Week 3 CBE Flashcards
what are lipoproteins
Protein-and-lipid substances in the blood that carry cholesterol and triglycerides.
3 pathways of lipid/lipoprotein transport
- Exogenous: GI to peripheral and liver
- Endogenous: Liver to Peripheral
- Reverse cholesterol transport: Peripheral back to liver
lipoprotein examples
chylomicrons, VLDL, IDL, LDL, HDL
exogenous lipid pathways
From small intestine transported to:
1. liver
2. peripheral tissues
How lipoprotein facilitates the exogenous lipid pathway - enzymes
Chylomicron
Chylomicrons get broken down by an enzyme (LPL)
FFA is given to peripheral tissue
Cholesterol (triglycerides) is given to the liver.
endogenous lipid pathways
From liver to:
1. muscle/adipose,
2. back to liver
How lipoprotein facilitates the endogenous lipid pathway- enzymes
VLDL is assembled in the liver and sent to circulation.
VLDL is broken down by LPL:
1. triglycerides (NEFA and glycerol) -> muscle & adipose.
Losing triglycerides: VLDL turns to IDL.
IDL has 2 destinies
1. IDL is taken by the liver
2. IDL turns to LDL and transport cholesterol to peripheral tissue
How did VLDL turn to IDL (intermediate density lipoprotein)
By losing triglycerides
IDL turn to LDL (significance & enzyme)
If IDL is not returned to liver, it will be processed by hepatic lipase (HPL) and turn to LDL.
LDL is very cholesterol-rich, bad cholesterol.
What enzymes facilitates reverse cholesterol transport
LCAT (Lecithin-Cholesterol Acyltransferase)
—Adds cholesterol to HDL
ABC-A1 (ATP binding cassette A1 transporter)
—transport free chol. from peripheral tissue to HDL
SRB-1 = scavenger receptor B type 1
—receptor on liver that accepts HDL - cholesterol
CETP = cholesterol-ester transfer protein
—convert HDL to VLDL
What lipoproteins are involved in reverse cholesterol transport
HDL
VLDL
Pathways of reverse cholesterol transport
HDL: main function - collect free cholesterol
ABC-A1 transports free cholesterol from peripheral tissue to HDL.
LCAT: when activated it esterifies free cholesterol to become a more hydrophobic cholesterol ester, thus transported inwards in the HDL particle.
2 Destinies for HDL:
- SRB-1 on liver accepts HDL.
- HDL gets converted (by CETP) to VLDL and goes into endogenous lipid pathway.
Where is HDL synthesized?
GI and liver
How is HDL transport disrupted?
CETP turns HDL into VLDL -> endogenous lipid pathway
(high VLDL means lower HDL levels)
what lipoproteins are triglyceride rich?
what lipoproteins are cholesterol rich?
Triglyceride rich: VLDL - endogenous pathway (trig to muscle..)
and chylomicron (trig to muscle, remnant to liver)
Cholesterol rich: HDL and LDL (LDL gives cholesterol and HDL collects cholesterol)
ApoA1 functions
HDL
- activates LCAT that is circulating (esterification).
- binds SRB-1
ApoB100
Mainly functions for LDL
Binds LDL receptor for faster cellular uptake (a major risk factor for atherosclerosis)
Facilitate formation of VLDL in liver.
ApoE
Mainly functions as ligand of liver receptor
- uptake of chylomicron remnants
- uptake of VLDL remnants, IDL.
ApoB48
structural component necessary for the assembly and secretion of chylomicrons
Which cells synthesise cholesterol
All nucleated cells:
Mitochondria -> Acetyl-CoA -> cholesterol
How do cells uptake cholesterol
LDL deliver cholesterol to peripheral tissues:
LDL-Receptor is expressed to uptake cholesterol from plasma.
Receptor expression will decrease if high intracellular cholesterol.
LCAT
HDL has this enzyme to collect free cholesterol
ABC-A1
Lipid transporter, from peripheral tissue to HDL
CETP
Disrupts HDL(exchange trig with HDL’s cholesterol), converts it to VLDL.
Lab measurement of lipid levels
Measure concentration of lipoproteins and apolipoproteins.
Routine clinical measure of lipid levels
Total cholesterol levels
HDL-C levels
Triglycerides
How is LDL-C calculated
Total - HDL-C - VLDL-C
What drug is used for reducing cholesterol
statin
Fatty streaks formation (early stage of atherosclerosis)
- When LDL penetrates the endothelial layer of the arteries
- O free-radicals oxidise LDL, these oxidised LDLs are consumed by monocytes.
- monocytes become foam cells.
- The streak of yellow foam cells are fatty streaks
Oxygen free radicals are produced by?
- Glycation reactions (diabetes)
- smoking toxin
Significance of fatty streaks
Fatty streaks are often detected during autopsies or imaging studies, predicting atherosclerosis.
3 Steps of atherosclerosis
- Macrophages uptake oxidised LDL. Becoming foam cells
- Macrophages stimulate SMC (smooth muscle cells) to become fibroblasts and migrate and form a fibrous cap. Cholesterol will pool beneath fibrous cap
- If plaque ruptures, a blood clot will form
Difference between angina and myocardial infarction
Angina: temporary decreased blood flow to heart
MI: cardiac muscle is damaged from blocked blood blow.
what is CRP and hsCRP
C-reactive protein
A marker for inflammation.
high sensitivity CRP: inflammation in heart disease.
