Lipids and Lipoproteins Flashcards
What is a lipid
A lipid is a fatty, oily, or wax-like compound that is insoluble in water (hydrophobic). It is a combination of glycerol and fatty acids. When mixed in a watery solution, lipids disperse into tiny droplets to produce an emulsion.
Serve as the precursor to compounds like hormones, prostaglandins, leukotrienes, and lipoxins
Roles of lipids in biology
Storage of excess energy
Important part of cell membranes due to physical properties
Fatty Acids
Linear chains of C–H bonds that terminate with a carboxyl group (–COOH)
The Carbon can be double bonded to another carbon molecule to form un saturated fatty acids
Monounsaturated fatty acids - have one carbon double bond
Polyunsaturated fatty acids - have 2 or more carbon double bonds
These double bonds give lipids their unique physical properties
Majority of plasma fatty acids are instead found as a constituent of ____________
Triglycerides or phospholipids
Most fatty acids are synthesized in the body from carbohydrate precursors, except ______ & ______ acids, which are referred to as essential fatty acids
Linoleic and linolenic acids
Trans fatty acids
Trans fatty acids are unsaturated fatty acids that go through the hydrogenation process.
Results in margarines and manufactured cooking oils.
Excessive consumption is associated with elevated LDL, decreased HDL, and increased risk for congenital heart disease (CHD)
Triglycerides Info
Contain three fatty acid molecules attached to one molecule of glycerol by ester bonds in one of three stereochemically distinct bonding positions
From plant sources, such as corn, sunflower seeds, and safflower seeds, are rich in polyunsaturated fatty acids and are oils at room temperature
Triglycerides from animal sources contain mostly saturated fatty acids and are usually solid at room temperature.
Hydrophobic, making it water insoluble
Uncharged molecule so it is a neutral lipid
Phospholipids info
Similar in structure to triglycerides except that they only have two esterified fatty acids
Has a hydrophilic phospholipid head group instead of 3rd fatty acid
Because they contain both hydrophobic fatty acid C–H chains and a hydrophilic head group, they are by definition amphipathic lipid molecules and, as such, are found on the surface of lipid layers or on the surface of lipoprotein particle.
Cholesterol
Also an amphipathic lipid and is found on the surface of lipid layers along with phospholipids
Can also exist in an esterified form called cholesteryl ester, with the hydroxyl group conjugated by an ester bond to a fatty acid
Almost exclusively synthesized by animals, but plants do contain other sterols (called phytosterols) similar in structure to cholesterol
Does not serve as fuel source unlike other lipids
Function is being converted to bile acids for fat absorption, conversion to vitamin D3, and conversion to steroid horomones
Chylomicrons
Rich in triglycerides
The largest and the least dense of the lipoprotein particles
Turbidity or milky appearance of postprandial plasma specimens
Principal role of chylomicrons is the delivery of dietary lipids to hepatic and peripheral cells
Very-Low-Density Lipoprotein
Produced primarily by the liver and like chylomicrons, they are also rich in triglycerides
Like chylomicrons, they also reflect light and account for most of the turbidity observed in fasting hyperlipidemic plasma specimens, although they do not form a creamy top layer like chylomicrons
Carry endogenous triglycerides from the liver to peripheral tissue, mostly during fasting, for energy utilization/storage
Intermediate-Density Lipoproteins
Also referred to as VLDL remnants, normally only exist transiently during the conversion of VLDL to LDL
IDLs are not typically present in high quantities in normal plasma due to conversion during overnight fast
In patients with hyperlipoproteinemia type III, elevated levels of IDLs can be found in plasma.
Low-Density Lipoproteins
Primarily contains apo B100 and is more cholesterol rich than other apo b–containing lipoproteins
Can exist in various sizes and compositions and have been separated into as many as eight subclasses through density ultracentrifugation or gradient gel electrophoresis
LDL particles have been shown to be more proatherogenic and may be a better marker for CHD risk.
