Chylomicron Transport dietary lipids from the intestine to the peripheral tissues

VLDL – IDL - LDL VLDL function: Deliver TG from liver to peripheral tissue cells LDL function: Deliver Cholesterol from live to peripheral tissue cells

HDL function: Reverse-transport cholesterol from peripheral cells to the liver for excretion

Cholesterol metabolism Exclusively found in animal: animal sterol 2g/kg for health person

Role of cholesterol An essential component of cell membranes, has a vital role for membrane functions. Used to synthesize bile acids in the liver. Used to synthesize steroid hormones. glucocorticoids mineralocorticoids androgens estrogens progestins 4. Used to synthesize Vitamin D.

Liver is most important organ for cholesterol metabolism

Cholesterol synthesis About 1g of cholesterol is synthesized per day in adults, liver: 50%; intestine 15%; other tissues: 35%. All C-atoms of cholesterol come from acetyl CoA; reducing equivalents come from NADPH Energy to drive synthesis comes from ATP hydrolysis Key enzyme (rate limiting enzyme) in cholesterol synthesis is HMG CoA reductase

Cholesterol synthesis First three acetyl CoA forms HMG CoA HMG CoA reductase catalyzes the rate limiting (regulated) step of the pathway, formation of mevalonic acid from HMG CoA and 2 NADPH

Decarboxylation of mevalonic acid forms isopentyl-pyrophosphate (IPP, 5-C unit). Condensation of two IPP forms geranyl PP (GPP, 10-C) Condensation of GPP and IPP forms farnesyl PP (FPP, 15-C). Condensation of two FPP forms squalene (30-C). Squalene becomes cyclized lanosterol, and then cholesterol

Regulation of cholesterol synthesis Regulation of cholesterol synthesis via : feedback inhibition of HMG CoA reductase by cholesterol cholesterol inhibits transcription of HMG CoA reductase gene Inhibit by drugs, such as Compactin and Lovastatin. R= H: compactin R= CH3: lovastatin

-- hormonal regulation of HMG-CoA reductase glucagon leads to phosphorylation: inactivate the enzyme insulin favors dephosphorylation: activate the enzyme

Metabolism of Bile acids Formed from cholesterol in the liver Rate limiting step is the conversion of cholesterol to 7-alpha cholesterol by 7-a-hydroxylase Utilized during digestion of fats (act as detergents)

Bile acids & salts Before leaving the liver, bile acids are conjugated in amide linkage to glycine (glycocholic acid) or taurine (e.g. taurochenodeoxycholic acid) These compounds are more fully ionized at neutral pH (carboxylate and sulfate, with low pKa) and are better detergents

Synthesis of Bile Acids

Conversion of cholyl-CoA to glycocholic acid Glycochenodeoxycholic acid

Conversion of cholyl CoA to taurocholic acid Taurine Taurocholic acid Taurochenodeoxycholic acid

Secondary bile acids Bacteria in the intestine can remove glycine and taurine They can also modify bile acids to form secondary bile acids (minus one -OH group, e.g., deoxycholic acid, lithochoic acid)

acid

Glycocholic acid Deoxycholic acid Taurocholic acid

Glycochenodeoxycholic acid Lithocholic acid Taurochenodeoxycholic acid

About bile acids Cholic acid is the bile acid found in the largest amount in bile Cholic acid and chenodeoxycholic acid are referred to as primary bile acids Bile acids are converted to either glycine or taurine conjugates (in humans the ratio of glycine to taurine conjugates is 3:1) Bacteria in the intestine can remove glycine and taurine. They can also modify bile acids to form secondary bile acids (minus one -OH group, e.g., deoxycholic acid, lithochoic acid).

