Structure and function of lipids

After a meal versus during fasting

--> After a meal, TAGs in chylomicrons or VLDL in the blood are cleaved to free fatty acids which are taken up by adipocytes for synthesis and storage of TAGs. --> During fasting, TAGs in fat cells are cleaved and the free fatty acids are released into the blood. --> Free fatty acids are transported in blood bound to albumin.

Naming fatty acids

--> Humans: fatty acids are elongated at the carboxyl end (carbon #1) --> they can only be desaturated between carbons 9 and 10 or between the double bond of 9 and the carboxyl end. --> plants form the fatty acids that are essential for humans --> The family is determined by counting backwards from the methyl end (last carbon omega) until the first double bond is reached (independent of the length of the fatty acid). --> You go to the last carbon no matter how long your fatty acid is and count backwards when you see the first double bond.

Dietary essential long-chain fatty acids

--> Linoleic acid and alpha-linolenic acid are dietary essential long-chain fatty acids that cannot be formed in animals.

Phosphatidylcholine and phosphatidylethanolamine

--> PE and PC are phospholipids and major components of membrane lipids. -->the overall charge is zero

Polar lipids in humans found in membranes

1) Phospholipids contain phosphate 2) Most phospholipids contain a glycerol backbone 3) Exception is sphingomyelin which is a phospho-sphingolipid

Phosphatidylinositol (PI)

--> PI is not major component of plasma membrane but it is important as it often contains arachidonic acid --> It can also be modified for the phosphoinositide (calcium ion) messenger pathway --> Membrane PI is 2X phosphorylated to phosphatidylinositol-biphosphate (PIP2). --> Cleavage by phospholipase C generates the second messengers DAG and IP3 (inositol-triphosphate) --> IP3 binds to a receptor to open the calcium ion channel of the ER

Omega-3 fatty acids

--> The omega-3 fatty acids are important for brain and vision and cardiovascular health. A) Alpha-linolenic acid (18:3, omega 3) can make: B) Eicosapentaenoic acid EPA 20:5, omega-3, intermediate in humans which can make C) Docosahexaenoic acid (DHA: 22:6, omega-3) DHA in phospholipids of the brain provides a high fluid microenvironment. DHA is important for brain functions and the visual cycle in the retina.

Fatty acids

--> amphipathic molecules, have a polar part and nonpolar part --> unsaturated fatty acids that are found in humans have double bonds that are in cis configuration (the bonds are always spaced at three carbon intervals).

Cholesterol

--> can be used for de-novo synthesis of steroid hormones only in steroidogenic cells. Adrenal cortex: (cortisol, aldosterone, androgens) Ovaries: (estradiol) Testes: (testosterone)

How is cholesterol (fatty acyl esters) transported?

--> cholesterol is transported in the blood inside of lipoproteins. --> Lipoproteins contain a phospholipid monolayer and contain in their core TAG and cholesteryl esters

Deficiency of lung surfactant

--> deficiency of lung surfactant can lead in preterm infants to Respiratory Distress Syndrome (RDS) --> Lung maturity of the fetus is often predicted by the (phosphatidylcholine) lecithin/sphingomyelin ratio. (Two or above is related to maturity). -RDS is also found in adults due to damage of lung surfactant producing cells

Dietary essential fatty acids

--> dietary essential fatty acids and fatty acids formed from them are polyunsaturated fatty acids (PUFA) with cis double bonds. --> Humans cannot change a fatty acid of the omega-6 family to a fatty acid of the omega-3 family but a smaller member of the same family can be used to form a larger fatty acid. As an example--> Lineolic acid (18:2, omega-6) can make or be changed to Arachidonic acid (20:4, omega-6) because both of the amino acids are from the same family. Eicosanoids are synthesized from a fatty acid with 20 carbons (prostaglandins, thrombaxane, leukotrienes)

Palmitate (16:0)

--> fatty acid synthesis in humans leads mainly to palmitate 16:0 (which is a long-chain fatty acid)--they of the length of 16-20 carbon atoms.

Phosophatidylserine (PS) and phosphatidylinositol (PI)

--> found in the inner leaflet of the plasma membrane --> overall charge is negative

Glycosphingolipids

--> found in the outer leaflet of the plasma membrane --> interact with the extracellular environment --> they are antigenic --> neutral glycosphingolipids contain ceramide and one sugar (then they are named cerebrosides) and ceramide and more sugars (then they are named globosides). --> Cerebrosides and globosides are found in brain and peripheral nervous tissue, with high concentration in the myelin sheath.

Importance of dietary essential fatty acids

--> in addition to being precursors of physiological important fatty acids, they are components in biological membranes --> they modify the fluidity of the membrane either by themselves or by their longer family members (20:4, omega-6 and 22:6, omega-3) --> essential fatty acids can pass through the adult blood-brain barrier --> Arachidonic acid, EPA and DHA are found in milk and can enter the developing brain in infants. --> deficiencies are rare, can lead to scaly dermatitis, hair loss, and poor wound healing and visual and neurologic abnormalities. --> total parenteral nutrition (TPN) is an intravenous form to administer dietary essential fatty acids.

