GlcNAc-GlcNAc-(mannose in triangle)
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5
Q

What is a dolichol and how is it used in glycoportein synthesis?

A
  • an isoprenoid compound with 16-20 isoprene units embedded in ER membrane
  • during the synthesis of N-linked glycoproteins it is attached to dolichol
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6
Q

How is a N-linked glycoprotein synthesized?

A
  • GlcNAc is attached to dolichol on cytoplasmic side of ER
  • Addictional glycosylation occurs then flipped to lumen of ER
  • 4 mannose and 3 glucoses added
  • Entire carbohydrate structure is transferred to Asn on a nascent protein
  • glucoses removed then put in vesicles to golgi
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7
Q

What is the final processing of a N-linked glycoprotein?

A
  • GlcNAc phosphate added
    • packaged in vesicles and merge with lysosomes
  • Trimming and addition of other sugars may occur goes through Golgi
    • Diverse final products
    • secreted or incorporated into membranes
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8
Q

Describe a O-linked Glycoprotein

A
  • GalNAc attached to either Ser/Thr
  • protein has to be assembled before it can be added
  • other types
    • O-mannosylation
    • O-fucosylation
    • Collagen: O-lined to 5-OH Lys
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9
Q

What is Type 1 Congenital Disorders of Glycosylation?

A
  • Most common
  • Problem occurs in the early steps in the synthesis of N-linked glycoproteins
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10
Q

What is type II congenital disorders of glycosylation?

A
  • Enzymatic defects in N-glycan processing enzymes
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11
Q

What is Walker-Warburg syndrome? and type of glycosylation disorder is it?

A
  • Walker is deficit in O-mannosyltransferase I
    • caueses alpha-dystroglycanopathies (congential muscular dystrophy)
  • example of O-linked glycosylation
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12
Q

What is the deficiency in a combined N- and O- glycosylation defect?

A
  • CMP-sialic acid transporter deficiency
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13
Q

What is lysosomal storage disease?

A
  • lysosomes contain exoglycosidases and endoglycosidases needed to break down glycoproteins and glycolipids
  • if the lysomes are not working correctly, incomplete degraded compounds accumulate in tissues and urine
  • results in hepatosplenomegaly, cataracts, and mental retardation
  • very rare usually autosomally recessive
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14
Q

What is I-cell disease (mucolipidosis II)?

A
  • defiency in GlcNAc-P glycosyltransferase
    • enzyme marks lysosomal proteins for their destination
  • lysosomal enzymes are instead secreted from cell and found in either the plasma or other body fluids
  • glycoproteins are not degraded and accumulate in enlarged lysosomes
  • severe psychomotor retardation, skeletal abnormalities, restricted joint movement, death by age 8
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15
Q

What are glycolipids built on mainly?

A
  • build on sphingosine
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16
Q

What is ceramide?

A
  • X is a H
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17
Q

What is a cerebroside?

A

If X is

  • a single monosaccharide (glucose or galactose)
  • most prevalent in neuronal cell membranes of brin
    • esstenial to myelin structure and function
  • occur in membranes of other tissues and is the precursor for most complex glycospingolipids
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18
Q

What is globoside?

A

If X

  • has multiple monosaccharides that are neurtal
  • Found in membranes of kidneys, RBCs, liver and spleen
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19
Q

What is a ganglioside?

A

If X is

  • sialic acid (NANA) is present
  • Most important Gm1, Gm2, Gm3
  • Act as
    • receptors for hormones and bacterial protein toxins
    • determinants for cell-cell recognition
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20
Q

What is a sulfatide?

A

If x

  • contains monosaccharidesulfates
  • important Myelin constituent, white matter
    • synthesized primary in oligodendrocytes
  • found in the membranes of kidney, spleen and retina
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21
Q

How is cerebroside synthesized?

A
  • made from ceramide
  • synthesized on luminal surface of the ER and then switched to cytosolic side of Golgi apparatus and reach plasma membrane through vesicle flow
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22
Q

How are globosides and gangliosides synthesized?

