1. Lipids and your health Biochem I Lecture 6 Sept 26 / 06 Chp 26.3 (exclude 1. to 4. on pp. 742-743); trans fat material is in lecture notes only http://www.shapirolab.org/tubby/tubby.html Tubby -/- Wild type

2. Fat consumption impacts human health When discussing modern diets this is usually in a negative manner, e.g., –High dietary fat content –“Trans fats” At the same time, a better understanding of the link between diet and susceptibility to disease has begun to be established –The roles of HDLs, LDLs and cholesterol (26.3) –Unsaturated FAs High-fat diets have become linked to the development of disease states through scientific research –Coronary heart disease –Type II diabetes Diet plans in the popular literature alternate between recommending extremely low fat intake and high fat intake (with protein: Zone, Atkins) Let’s examine two of these issues from a biochemical perspective

3. Recall –That lipoproteins are lipid-binding proteins that serve as carriers to transport cholesterol and TAGs in the bloodstream –How ingested fat gets carried from the intestine to the bloodstream… in vesicles called c____________ that have a high lipoprotein content Fig 26.15: LDL particle Fats and health issue 1: lipoproteins, cholesterol and disease Lipoproteins (a/k/a apolipoprotein; apo=protein joined to other molecules) –Solubilize hydrophobic lipids (blood=aqueous!); forms amphipathic spherical shell around fat globules –Contain cell targeting signals for binding to cell membrane receptors (to storage in a_________ or to immediate oxidation in exercising muscle) Cholesterol esterified to FAs

4. The lipids present in lipoprotein vesicles affects their density Lipoprotein vesicles (or “particles”) vary according to their density: Remember, lipids sink in water –Chylomicrons are the lowest density lipoprotein particle because they contain the most TAG (85%) –low density = mostly lipids (40-50%) and cholesterol (~40%) LDLs are major carriers of cholesterol in the blood Role is to transport cholesterol from site of synthesis in liver to peripheral tissues in body and regulate cholesterol synthesis there –High density = lower cholesterol content (20-30%, found mostly as cholesterol esters), low TAG content (5-10%), lots of lipoprotein (~40%) HDL moves cholesterol throughout the body HDL role is to pick up blood cholesterol from apoptotic (dying) cells, transfers esterified cholesterol to LDL or liver, or to tissues that synthesize steroid hormones This is “reverse” cholesterol transport The liver synthesizes both TAGs and cholesterol (if inadequate amounts are supplied in the diet) and thus plays a key role in lipid metabolism

5. Susceptibility to heart disease is quantified by the HDL/LDL ratio HDL role appears to be as an important cholesterol scavenger: free cholesterol is insoluble in blood and contributes to athrosclerosis (plaques in arteries) Cholesterol successfully scavenged from the blood, where it can do this damage, HDL is thus “good”, while LDL is often called “bad” cholesterol HDL/LDL ratio is reported from blood tests –in healthy adults is ~3.5; lower (more LDL) indicates an increased risk of plaque deposition Fig 26.21 Fig. 26.21, 5 th edn Fig. 26.20 Normal artery Artery blocked by cholesterol deposit

6. Protective nature of HDL unknown, but… One possible mechanism explaining the HDL/LDL link to heart disease is found in families suffering from the genetic disease hypercholesterolemia (single gene mutation, recessive) LDL levels are ideally 650 and cholesterol deposits in tissues Most sufferers die in childhood of coronary artery disease What happens in hypercholesterolemia? Some blood LDL is oxidized and is engulfed by macrophages These are trapped in blood vessel walls and accumulate more cholesterol, leading to plaque formation, arterial blockage, and less O2 being delivered to target tissues HDL can counteract these effects! HDL contains an enzyme that destroys oxidized lipids Low levels of oxidized lipids may thus be key in preventing heart disease Disease caused by lack of LDL receptors in membranes of cells The LDL particles in the blood have nowhere to “park” and then release their cholesterol cargo Blood LDL levels build up High serum LDL level = high serum cholesterol level = higher probability of athrosclerosis

