VPHY 4200 Case 10: Key Terms in Liver Health & Inflammation

stroke ("brain attack")

sudden impairment in brain function, sudden paralysis or sensation

ischemic, hemorrhagic

two types of stroke

ischemic

stroke caused by blockage of a blood vessel due to a clot; includes subtypes of thrombotic and embolic

hemorrhagic

stroke caused by a ruptured blood vessel

2

the human brain makes up about ?% of body weight

15-20

the human brain receives about ?% of cardiac output

20

the human brain consumes about ?% of resting O2

gray

about 2/3 of the normal cerebral blood flow (CBF) is in the (gray/white) matter

8

? seconds of interruption of blood flow will lead to unconsciousness

face (smile/symmetry)

What does the F stand for in FAST acronym for spotting a stroke?

arm (ask person to raise both arms)

What does the A stand for in FAST acronym for spotting a stroke?

speech (ask person to speak simple sentence)

What does the S stand for in FAST acronym for spotting a stroke?

time (time lost is brain lost)

What does the T stand for in FAST acronym for spotting a stroke?

SHAME

acronym for risk factors of stroke

smoking

What does the S stand for in SHAME acronym for stroke risk factors?

hypertension

What does the H stand for in SHAME acronym for stroke risk factors?

atrial fibrillation

What does the A stand for in SHAME acronym for stroke risk factors?

male

What does the M stand for in SHAME acronym for stroke risk factors?

elderly

What does the E stand for in SHAME acronym for stroke risk factors?

amphipathic, apo-lipoproteins

lipids must bind to (hydrophilic/hydrophobic/amphipathic) proteins called ? to be transported in the blood

lipoproteins

protein-and-lipid substances in the blood that carry fats and cholesterol; classified according to size, density, and chemical composition

chylomicrons (CM)

lowest density lipoproteins

CM, VLDL, IDL, LDL, HDL, FFA

the six lipoprotein forms based on densities, in order from lowest to highest

pancreatic lipase

digests triacylglycerols (triglycerides/neutral fat) into fatty acids + monoacylglycerol, which can be absorbed by enterocytes (intestinal mucosal cells)

enterocytes (intestinal mucosal cells)

nascent chylomicrons are formed in ?

triacylglycerols, apolipoprotein

in enterocytes, ? are resynthesized and added to ? to form nascent chylomicrons

lacteal

the lymphatic vessels of the small intestine that absorb digested fats

exocytosis

nascent chylomicrons are transported from enterocytes to the central lacteal via ?

adipose, muscle, liver

chylomicrons deliver ~80% to ? tissue, ? tissue, and peripheral tissues; ~20% to the ?

HDL

the nascent CM is rapidly modified into CM by combining apoE + apoC-II from circulating ?

apoC-II

an apoprotein that is important for the metabolism of lipids in the CM b/c it activates lipoprotein lipase

lipoprotein lipase (LPL)

an enzyme that hydrolyzes triglycerides in lipoproteins into three fatty acids and monoacylglycerol

adipocytes

lipoprotein lipase (LPL) is mainly produced by ?

capillary, adipose, cardiac, skeletal, lactating mammary

LPL resides on the ? walls mainly on ? tissue, ? and ? muscles, and ? glands

lipogenesis

the monoacylglycerol and fatty acids from the hydrolyzed triacylglycerol are transported to adipocytes, where they promote ?

increases

LPL is insulin-sensitive--insulin (increases/decreases) LPL activities

apoC-II, HDL

after being degraded by LPL, CM decrease in size and increase in density -> ? is returned to the ? -> the remaining particle is called a "CM remnant"

liver

CM remnants in the blood are transported to the ?

leftover lipids

CM remnants deliver ? to the liver

hepatocytes (liver)

What type of cells produce VLDL?

fats, carbohydrates

the dietary intake of both ? and ?, in excess of the needs of the body, leads to the conversion into triacylglycerols in the liver

liver, peripheral, muscle, adipose

the function of VLDL is to transport endogenously synthesized triacylglycerols from the ? to ? tissues (mainly ? and ? tissue)

apoC

nascent VLDL released from the liver acquires ? and apoE from circulating HDL

non-alcoholic fatty liver (NAFLD)

a high rate of liver lipogenesis (from high lipid or carb intake) will exceed liver production of VLDL, leading to ? disease

cholesterol

LDL is made up ~80% by lipids--mostly ?

cholesterol, peripheral (liver 75%, adrenals, gonads, blood vessels, adipose tissue)

the primary function of LDL is to provide ? to ? tissues

insulin, LDL

? and tri-iodothyronine (T3) increase the binding of ? to liver cells -> cholesterol is eliminated via bile

diabetes

? or hypothyroidism -> hypercholesterolemia -> high risk of atherosclerosis in primates (b/c that cholesterol can't be metabolized by the liver)

liver

HDLs are synthesized de novo in the ? and small intestine, as protein-rich particles

reverse cholesterol transport

a process in which HDL molecules attract cholesterol and carry it back to the liver, where it is converted into bile acids and eventually excreted through feces

atheroma

the lipid deposits in intima of arteries, producing a yellow swelling on the endothelial surface

intima

inner layer of blood vessels containing endothelial cells, the underlying extracellular matrix, and a smattering of smooth muscle cells

atherosclerosis

disease in which plaque builds up inside the arteries

increased, NO, adhesion, chemo-attractants

characteristics of endothelial dysfunction: (increased/decreased) vascular permeability, decreased synthesis and/or release of ?, increased secretion of ? molecules, and increased secretion of ?