A
  • Synthesized by a series of specifc glycosyltransferases
  • UDP-Gal + glucocerebroside -> lactosyl ceramide
    • lactosyl ceramide is the precursor to both globosides and gangliosides
  • Glycosyltransferases add remaining hexoses
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23
Q

What is Tay-Sachs Disease?

A
  • Autosomal recessive defiency in hexoaminidase A
  • Ganglioside GM2 accumulates as shell-like inclusions in lysosomes. Looks like a milky halo occurs around the fovea of eye due to a build up ganglioside
  • red dot that develops in fovea is the result of the ganglion nerve death
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24
Q

What does glycocaylax with the microvilli?

A
  • glycocaylax provide the final stages of protein and carbohydrate breakdown for absorption
  • enzymes at the microvilli surface make sure the nutrients get absorbed immediately
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25
How does the intestinal structure ensures max absorption?
* Each villi receives blood supply and has blind ended leacteals from lymphatic system * Extensive blood supply ensures optimal removel of absorbed peptides , aa, sugars and fats
26
What is oral amylase?
* 30-40% of starches being hydrolyzed to maltose * hydrolysis continues for up to hour in the stomach
27
What does pancreatic amylase digest?
* maltose * maltotriose * alpha-limited dextrins
28
Where is the site of action of carbrohydrate enzymes?
* enzymes located near the carrier of membrane transports that transports the free glucose or galactose into enterocyte * reduces the possibility of osmotic diarrhea
29
What splits lactose, sucrose, maltose and non-specific destrin?
* lactase-lactose into glucose and galactose * Sucrase- sucrose into glucose and fructose * Maltase - maltose into glucose * alpha-dextrinase - non specific
30
How does glucose get into the blood from the intestine?
* Active: Na+/glucose co-transporter **SGLT1** * Passive: glucose moves into the blood through GLUT2
31
What is lactose intolerance?
* Develops from the lack of membrane bound enzymes resulting in malabsorption of carbohydrates * Undigested lactose causes osmolality changes * Test: overnight fasting followed by 50g of lactose in a 10% aqueous solution * low lactose tolerance curve or failure to blood glucose to rise
32
What are the sources of protein?
* dietary protein * intestinal mucosa that is continually sleuthed off lumen ~50% of dietary protein * enzymatic proteins that are secreted into GI tract and are not used will be digested
33
How are pancreatic proteolytic enzymes activated?
* Enterokinase is stimulated by the presence of trypsinogen * EK activates trypsinogen by releasing a hexapeptide from N-terminal * Active trypsin then autocatalytically to activate the bulk of trypsinogen and other peptidase
34
How do proteins enter the intestinal cell?
* PEPT1 * di and tripeptides are readily absorbed * coupled transport with Na+ * various peptidases in cells break remaining linkages * protein meal: 40% free AA's and 60% small peptides
35
What is celiac sprue?
* a certain type of wheat protein attacks mircovilli of mucosa and removing it from the cells * patients are thought to lack certian peptidases and results in productin of toxic substances
36
What protein absorption disease is associated with cystic fibrosis and hereditary pancreatitis?
* may lead to a decrease or absence of trypsin leading to poor absorption of protein
37
What protein absorption disease is associated with cystinuria?
* Characterized by defective transport of cystine in proximal renal tubule and small bowel
38
What protein absorption disease is associated with Hartnup Disease?
* Hereditary condition in which the active transport of several netural AAs is deficient in both the renal tubules and small bowel * when patients are fed dipeptides these are readily absorbed, just not free AAs
39
What property is important for digestion and absorption of lipids?
* insolubility of lipids in water are important properties for the digestion and absorption of lipids
40
What is the process of absorption on 4 major events?
* Secretion of bile and various lipases * Emulsification * Enzymatic hydrolysis of ester linkages * Solubilization of lipolytic products within bile salt micelles
41
What is lipase?
* water-soluble enzyme that only acts on the triglyceride droplet surface * produces monoglycerides and fatty acids
