Lipid Metabolism Flashcards
Cardiovascular Disease risk factors (5)
Obesity
Smoking
Type 2 diabetes
Genetic risk factors - family history of vascular disease
Hyperlipidaemias - in particular relating to cholesterol
Lipids and _____________ are central to energy metabolism and closely associated with coronary heart disease.
Lipoproteins
Chylomicrons
Transport triglycerides throughout the body. Large core with TG and Chol-Ester.
VLDL
Very low density lipoprotein. Carry TG from liver to periphery.
LDL
Low density lipoproteins. Carry cholesterol to periphery.
HDL
High density lipoproteins. Carry excess cholesterol from periphery to liver. Anti-atherogenic. “Good”
Apolipoproteins
located on the surface of lipoprotein particles. Provides structure and act as ligands for receptors - targeting.
Important for diagnostic tests.
Accurate measurement of lipid is important for diagnosis and treatment of patients.
ApoA1
Major protein in HDL
Used to measure the amount of anti-atherogenic HDL in plasma
ApoB
Major protein on LDL and VLDL, chylomicrons
Ligand for LDL receptor
High levels = heart disease
Better overall marker of risk than LDL alone and better risk marker of vascular disease
Used as a guide to the adequacy of statin treatment , better than any cholesterol index
ApoE
Majorprotein on LDL, VLDL, HDL
Ligand for LDL receptor
What are the three isoforms of ApoE?
Apo E2, E3, E4
Components of a lipoprotein
Triglyceride
Phospholipid
Cholesterol
Cholesterol ester
Apolipoprotein
Building block for triglycerides and phospholipids
Fatty acid
Triglyceride structure
3 fatty acids connected to a glycerol with ether bonds
Important for storage and transport of energy in the body
No charged groups => very hydrophobic
May contain both saturated and unsaturated fatty acid
Phospholipids
2 fatty acids, glycerol and a phosphogroup (neg)
Cholesterol
Unsaturated steroid alcohol
Can form an ester bond with a fatty acid generating a cholesterol ester
Essential part of cell membranes and for formation of hormones and bile salt
Functions of fatty acids
Building blocks of triglycerides and phospholipids
Source of metabolic energy
Function of triglycerides
Part of the cell membrane
Storage of energy (adipose tissue)
Where are triglycerides synthesised?
Liver
Where are triglycerides metabolised?
Intestine
How are dietary TGs transported?
In chylomicrons
High levels of ___________ are related to a higher risk of heart and blood vessel disease independent of high cholesterol.
TGs
What decreases levels of TGs? (3)
Beta-lipoproteinemia
Malnutrition
Drug use
Phospholipid structure
Glycerol backbone and 2 fatty acid chains
Amphipathic
Function of phospholipid
Important component of the cell
Cholesterol function
Important structure to cell membranes
Starting material for synthesis of steroid hormones (testosterone) and vitamin D
Formation of bile salts in the liver -> excretion
Plaque formation in blood vessels
Cannot be catabolised in most cells
Mainly synthesised in liver
Excess cholesterol can lead to cardiovascular disease
What is the rate limiting step of cholesterol synthesis?
HMG CoA reductase
Explain the action of statins on cholesterol synthesis
Statins inhibit HMG Co reductase action -> lowering cholesterol levels
Why percentage of cholesterol is esterified?
75%
What catalyses cholesterol+fatty acid esterification?
Enzyme lecithin:cholesterol acyltransferase (LCAT)
What are the two most abundant cholesterol esters?
Cholesterol linoleate
Cholesterol oleate
What are the four lipid metabolism pathways?
1️⃣ lipid absorption pathway
2️⃣ exogenous pathway
3️⃣ endogenous pathway
4️⃣ reverse cholesterol transport pathway
Functions for pathways 1️⃣-3️⃣ of lipid metabolism (3)
Transport lipid from liver (diet) to peripheral cells
Energy metabolism TG->FA
Forward transport of cholesterol
Features of lipid digestion
Small intestine
Pancreatic fluid creates a basic pH
Bile salts from gall bladder form water-soluable complexes
Pancreatic enzymes hydrolyse lipids
Features of lipid absorption
Free fatty acids - absorbed across the intestinal epithelia
Triglycerides - hydrolysed by lipase, which act on the ester bond
Cholesterol - not metabolised in the intestine. Bile salts mediate transport across intestine wall. Liver.
Lipid absorption pathway
TG -> monoglycerides, diglycerides
Cholesterolesters -> cholesterol
Phospholipids-> lysopholipids
Chylomicrons are formed from dietary fat
Exogenous pathway
Chylomicrons
TG-> fatty acids glycerol
LPL protein lipase
Mutations in LPL or ApoCII
Familial hyperchylomicronaemia
Chylomicron lipolysis
LPL enzyme attached to endothelium wall via glycosaminoglycans
ApoC II will bind to LPL on the endothelial surface and activate it
Active LPL hydrolyse TG to glycerol and fatty acids
Chylomicron remnants cleared by liver
Chylomicrons cannot be detected in a fasting plasma sample
Endogenous pathway
VLDL transports endogenous TG
LPLacts on the VLDL to remove TG
VLDL remnants releases cholesterol to HDL where it is esterified by cholesteryl ester transferase protein (CETP)
This results in VLDL converting to the denser LDL (via IDL)
LDL delivers cholesteryl esters to cells
Endocytosis mediated by the LDL receptor
Receptor mediated internalisation and metabolism of LDL
Internalised LDL is degraded to amino acids and cholesterol which is released into the cytosol
The free cholesterol activates 3 regulatory mechanisms
What are the three regulatory mechanisms of LDL metabolism?