Melting point of fatty acids

--> increases with chain length --> decreases with the degree of unsaturation (double bonds) Palmitate 16:0 Linoleic acid 18:2 Alpha-linolenic acid 18:3 Arachidonic acid 20:4

Phosphatidylcholine function

--> liver releases PC together with bile salts into the bile to increase the solubility of free cholesterol in bile. --> PC can be formed in the hepatocyte from dietary choline but also by methylation of PE using 3X SAM. --> Free cholesterol is then eventually excreted in the feces. --> In the duodenum, PC is cleaved to lyso-PC and a free fatty acid --> Both have detergent character and aid with lipid digestion

Phosphatidylethanolamine

--> mainly in the inner leaflet near the cytosol -> PE can be 3X methylated to form PC (S-adenosylmethionine SAM is used) --> Phosphatidic acid is found in phosphoacylglycerols, which leads to the naming "phosphatidyl"

Phosphatidylcholine is special

--> major component of cellular membranes --> provides monolayer in lipoproteins --> secreted by the liver into the bile for cholesterol transport and also for dietary lipid digestion --> provides lung surfactant (dipalmitoyl-PC) in the alveoli of the lung --> used for synthesis of sphingomyelin

Free cholesterol

--> needed in the plasma membrane in both leaflets --> regulates and stabilizes the correct fluidity of the plasma membrane -->Dietary high cholesterol levels do not seem to significantly raise blood cholesterol levels over time in healthy individuals --> fatty acid composition has a larger influence. An increase in blood cholesterol levels is seen after a diet rich in saturated fatty acids, especially palmitate. Trans-fatty acids shall not be eaten. --> In patients with hypercholesterolemia, a diet low in cholesterol and low in palmitate is recommended

Acidic glycosphingolipids

--> negatively-charged at physiological pH --> Sulfatides are cerebrosides that contain sulfated galactosyl residues. --> They are mainly found in nerve tissue and kidney. --> Gangliosides are globosides after addition of N-acetyl-neuraminic acid (NANA) (sialic acid) --> Gangliosides are primarily found in the CNA: brain nuclei, spinal cord, retina.

Cardiolipin

--> phospholipid that is antigenic and recognized by antibodies raised against Treponemia pallidum, the bacterium that causes syphilis --> deficiency of cardiolipin leads to Barth's syndrome (rare but severe cardiomyopathy)

Plasmalogens

--> phospholipids found in membranes that contain a vinyl ether linkage at Carbon-1 and are named phosphatidal.... --> The PC analogue is mainly found in the heart (1/3 of phospholipids) --> The PE analogue is mainly found in nerve tissue (Brain: 1/3 of phospholipids and up to 70% in the myeline sheath)

Sphingomyelin

--> phosphosphingolipid sphingomyelin is found in most plasma membranes together with phosphatidylcholine --> the synthesis of sphingomyelin uses phosphatidylcholine --> Sphingomyelin is a major structural phospholipid in myelin of nerve fibers and in gray matter of brain

Sphingolipids

--> polar membrane lipids that contain sphingosine as backbone instead of glycerol --> they are found mostly in the outer leaflet of the plasma membrane --> the synthesis starts with palmitoyl CoA and serine. (Pyridoxalphosphate vitamin B6 is needed as coenzyme). -N-acyl-sphingosine (ceramide) is formed which is a component of sphingomyelin and glycosphingolipids. -->It is special that a ceramide containing a 30C fatty acid is a major component of skin and regulates skin's water permeability

Phosphatidylcholine function

--> precursor for the lipid part of lung surfactant (90% lipid, 10% protein) released by alveolar Type II cells. --> 2 esterified saturated fatty acids (palmitates) are needed in order to generate an extracellular fluid that prevents alveolar collapse during exhalation. --> mainly dipalmitoyl-phosphatidylcholine (disaturated) is released together with monosaturated PC

The liver

--> releases free cholesterol into the bile for excretion in feces --> only hepatocytes synthesize bile acids from cholesterol and release conjugated bile salts together with free cholesterol into the bile. --> in the skin, a precursor of cholesterol can be used to form Vitamin D.

Cardiolipin

--> special phospholipid found mainly in inner mitochondrial membrane in eukaryotes --> needed for respiratory complexes of the ETC --> Cardiolipin is found in bacteria --> also known as di-phosphatidylglycerol and contains 4 fatty acids, mainly 18:2, omega-6

Triacylglycerols (TAGs)

--> totally nonpolar and have glycerol backbone --> TAGs represent about 40% of the normal diet --> TAGs are main storage form of fatty acids --> TAG synthesis occurs mainly in the liver, adipose tissue, lactating mammary gland and intestinal mucosal cells

Dietary lipids

--> transported inside of chylomicrons --> the liver releases VLDLs which eventually become LDLs in the blood. --> Increased blood levels of LDLs can lead to CHD. HDLs perform the reverse cholesterol transport and deliver cholesteryl esters to the liver

Free fatty acids

--> usually long, hydrophobic hydrocarbon chains with a negatively-charged carboxyl group at physiological pH --> in humans, fatty acids have an even number and mainly 16-20 carbons. --> Free fatty acids: have detergent character, they are inside of cells esterified in mainly triacyglycerols (TAGs) or membrane lipids

Phosphatidylcholine

-->found in the outer leaflet

Polar lipids in humans found in membranes

1) Glycolipids contain sugars 2) Most glycolipids contain sphingosine as backbone

Dietary essential fatty acids EFA

1) Linoleic acid (18:2, omega-6) 2) Alpha-linolenic acid (18:3, omega-3) --> Essential fatty acids cannot be formed in humans from oleic acid (18:1, omega-9)

Fatty acids with cis versus trans configuration

Cis configuration--> forms bends in the hydrocarbon chain. Trans fatty acids--> formed artificially (margarine) and shall not be ingested. They can lead to cardiovascular disease.