42
What are micelles and how are they used?
* essentially small aggregates of mixed lipids and bile acids suspended within ingesta * micelles bump into brush border of enterocytes and monoglyceride and FA are taken up into epithelial cell
43
How do lipids enter the blood?
* After the FA and monoglycerol enters thecell, triglycerides reassemble along with cholesterol and cholesterol ester and are packaged into lipoproteins * intestine produces chylomicrons
44
What are the fat soluble vitamins?
* Vitamins A, D3, E and K
45
What is the source of vitamin A?
* from animal sources or from beta-carotene * one molecule of beta-carotene makes vitamin A * becomes water soluble by micellar solubilization and absorbed by small intestine passively * converted to retinyl ester, made into chylomicrons and eventually taken by liver
46
What is the source of Vitamin D3?
* Cholecalciferl from either milk or formed in sun exposed skin * similar absorption mechanism to vitamin A * Vitamin D3 is transferred to a vitamin D binding protein in plasma and stored in various organs
47
What is the source of Vitamin E?
* derived from vegetable oils by passive diffusion * transported in circulation associated with lipoproteins and erythrocytes * helps protect membranes and RBCs from free radical damage
48
What is the source of vitamin K?
* derived from green vegetables or gut flora * phylloquinones from veggies is absorbed passively * menaquinones from gut flora are taken up passively
49
What are the water soluble vitamins?
* Vitamin C actively taken up in ileum * B1 at low concs are actively uptaken but higher cons areby passive diffusion * B2 by specific, saturable, active in small intestine * B6 simple diffusion * Folic acid
50
How is water and electrolyte absorbed?
* Active Na+ transport, which passively draws along anions and water * increased effectiveness in absorbing ions along GI tract because the decreased premeability to ions to prevent back flow
51
How is Ca2+ absorbed?
* proximal intestine * pathway * entry at brush border * regulation of intracellular Ca2+ * Ca2+ exits basolateral side * Ca2+ ATPase * 1,25-dydroxyvitamin D3 sensitive
52
How is iron absorbed?
* Heme absorbed by endocytosis and digested by lysoenzymes to release iron * Non-heme iron * enterocytes of proximal small intestine release transferrin that binds iron in lumen * transferrin-iron is absorbed at brush border by specifc transporters
53
What is hemochromotosis?
* unregulated iron absorption leading to overload * leads to * cirrhosis * diabetes * cardiomyopathy
54
What kind of pathologies can be identified with plain film?
* acute and chronic, diffuse or localized abdominal pain * obstructing voiding symptoms * renal calcuili * search for foreign bodies * evaluation of pneumperitoneum, congential abnormalities
55
What is the bony inspection?
* Lower rib cage * lumbar spine * sacrum * pelvis * hip joings
56
How do you read abdominal plain films?
* Projection of film: PA, AP (most are) * View: supine, erect, lateral decubitus * Exposure: spine visible? * Solid organs * Hollow organs
57
What is the structure of the ABO blood system?
* complex polysaccharides * Same backbone but different antigens * sphingolipids * glycoproteins * H antigen is the precursor to all
58
What does a N-acetylgalactosamine glycosyltransferase?
* coded by A allele * Adds a GalNAc to the terminal Gal in a alpha-1,3 linkage
59
What does galactosyltransferase do?
* coded by B allele * Gal is added to terminal Gal in alpha-1,3 linkage
60
What does the O allele code for in the ABO blood system?
* codes for an inactive protein * O group has neither of these monosaccharides at terminus antigen
61
What is the Lewis blood group system?
* H gene in epithelial and secretory tissues but detected in blood * either glycoproteins or spingolipids * fucosyltransferase * FUT1-RBC * FUT2-epithelial and secretory tissues * FUT3- epithelial and secretory tissues but adds a fucose to GlcNAc in a1,3 or a1,4
62
Describe a GPI
* structure * phosphoethanolamine binds to C terminus of protein * core tetrasaccharids * phosphatidylinositol with 2 FA in membrane * binds proteins and concentrates them in lipid rafts * phospholipase will cleave the anchor from the membrane and release the protein
63
Where does the synthesis of GPI anchors occur?
* occurs at first the exterior and then interior of ER * Exterior GlcNAc is added then flipped to the lumen * proteins end up on exterior of plasma membrane