macrophages

adhesion molecules include VCAM-1, which mediates the adhesion of monocytes (?), lymphocytes, eosinophils, and basophils to the vascular endothelium

chemo-attractants

recruit inflammatory cells to areas of lipid accumulation

LDL, monocytes

the intact and yet dysfunctional endothelium becomes sticky -> infiltration of plasma ? and ?

decreased, increased

atherosclerosis risk factors result in (increased/decreased) NO production, and (increased/decreased) free radicals

antioxidants

important for reducing risks of atherosclerosis

shear stress, lipids (LDL), inflammatory

turbulent blood flow creates endothelial ? -> decreased NO production -> vasoconstriction -> infiltration of ? and ? cells

shear stress

endothelial ? is the friction of blood against the endothelium, which is exacerbated by hypertension

vascular inflammation

endothelial dysfunction -> ? -> accumulation of lipids and cellular debris in intima; this plays a key role in atherosclerosis

in

atherosclerotic deposits are (in/on) vessel walls

ROS, oxi-LDL

endothelial dysfunction recruits LDL which passes into the vascular intima -> LDL is oxidized by ? into ? (pro-inflammatory)

endothelial, adhesion, monocytes

oxi-LDL activates ? cells through the induction of the cell surface ? molecules -> ? are adhered then entered across the endothelium to the sub-endothelial matrix

macrophages, oxi-LDL

after blood monocytes infiltrate into the subendothelial area of the vascular wall, they differentiate into ? which then take up ?, forming foam cells

scavenger

foam cells contain ? LDL receptors (no feedback) -> more and more cholesterol in foam cells -> secrete more cytokines -> inflammation -> cell death

foam cells

lipid-loaded white blood cells that have surrounded large amounts of a fatty substance, usually cholesterol, on the blood vessel walls

CRP (C-reactive protein)

substance that is produced by the liver and released to the blood that increases in the presence of inflammation in the body

biomarker, mediator

CRP functions as a ? and a ? in pathogenesis of atherosclerosis

biomarker

an individual protein that is uniquely produced in a diseased state

(inflammatory) mediator

a chemical that impacts the immunoinflammatory process causing either exacerbation or reduction

macrophages, adipocytes

CRP is synthesized by the liver in response to factors released by ? and ?

acute

the levels of CRP increase during ? inflammation

smooth muscle cells (SMC), fatty, extracellular matrix

foam cells secrete pro-inflammatory cytokines -> ? proliferation and migration to the intima, where they secrete cytokines; also, increased ? deposits and formation of ? in the intima

stable

atheroma characterized by a thick fibrous cap, small lipid core, more SMC, and well-preserved endothelium

vulnerable

atheroma characterized by a thin fibrous cap, large and necrotic lipid core -> more inflammatory cells -> eroded endothelium

proteolytic enzymes

heavily infiltrating foam cells secrete ?, degrade the collagen-rich cap matrix, and cause the gradual loss of SMCs and collagen from the fibrous cap

pathological thrombosis (formation of blood clot)

endothelial disruption due to rupture -> platelet aggregation -> activation of coagulation cascade -> conversion of fibrinogen into fibrin -> blood clot formation -> ?

brain

What part of the body does stroke involve?

weakness, numbness, blurred, headache

symptoms of stroke include: one-sided ? and ?, speech difficulties, ? vision, and terrible ?--does not include chest pain

mini-stroke (transient ischemic attack/TIA)

equivalent to "angina" of the brain; reversible focal brain dysfunction due to ischemia; transient stroke symptoms that last from seconds to hours; it is a key opportunity to prevent stroke (permanent damage)

BP, heart, arteries

causes of TIA are essentially the same as those for stroke and heart diseases: high ?, ? diseases, and narrowing of ?

dissolution

TIA mechanism: blood clot forms -> body recognizes the presence of clot -> triggers clot ? mechanism -> vessel reopens -> symptoms go away

85

about ?% of strokes are ischemic strokes

HTN (hypertension), DM

about 2/3 of thrombotic strokes are associated with ? and ?

embolus

a clot that breaks loose and travels through the bloodstream

hypertension

the most important cause of intracerebral hemorrhage, which commonly occurs during activity

glutamate

stroke greatly increases release of the NT ? -> overstimulation of receptors -> neurodegeneration and neuronal damage

glutamate

the most prominent NT in the body; the brain's main excitatory NT, present in >50% of nervous tissue; the precursor for GABA, the brain's main inhibitory NT

postsynaptic

glutamate is responsible for neurons' (presynaptic/postsynaptic) excitation, and for memory formation, learning, and regulation

Ca2+, excitotoxicity

glutamate-R binding activates the R's and opens ion channels coupled to the R -> allows extracellular ? to pass into the intracellular cytosol -> ? -> neurodegeneration and neuronal damage

microglia, astrocytes, cytokines, metalloproteases

initial ischemic event -> excitotoxicity -> ? and ? activated + increased neutrophil infiltration -> secrete ? and matrix ? -> neuronal death

t-Pa (tissue plasminogen activator)

a naturally occurring enzyme that is released into the blood very slowly (days) by the damaged endothelium and breaks down blood clots and clears blocked blood vessels; treatment for acute ischemic stroke and heart attack

fibrinolysis

breakdown of a clot; a normal process after damaged vessel is repaired

liver

plasminogen is produced in the ? -> blood

plasminogen activators (PAs)

convert plasminogen into plasmin (active)

plasmin

an enzyme that dissolves the fibrin of blood clots