⬇️ HMG CoA reductase
⬆️ ACAT
⬇️ LDL receptors
Deposition of cholesterol on the artery wall by ____,and attraction of macrophages contribute to plaque formation.
LDL
Modified LDL is recognised by ___________ receptors.
Scavenger
________________________ is downregulated due to high cholesterol concentration.
LDL receptor (LDLR)
__________________ is internalised into the cell by alternative receptors and thereby bypass the feedback mechanism.
Oxidised LDL
LDL oxidation
Balance between antioxidants and pro-oxidants in the cell and lipoprotein determine how much lipoprotein is. Oxidised and hence atherogenic potency.
Antioxidant
A molecule capable of delaying or inhibiting oxidation of a substrate. Vitamin C, E, ubiquinol Q10, flavonoids
Modified LDL
Pro-inflammatory => atherothrombotic disease
LCAT
Transfers an acyl group (FA residue) from lecithin to cholesterol to cholesterol ester. HDL
LPL
Digests TGs into glycerol +free FA
Activated by ApoC-II (at TG-positive lipoproteins) in the capillary endothelium
Hepatic lipase
Similar function to LPL
Reverse cholesterol transport pathway - HDL
To balance the concentration of cholesterol in the periphery
HDL removes excess cholesterol
CETP increases the rate of transport
LCAT catalyses cholesterol esterification -> HDL-mediated removal of excess cholesterol from macrophages in the arterial wall (activated by its cofactor ApoA1)
CETP
Reduces circulating cholesterol-HDL levels by transferring cholesterol-esters to LDL particles
High CETP => atherosclerosis
________ is a risk factor for CVD
Cholesterol
Treatment to lower plasma LDL cholesterol
Diets and lifestyle changes
HMG-CoA reductase inhibitors (statins)
QRISK2 risk calculator
Hypercholesterolemia
The lipid abnormality most closely linked to heart disease. Increased LDL cholesterol.
Hypertriglyceremia
Caused by genetic abnormality or hormone imbalance. Insulin, glucagon, pituitary hormone, epinephrine.
Combined hyperlipoproteinemia
Elevated levels of both cholesterol and TG. Increased risk of heart disease.
Total cholesterol test
Directly linked to a risk of heart disease
Decreased in cancer, malnutrition and hyperthyroidism
Caveat - measures sum of lipoprotein-cholesterol
Total plasma cholesterol levels are affected by: (5)
Diet - polyunsaturated fats lower cholesterol
Excercise - increases plasma HDL
Age - increases with age
Sex - lower in women
Genetics/environment - north Europeans higher
Bad cholesterol
LDL
New research shows IDL, VLDL and apolipoproteins as bad cholesterol also 2014
Good cholesterol
HDL
Total cholesterol level
LDL (bad cholesterol) estimated from ______ concentration.
ApoB
Lipoprotein A
LP(a) is a LDL attached to a protein called apo(a)
Not fully known what it does
If high levels=> increased risk of heart attack and stroke
Independent risk factor for cardiovascular disease
Largely genetically determined
Quantification by immunoassay
ApoC
Synthesised in the liver
Mainly associated with HDL
ApoB48
Chylomicrons
ApoB100
Major component of LDL,VLDL, which will give a concentration os these two in serum
Immunoassay
May be a better indicator of atherogenic particles than LDL cholesterol
APO A1
Major protein of HDL
Low levels => HDL deficiency and increased risk of early cardiovascular disease
LDL-associated PLA2 (PLAC)
Measures the level of lipoprotein associated-phospholipase A2, an enzyme associated with inflammation, stroke and heart attack risk.
However levels may also be due to non-arterial causes.
C reactive protein and cardiovascular disease
Inflammation of the arteries is a risk factor for cardiovascular disease. CRP has been linked to an increased risk of heart disease, heart attack, sudden death, stroke, and peripheral arterial disease.
High Sensitivity (also called Ultra-sensitive) C-reactive protein is known as HS-CRP, US-CRP or CRP for short is used for patients with a predisposition for CVD e.g. genetic.
In studies involving large numbers of patients CRP seems to be at least as predictive of cardiac risk as cholesterol levels.
CRP
Acute phase protein produced by the liver
Released after onset of injury or infection that is causing inflammation
Apolipoprotein immunoturbidity assay
Antiserum + antigen → antibody-antigen complex (creates turbidity)
Samples read against a known standard on an automated autoanalyzer instrument, such as the ILab, CABAS FARA and Beckman Synchron