64
Describe GAGs
* long and unbranched heteropolysaccharides * highly charged so protein ligands can bind electrostaticlly * disaccharid repeating units * sulfate groups
65
Where are GAGs located and why are they so good in that environment?
* found in extracellular space in ground substance, gel-like consisteny * Physical properties * not easily compressed - ideal for joints * negatively charged and attracts Na+ and K+ ions which absorbs water * maintains fluid and electrolyte within tissues
66
Describe Hyaluronate
* D-glucuronic acid + GlcNAc * beta 1,3 * units beta 1,4 * can be huge * not sulfated * not covalently bound to protein
67
Describe chondroitin sulfates
* D-Glucuronic acid + GalNAc * b1,3 * B1,4 links * sulfated * O of C4 of GalNAc (chondroitin-4-sulfate) * O of C6 of GalNAc (chondroitin-6-sulfate)
68
Describe Dermatain Sulfate
* L-uduroincid acid + GalNAc * B1,3 * B1,4 unit link
69
Describe Heparin
* D-glucuronic acid +glucosamine * B1,4 * a1,4 unit links * varibly sulfated * glucoasamine may sulfated or acetylated * most negatively charged polyelectrolyte * found exclusively only in granules of mast cells
70
How is Heparin used as a anticoagulant?
* Heparin binds to Antithrombin III (AT) * AT activated, increases rate by 1000x when compared AT activation w/o heparin * AT inactivates trombin and other clotting proteases
71
Describe Heparan Sulfate
* same as heparin * Dglucuronic acid (or L-iduronic acid) + glucosamine * B1,4 * a1,4 * exceptions * increased N-acetyl groups * decreased N-sulfate groups * decreased O-sulfate groups * more varibale composition
72
Describe Keratan sulfate
* Gal + GlcNAc * B1,3 * B1,4 repeating unit * two types of sulfate content * Keratan sulfate I (cornea) - protein linked via GlcNAc-Asn bond * Keratan sulfate II (cartilage) - linked to protein via GalNAc-Ser/Thr bond
73
How are GAGs synthesized?
* GAG chains asembled in Golgi on intact proteins * synthesis * tetrasaccharide core attached to protein by glycosyltransfereases * repeated * GalNAc transferease * GluUA transferase * Sulfation happens as the chain grows
74
What are proteoglycans?
* large molcule with GAGs (can be more than 1 type) and protein core * main part of ground substance * negatively charged to attract ions and water
75
What is aggrecan proteoglycan?
* proteoglycan expressed in chondrocytes (healthy cartildge) * core protein binds many sacchrides in 3 regions * inner (N terminus)- N linked carb structures * Central - O linked carbs and binds GAGs via Ser/Thr * Outer - chondroitin sulfate
76
What is monopolysaccharidoses?
* proteoglycans are degraded by sequential actions of lysosomal enzymes * symptoms * skeletal abnormailites * metal retardation * psychomotor regression
77
How are GAGs regulated?
* controlled at the level of hexoasmine synthesis * controlled at step that produces glucosamine * regulatory step: UDP-glucose DeH * UDP-glucose -\> UDP-GlcUA * inhibited by UDP-xylose
78
What are the 4 pathways of lipid transport?
* Food -\> any tissue * Liver -\> other tissues * Other tissues -\> liver * Adipose tissue -\> other tissues
79
How are lipids basically transported?
* large molecular assemblies of protein and lipids * protein - apolipoportein * lipid- TAGs, FFA, cholesterol, cholesterol esters, phospholipids * chylomicrons move into the lymph and then enter the bloodstream via the left subclavian vein * chylomicrons have ApoB48
80
How do lipids get from food to other tissues?
* Bile salts emulsify fats * intestinal lipases degrade TAGs * FA and other breakdown products are absorbed into mucosa and reassembled into TAGs * TAGs, cholesterol, and apolipoproteins are assembled into chylomicrons * chylomicron sent into bloodstream * Lipoprotein lipase activated by apoC-II and convertags TAGs into FA and glycerols * FA and glycerol enter cell and either oxidized for fule or reassembled to TAGs for storage
81
What is the role of apolipoproteins?
* Regulate plasma lipid metabolizing enzymes * activate Lipoprotein lipase * Facilitate lipid transfer * Mediate endocytosis Chylomicrons get more Apos from HDLs
82
What does ApoE do?
* Apolipoprotein required to mediate hepatocyte receptor endocytosis * Occurs after chylomircon has delivered its TAGs to tissues and is now smaller and composed of cholesterol and cholesterol esters
83
How do lipoproteins get transported from liver to other tissues?