What is troponin - heart disease
Regulates muscle contraction.
Specificity: cardiac troponin isoforms can be detected using immunoassays.
Whyis troponin used for measurements (3 reasons)
1.Elevation in response to myocardial damage.
2. Specific to cardiac muscles.
3. Very sensitive to cardiac damage
Threshold for troponin indication of MI
Need to be above 99th percentile of the reference population.
Heart failure diagnosis - alternatives from imaging
Imaging (expensive)
Biochemical diagnosis: Natriuretic Peptide
NP in heart failure
During heart failure, heart ventricles dilate. Myocytes stretch and release NP.
Atrium releases ANP and ventricles release BNP
what do ANP and BNP do - why do myocytes release them (2 reasons)
- Vasodilation, reduce work for the muscle
- promote natriuresis (blood volume)
BNP and measurement of it
BNP is released by the heart ventricle
After cleavage:
Nt-pro BNP and BNP.
Nt-proBNP is more stable
Complications of BNP measurement
It has a relatively poor specificity: but it is sensitive
BNP levels can rise due to aging, and many other factors
How is BNP measurements used despite poor specificity
Normal levels of BNP can be used to rule out heart failure.
Complications of cardiac troponin measurements
Even though sensitive and high specificity, it doesn’t differentiate the mechanisms of heart injury.
Classic:
symptoms of BNP
symptoms of troponin
- breathless (failure of the heart to pump)
- chest pain (obstructed blood flow to cardiac muscles)
regulate Hydrogen Ion level (Chemical: buffering and ion exchange. Physiological)
- Buffering with Haem - (Hb-)+(H+) -> HbH
- Buffering with bicarbonate (HCO3-)
- Phosphate buffer
- K+ exchange with H+, intra. K+ goes out, H+ goes in.
- Physiological
Lungs remove CO2 (fast), H+ is also used.
Kidney excrete H+ (slow)
Metabolic alka/acidosis and potassium levels
To maintain charge balance to some degree
K+ and H+ will exchange:
Metabolic acidosis: Due to H+ accumulation, K+ will be exchanged out
Metabolic alkalosis: Due to low levels of H+, K+ will be exchanged to let intracellular H+ out.
Respiratory acidosis and compensatory mechanism (chemical and physiological)
carbon dioxide retention -due to-
respiratory defects, CNS disease.
Increased carbon dioxide –> increase H+ conc
Respiratory acidosis
Compensatory:
1. buffering -> Increased bicarbonate (HCO3-)
2. increased kidney excretion H+
acute/chronic/acute-on-chronic respiratory acidosis differences
chronic will: H+ level isn’t very very high.
–have a higher bicarbonate than acute- as it is always trying to compensate for the high H+.
kidneys increase bicarbonate reabsorption
acute on chronic: very high H+ and very high bicarbonate.
chronic respiratory acidosis (physiological compensatory mechanism)
Increase renal bicarbonate reabsorption to compensate for sustained high levels of H+ in circulation.
Metabolic Acidosis 2 causes and Anion gap
Metabolic acidosis: 2 causes
Increased H+
Decreased HCO3-
High anion gap:
Increased unmeasured -ve acids
- diabetic ketoacidosis: ketoacids
- lactic acidosis: lactic acid
- renal failure: decreased H+ excretion
- toxins (ethylene glycol): oxalic acid
Normal anion gap:
Decreased bicarbonate, this is compensated by Cl- reabsorption.
Diarrhea.
High anion gap, normal anion gap
- Increased unmeasured -ve acids (gap between measured)
- Increased loss of HCO3- (compensated by Cl- reabsorption)
Anion gap
Blood is neutral:
cation = anion
but we calculate it with measured cation - measured anion
there is a gap, because there are unmeasured anions
This gap increases, when unmeasured anions increase.
Respiratory alkalosis and compensatory mechanism (physiological and buffer)
Decreased carbon dioxide -due to respiratory problems
Decreased H+
Respiratory alkalosis.
Compensatory:
1. Reduced H+ excretion,
2. reduced kidney bicarbonate generation.
3. Buffer -> reduce bicarbonate
Causes of Metabolic acidosis
- Diabetic Ketoacidosis (DKA): increased H+ production.
- Severe diarrhea: Loss of HCO3-
-
Renal failure: Decreased H+ excretion.
poison…
Metabolic acidosis
High H+, lactic acidosis, DKA
Compensatory:
low CO2, as lung is over-functioning.
H+ will return to normal.
Metabolic acidosis effects
Increased plasma K+.
Chronic acidosis can lead to bone decalcification
- bone decalcifies to produce phosphate as a buffer.
Metabolic alkalosis cause
elevated bicarbonate
-abnormal renal absorption
-K+ deficiency, overall increased renal reabsorption
including bicarbonate
Metabolic alkalosis is due to
(biochemical)
Elevated bicarbonate -> decreases H+
Metabolic alkalosis compensatory responses
- Release of H+ from buffers
- Increased renal bicarbonate excretion despite intial bicarbonate reabsorption.
predisposition of fatty streaks
- High LDL concentration
- damage to arterial wall (hypertension, oxidation/glycation)