Lipoprotein (a)
Are heterogeneous in both size and density as a result of a differing number of repeating peptide sequences, called kringles, in the Apo(a) portion of the molecule
Clinical studies have demonstrated increased risk of both myocardial infarction and stroke with increasing Lp(a) concentration.
- The measurement of Lp(a) is often underutilized in clinical practice
High-Density Lipoproteins
Smallest and most dense lipoprotein particle, is synthesized by both the liver and the intestine
Ability of HDL to remove cholesterol from cells, called reverse cholesterol transport, referred to as good cholesterol
Lipoprotein X
Abnormal lipoprotein only produced in patients with cholestatic liver disease or in patients with mutations or deficiencies of lecithin–cholesterol acyltransferase (LCAT)
Is mainly removed by the reticuloendothelial system of the liver and the spleen
Lipoprotein Physiology & Metabolism …. Pathways
4 major pathways involved in lipoprotein metabolism
3 of the 4 (lipid absorption pathway, exogenous pathway, and endogenous pathway) depend on Apo B containing lipoproteins
The cholesterol transport pathway is responsible for maintain cholesterol equilibrium
Lipid Absorption
During the process of digestion, pancreatic lipase first converts dietary lipids into more polar compounds with amphipathic properties by cleaving off fatty acids.
- Triglycerides are transformed into monoglycerides and diglycerides. - Cholesterol esters are transformed into free cholesterol. - Phospholipids are transformed into lysophospholipids.
Exogenous Pathway
New synthesized chylomicrons are initially secreted into the lac-teals (small intestine lymphatic vessels) and then pass into the lymphatic ducts, eventually entering the circulation by way of the thoracic duct
A key protein in triglyceride metabolism is Apo C2
Once in the liver, lysosomal enzymes break down the remnant particles to release free fatty acids, free cholesterol, and amino acids.
Endogenous Pathway
Most triglycerides that are packaged into VLDL are derived from the diet after recirculation from adipose tissue.
IDL is taken up by the liver via Apo E and the LDL receptor, and the triglycerides in IDL are removed by hepatic triglyceride lipase, located on hepatic endothelial cells, ultimately producing LDL.
Abnormalities in LDL receptor function result in elevation of LDL in the circulation and lead to hypercholesterolemia and premature atherosclerosis.
Reverse Cholesterol Transport Pathway
One of the major roles of HDL is to maintain the equilibrium of cholesterol in peripheral cells by the reverse cholesterol transport pathway.
- Believed to remove excess cholesterol from cells by multiple pathways
- In the aqueous diffusion pathway acts as a sink
Another pathway in which HDL mediates the removal of cholesterol from cells involves the ABCA1 transporter.
- A member of the ATP-binding cassette transporter family, which pumps various ligands across the plasma membrane
- Defects in the gene for the ABCA1 transporter lead to Tangier disease, a disorder associated with low HDL and a predisposition to pre-mature CHD.
Lipid and Lipoprotein Population Distributions
Men and women both show a tendency toward increased total cholesterol, LDL-C, and triglyceride concentrations with increased age.
Incidence of heart disease is strongly associated with serum cholesterol concentration, particularly LDL-C.
National Cholesterol Education Program
It is recommended that all adults (20 years and older) have a fasting lipo-protein profile performed (total cholesterol, LDL-C, and HDL-C and triglycerides) once every 5 years.
Dyslipidemia and Children
Data collected between 1998 and 2010 estimated that 24.6% of US children aged 9 to 11 had either abnormally low HDL cholesterol or elevated non-HDL cholesterol.
Total cholesterol levels
Youth….
Acceptable = < 170
Borderline = 170 - 199
High = > 200
Adults…..
Acceptable = > 190
Borderline = 190 - 225
High = > 200
Should be less than 200 mg/dL
Low Density Lipoprotein levels
Youth….
Acceptable = < 110
Borderline = 110 - 129
High = > 130
Adults…..
Acceptable = < 120
Borderline = 120 - 160
High = > 130
Non-High Density Lipoprotein levels
Youth….
Acceptable = < 120
Borderline = 120 - 144
High = > 145
Adults…..