* extra carbohydrates and fats in liver and used to make FA to assemble TAGs and lipids * assembled in VLDLs (ER and Golgi) * VLDL are exocytosed directly into blood
84
Describe VLDLs
* once VLDLs enter blood they quickly get more ApoC and ApoE from HDL * Cholesterol ester transfer protein (CETP) - VLDLs get more CE from HDL * Short lifespan \<1hr * has ApoB100
85
What is the fate of VLDL remants?
* larger ones that have lots of apoE are endocytosed by liver * smaller ones become IDLs then LDLs * become LDLs by hepatic lipase * apoE leaves and LDL will be endocytosized by tissues/liver
86
What are the properties of LDLs?
* ~40% CE and 20% phospholipids * Only carry apoB-100 * 2/3 able to be endocytozied by hepatocytes to be degrade * 1/3 induces ACAT to create CEs for storage and inhibits HMG-CoA reductase. Also reduces LDL receptors * 3 day lifespan
87
What happens to the LDLs that are not cleared by LDL receptor?
* Macrophages and some endothelial cells (spleen and intestines) have scavenger receptors * look for old LDLs
88
How do lipids get from other tissues to liver?
* ApoE mediated endocytosis of remnant particles containing CE (obtained from HDLs mediated by CETP) * CE is selectively transferred to hepatocytes via SR-B1 * endocytosis of large HDLs with ApoEs
89
Describe HDLs
* Rich in phospholids released by liver and small intestine * looks like a disc * HDLs are converted into spherical lipoportein particles by accumulating cholesterol and CEs * dock on cell surface through apoA-I or apoE
90
What does ABC1 do?
* ATP-binding cassette protein-1 * located in cell membrane and pumps free cholesterol from cell surface into HDL
91
What does LCAT do?
* Lechithin-cholesterol acyl-transferase * soluble protein made by liver * binds to surface of HDL and is activated by apoA-1 * catalyzes the esterfication of cholesterol
92
What is the fundamental difference in cholesterol delivery between LDL and HDL to hapatocytes?
* During cholestrol transport via LDLs, LDL + C+ CE are endocytosed in one piece * HDL remains intact but gives off CEs to hepatocytes * very few HDL acquire enough apoE to be endocytosed
93
What occurs in A-betalipoproteinemia?
* Deficient in TAGs transfer protein in ER * no ApoB lipoprteins are assembled (chylomicrons, VLDLs, LDLs) * rare, severe fat malabsorption * TAG accumulation in intestinal mucosa and liver
94
Describe Tangier disease
* Absence of ABC1 protein * apoA cant get lipids and mature HDls dont form * Deposit of CE in reticuloendothelial cells, bone marrow, Schwann cells * tonsils are orange
95
What is ApoCIII deficiency?
* absence of ApoCIII inhibits Lipoprotein lipase that decreases plasma TAGs and LDL while increasing plasma HDLs * found in Amish and ashkenazi jewish populations
96
What is CETP deficiency?
* CE cant be transferred to othe remnants * Benign condition * LDL is normal to lo * HDL is elevated
97
How do lipids transport from adipose to other tissues?
* TAGs are converted to FA and sent out to the blood * pyruate is converted at first very similar to gluconeogenesis but PEP is converted to glycerol 3-phospahte and made into TAG
98
How is the mucosal afferent endings stimulated?
* Stimulated by 5-HT (serotonin) released by EC cells in intestinal mucosa as the result of chemical and mechanical stimulation * creates a generator potetial * size of potential depends on the strength of stimulus\ * Stimulates * Extrinsic (vagal and spinal afferents) * Intrinsic (IPANs)
99
What are the three pathways that connect the gut to the CNS?
* vagal affarents from upper GI * pelvic afferents from colorectal * splanchnic afferrents from entire GI, mainly nociceptive
100
What are nociceptive fibers?
* splanchnic/spinal afferents that sense pain but vagal nerves stimulation doesnt produce pain * slow, unmyelinated C fibers * pain is felt as a dull ach and hard to locate * activated by STRONG distortion or contraction of bowel wall
101
What do vagal and pelvic afferents do?
* Afferents regulate visceral tone, distension, motility and secretion
102
What do IMAs do?
* forms ending in either longitudinal and circular muscle layers or in myenteric plexus * Activated by stretch, distension, and contraction
103
What do IGLE's do?
* Nerve endings are in contact with CT casule and enteric glial cells surrounding myenteric ganglia * Detect shearing forces between orthogonal muscle layers
104