7. How to treat high serum LDL levels? Cause is not enough LDL receptors, leading to high serum levels (hypercholesteremia) LDL receptor is a protein embedded in the membrane of target cells = an i______ membrane protein Fig 12.30 LDL receptor protein synthesis is controlled by cell’s need for cholesterol (more protein in response to higher need) Clinical strategy is to get cells to make more receptors Homozygotes in trouble: the gene is defective –This means that they only have one form (a_____ ) of the gene –Only hopes: Liver transplant, gene therapy, dietary restrictions For heterozygotes, drugs can induce (trick) the body into biosynthesizing more receptor proteins

8. Drugs can induce higher rates of LDL receptor protein synthesis “Trick” receptor cells into perceiving low cholesterol levels inside the cell by Preventing reabsorption of bile salts –recall that bile salts are cholesterol derivatives solubilize fats and make them available for absorption –Orally administer charged polymers that bind bile salts and carry them out in the stool Blocking synthesis of cholesterol in the liver Use statins (e.g., lovastatin) to inhibit first committed step in cholesterol biosynthesis (mevalonate synthesis from yesterday’s lecture) Do both! Combination therapy lowers serum cholesterol levels by ~50% This strategy significantly lowers deaths by heart disease, the #1 killer of adults in the West

9. Fats and health issue 2: Trans fats We know what they are! they have a double bond, and are thus un_______ FAs that are not c____! Naturally occurring unsaturated FAs are mostly cis Trans FAs are vegetable fats that are solid at RT Produced artificially by heating liquid vegetable oils in the presence of metal catalysts and hydrogen This process, partial hydrogenation (= partial reduction) reduces double C=C bonds present in unsaturated FA chains –causes carbon atoms to bond in a straight configuration and remain in a solid state at room temperature http://www.drmcdougall.com/news/trans-fat2.html Bent and liquid

10. Trans fats are useful for preserving the shelf life of food products Trans fats produced commercially in large quantity for margarine, baked goods, to fry fast foods Original oils from which they are derived are rich in double bonds: fish oil, canola oil, corn oil Why do food companies hydrogenate their oils? More consumer appeal: solid vs. liquid margarine Fats in products have better mouth feel (e.g., in fried foods) Unsaturated FAs (e.g., linolenic [18:2] and linoleic [18:3]) become oxidized with time = rancid Their –But recall these polyunsaturated FAs are also essential ! Any snack food rich in fat but solid at room temperature is likely not a good source of essential unsaturated FAs!

11. Much evidence of negative impact on cardiac health Affect LDL/HDL ratio by both increasing LDL ("bad") cholesterol levels while decreasing those of HDL ("good") cholesterol High dietary saturated FA levels (e.g., from eating a high quantities of red meat with fat [18:0=stearate: good source!]) also have this effect Health effects of trans fats However, the effect of consumption of trans fats on the LDL/HDL cholesterol ratio is double that of saturated fatty acids –Both increase LDL levels by the same amount –Trans FAs decrease HDLs more than cis unsaturated or saturated FAs (which had no effect)

12. Trans fats are currently being eliminated from most food products Recent review predicted that replacement of partially hydrogenated fat in diet with natural unhydrogenated vegetable oils would prevent 30,000 to 100,000 deaths/year in the US Trans fats now listed separately on US Nutrition Facts labels There have been many proposed mechanisms explaining how trans fats may negatively impact human health –Affect cell membrane structure: more rigid membranes with tightly packed saturated or trans FA chains that reduce membrane fluidity –Increase LDL specific lipoprotein levels and thus blood LDL levels –Increase fasting levels of TAGs in the blood –May increase LDL oxidation In summary, studies provide strong evidence that trans fatty acids consumption substantially increases substantially the risk of coronary heart disease