Acceptable = < 150
Borderline = 150 - 190
High = > 145
Triglyceride levels
0-9 years…..
Acceptable = < 75
Borderline = 75 - 99
High = > 100
10-19 years……
Acceptable = < 90
Borderline = 90 - 129
High = > 130
High Density Lipoprotein levels
Youth….
Acceptable = > 45
Borderline = 45 - 40
*Low = < 40
Adults…..
Acceptable = > 45
Borderline = 45 - 40
*Low = < 40
Arteriosclerosis
Relationship between heart disease and dyslipidemias (high levels of lipids in the blood) stems from the deposition of lipids, mainly in the form of esterified cholesterol.
Plaque formation involves repeated cycles of cell injury, followed by infiltration and cell proliferation to repair the site. LDL is believed to play a central role in initiating and promoting plaque formation.
Measurement of total cholesterol, HDL-C, LDL-C, and triglyceride levels is key.
Hyper/Hypo-lipoproteinemia
Caused by malfunctions in synthesis, transport, or catabolism of lipoproteins
Dyslipidemias can be subdivided into two major categories:
1. Hyperlipoproteinemia
2. Hypolipoproteinemia
Hyperlipoproteinemia
Are diseases associated with elevated lipoprotein levels
Hypolipoproteinemia
Are diseases associated with decreased lipoprotein levels.
Hypercholesterolemia
Studies continue to show a strong correlation with hypercholesterolemia and coronary heart disease mortality.
Associated with genetic abnormalities that predispose affected individuals to elevated cholesterol levels, is called familial hypercholesterolemia (FH).
Hypertriglyceridemia
Borderline high triglycerides as levels of 150 to 200 mg/dL.
Very high triglycerides are levels greater than 500 mg/dL.
Severe would be levels triglyceride levels of >880 mg/dL associated with recurrent/acute pancretitis.
Are influenced by hormones like insulin, pituitary growth hormone, adrenocorticotropic hormone (ACTH), etc…
Treatment of hypertriglyceridemia consists of dietary modifications, fish oil, and/or triglyceride-lowering drugs.
Combined Hyperlipidemia
Generally defined as the presence of elevated levels of serum total cholesterol and triglycerides
Lp(a) Elevation
Elevations in the serum concentration of Lp(a), especially in conjunction with elevations of LDL, increase the risk of CHD and CVD.
Non-HDL Cholesterol Elevation
Recent studies have shown that elevated levels of non-HDL-C are associated with increased CVD risk, even if the LDL-C levels are normal.
Cholesterol Measurement
Prefer 12 hour fasting sample, stable for several days refrigerated
First part of the lipid panel
Reference method is Gas Chromatography-Mass Spectrometry
Enzyme cholesteryl ester hydrolase reaction sequence is most commonly used to measure cholesterol.
Measured at 500 nm
Vitamin C and bilirubin are reducing agents that interfere with this reaction
Triglyceride Measurement
Used in the estimation of LDL-C
Endogenous free glycerol interferes and about 20% of samples have higher glycerol levels
Current reference method is Gas Chromatography-Mass Spectrometry
HDL Methods
For many years was separated almost exclusively by chemical precipitation, involving a two-step procedure with manual pretreatment
Been replaced with the development of anew class of direct, sometimes termed homogeneous, methods, which automate the HDL quantification
- Have been shown to lack specificity for HDL in unusual specimens like patients with kidney/liver conditions
LDL Methods
Research method for LDL-C quantitation and the basis for the reference method has been designated β-quantification. Requires ultracentrifugation.
A common approach is using the Friedewald calculation.
- HDL-C is quantified either after precipitation or using one of the direct methods, and total cholesterol and triglycerides are measured in the serum.
LDL-C = Total CHOL – HDL – Trig/5
Lipid Panel Sample
Primarily done on fasting samples
Serum is sample of choice
EDTA plasma used to be sample of choice
- Microclots and EDTA dilution were disadvantages
- Use of this sample requires a correction factor of 1.03