How much stimulus is need to activate vagal and splanchinc afferents?
* Vagal - often need lowerlevels of distension to be activated * Splanchnics - often need a strong stimulus to be activated
105
What are IPANs?
* multipolar and their terminal are confined to the wall of the intestine near the plexuses * involved in motility, secretion, and vasodilation within intestine * when exicted it will release 5-HT
106
Where are cell bodies of vagal afferents located?
* nearly all parasympathetic afferents return and synapse onto nucleus tractus solitarius (NST) * cells bodies of neurons sit just ouside the CNS in nodose ganglion * NST receives info about BP, CO levels, and gut distension
107
What do IVAs do?
* free nerve endings that termina in the mucosa * have a low threshold * respond to mechanical stimuli applied to villi and detect material that is absorbed
108
Why is serotonin important in the gut?
* released by EC cells as the result of mechnical or chemical stimulation * 5-HT activates IPANs that activates ascedning excitatory and inhibits descending * SERT uptakes 5-HT from synaptic cleft to terminate serotonin action * not all absorbed some escapes to blood to be stored in platelets and used to vasocontrict during clotting
109
What occurs during vomiting?
* Sympathetic - sweating, pallor, increased respiration, and HR and dilation of pupils * Parasympathetic - profuse salvation, pronounced motility of esophagus, stomach and duodenum, relaxation of sphnincters * vomiting is coordinated in vomiting center in brain stem * chemo can also activate vomiting center
110
What can occur during visceral hypersensitivity?
* may be the result of an ulcer or gastric distension by causing sensory neurons to be more sensitive * nocipceptors can be damaged * damage can cause them to fire randomly without a stimulus
111
Define hyperalgesia
* exaggerated pain in response to a painful stimulus
112
Define allodynia
113
* pain from a stimulus that usually doesnt cause pain
114
How can inflammation affect nociceptive fibers?
* when damage cells release their cellular contents, their prescence can cause the secretion of other molecules and dilation of blood vessels * bradykinin, histamine, and prostaglandins trigger action potentials in nociceptive fibers * lysed cells will release large amounts of K+ which is related to the degree of pain expieranced
115
What is a sensory TRP channel?
* sense distinct thermal thresholds from very hot to cold * each thermo-TRP is activated by a specific natural compounds and synthetic substances
116
Irritable bowel syndrome
* associated with strong contrctile activity of gut * doesnt lead to other health problems * increased gut awareness is due to visceral afferent nerves being hypersensitive and increased 5-HT release from gut mucosa
117
What is Crohns disease?
* formation of patchy inflammation (cobblestone) mostly in small intestine but can be located in other GI locations * extends to all tissue layers * symptoms * abdominal pain, vomiting, diarrhea, blood in stool, fatigue, weight loss, growth failure
118
What is ulcerative colitis?
* limited to large intestine and inflamed area can vary from patient to patient * symptoms * bloody, diarrhea, abdominal cramping, and fealing of urgency or little warning when they have a bowel movement
119
How is gut pain treated?
* opiods are used to manage severe diarrhea and control high output ostomies * loperamind, diphenoxylate, and difenoxin only opioid derivatives approved to treat diarrhea
120
What are the four major forms of single gene hypercholesterolemia?
* LDLR * loss of function mutations autosomal dominant * APOB * receptor binding site mutations autosomal dominant * PCSK9 * gain of function-enhanced activity, autosomal dominant * LDLRAP1 * loss of function, autosomal recessive, overall rare
121
What are the symptoms of familial hypercholesterolemia?
* angina * buildup of cholesterol in tissues * calves camping * stroke-like symptoms * sores on toes that doenst heal
122
What happens with LDL-R gene deletion?
* loss of function mutation * occurs in low density lipoprotein receptor in liver * Test detects 99% of mutation in LDL-R and PCSK-9 genes * 80% of mutations in APOB Exon 26
123
Describe ApoB binding mutations
* Normally ApoB facilitates receptor-mediated endocytosis * endosome fuses with lysosome * removes aa and FA * creates cholesterol ester droplet
124
What occurs in a PCSK9 mutation?
* gain of function * typically LDL receptor is part of the internalisation of the LDL then recycled * Mutation causes PCSK to bind to LDL-R and be internalized * no dissociation, degradation of LDLR in lysosomes
125
What occurs because of LDLRAP1 mutation?
* loss of function, autosomal recessive * LDL receptor adaptor protein is required for LDL receptor binding to clathrin * losses this adaptor protein
126
What is the mechanism of action of statins?
* inhibit HMG-CoA reducatse * mainly inhibit enzyme in liver * reduces circulating LDL because it causes the hepatocyte to upregulate LDL-R expression since it cant make cholesterol * Activates SREBP
127
What is the mechanism of action of fibrates?
* Fibrates bind to nuclear receptor PPAR-alpha * Fibrate increases HDL levels and decreases TAG levels * Decreases VLDL * Receptor works as a transcription factor to change gene expression in target cells
128
What is a mechanism of action of Niacin?
* at high doses, niacin increases HDL levels and decreases TAGs adn LDL levels * mechanism is not completely clear * niacin thought to inhibit TAG synthesis enzyme, decreasing VLDL production
129
What is the mechanism of action of Ezetimibe?
* inhibits cholesterol absorption in small intestine * reduces absorption of dietary cholesterol and promotes cholesterol excretion
130
How does adipose tissue buffer dietary fat?
* buffer daily influx fat * obesity leads to enlarged adipocytes which decreases lipid buffering capacity * when not functioning properly, other tissues are exposed to excess FA and TAGs * interferes with insulin sensitivity (skeletal muscle and liver) and insulin secretion (pancreas)
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What role do macrophages in obesity?
* macrophages in adipose tissue are a hallmark of inflammation in obesity * adipose cells die because they become necrotic and dont function
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What does thiazolidinediones do?
* PPAR-y activator, insulin sensitizer * induces the differentiation of preadipocytes (stem cells) into small, young active adipocytes
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Why is glucose important to adipose cells?
* glucose is converted into Glycerol-3P * Fatty acyl CoA will combine with G3P to make TAGs * adipose cells have no way to make glycerol because they lack glycerol kinase
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How does insulin resistance affect adipose cells?
* insulin regulates lipoprotein lipase and glucose transport * low insulin inhibits both of there actions * leads to improper chylomicron degradation
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What are the common features of all glycoproteins?
* most common posttranslational modification * almost all secreted * lysomosal and membrane associted * almost never are in the cytoplasm * synthesized on rER via secretory pathway and go through the Golgi * can have alot of heterogenity
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What is a mucin?
* O-linked glycoprotein * can form gels that lubricate, provide chemical barriers and hold water * very negative structure * pulls in ions and water * structure * middle part has 50% of Ser or Thr that is glycosylated * mucins are increased in many cancers, asthma, bronchitis, COPD and cystic fibrosis
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What does ApoA do?
* cofactor for "LCAT", chlyomicrons, HDL
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Function of ApoB48?
* help Chlyomicrons remants return remants to liver
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Function of ApoB100?
* on VLDL, IDLs and LDL * binds to LDL receptor
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Function of ApoCII?
* on chylomicrons, VLDL, HDL * activate binding to Lipoprotein lipase to cleave TAGs
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What is the function of ApoE
* activates reuptake with liver * on everything except LDL
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Function of LCAT
* Converts cholesterol to CE * allows membranes to accept more cholesterol
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Function of CETP
* moves CE to LDL and LDL
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Function of hepatic liapse
* on liver cells to acquire TAGs from IDL to convert it to LDL
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