Function of bile acids Aid in digestion and absorption of dietary fat: emulsify fats due to detergent activity Stimulate the action of pancreatic lipase Stimulate intestinal motility Keep cholesterol in solution (as micelles)

Emulsification of Fat by Bile 24

Mixed micelle formed by bile acids, triacylglycerols and pancreatic lipase Detergent character of bile salts is due to the hydrophobic-hydrophilic nature of the molecules

Bile acids are efficiently recycled Enterohepatic circulation: Bile acids are efficiently reabsorbed in the intestine and returned via the portal vein to the liver for reuse (enterohepatic circulation) Of 15-30 g of bile acids secreted/day, only 0.5 g are lost in feces (i.e., 0.5 g of cholesterol is excreted)

Cholelithiasis If more cholesterol enters the bile than can be excreted, cholesterol may precipitate/ crystallize in the gall bladder leading to gallstone disease Causes: severe ileal disease obstruction of the bile duct severe hepatic dysfunction excessive suppression of bile acid synthesis

Lipoproteins and Atherosclerosis LDL: Risk factor for atherosclerosis HDL: Protective factor for atherosclerosis

Atherosclerosis hardening of the arteries due to the deposition of atheromas caused by the deposition of cholesteryl esters on the walls of arteries atherosclerosis is correlated with high LDL and low HDL Author: Sukhinder C. Kaur 572 pages, Springer; $139.00

Cholesterol & risk of heart disease Total Cholesterol Category Less than 200 mg/dL Desirable level 200-239 mg/dL Borderline high 240 mg/dL and above High blood cholesterol (more than doubles risk) LDL Cholesterol Level Category Less than 100 mg/dL Optimal 100-129 mg/dL Near or above optimal 130-159 mg/dL Borderline high 160-189 mg/dL High 190 mg/dL and above Very high HDL Cholesterol Level Category Less than 40 mg/dL A major risk factor for heart disease 40-59 mg/dL Moderate 60 mg/dL and above Protective against heart disease

LDL must be oxidized to be pathogenic (atherogenic)

Lipoproteins and atherosclerosis The endothelium in the arterial wall becomes more permeable to lipoprotein and allows migration of cells to the underlying layer (intima). LDL penetrate the vascular wall and deposit in the intima, where they undergoing oxidation to become oxidized LDL (OxLDL). Oxidized LDL stimulate endothelial expression of some adhesion molecules. Adhesion molecules attract monocytes, which enter the wall and transform into macrophages.

Macrophage take up oxidized LDL, when overload with lipid, become “foam cells”. Conglomerate of foam cells form fatty streaks or yellow patches visible in the arterial wall. Dying foam cells release lipid that form lipid pool within the arterial wall. Foam cells

Surrounding smooth muscle start to secrete a range of small peptides, which stimulate smooth muscle cells to proliferate and to migrate toward the lumen side of the arterial wall. In the same time, smooth muscle cells start synthesizing extracellular matrix, such as collagen. Relocated smooth muscle cells, collagen-rich fibrous tissue, macrophages all together form a “Cap” that cover the lipid pool. This is a matured atherosclerotic plaque.

The plaque protrudes into the arterial lumen, grows slowly over years, and finally obstruct the artery. This decreases blood flow in the affected vessel. Rupture or ulceration of fibrous cap rapidly leads to thrombosis and obstruct the artery. Thrombus Fibrous cap Lipid core

HDL is Protective HDL prevent foam cell formation HDL inhibits oxidative modification of LDL HDL inhibits expression of adhesion molecules

Improving Your Levels Exercise Improved diet Maintain a healthy weight Quit smoking Possibly cholesterol drugs Once you have your results, how do you make your numbers better? How do you increase your HDL and lower your LDL and triglyceride numbers? One of the most important things you can do after getting your results is follow up with your doctor and follow through with his/her recommendations. You can make several dietary changes to help. Dietary changes, along with improved exercise habits, can greatly influence your cholesterol levels. If someone who is slightly overweight loses a little weight, they can improve their cholesterol numbers along with many other health benefits. It is important to maintain a healthy weight if you are already at an optimal weight level. Realize, however, that just because someone is skinny does not mean they have low or normal cholesterol. They, too, could just as easily have high cholesterol as someone who is overweight. If you are a smoker, getting back a test showing high cholesterol levels is just another good reason for you to kick the habit. Now is as good of a time to quit as ever! If you would like information on quitting smoking, please see me after class. I can help you find resources right here in the community to do that. Finally, If you are at very high risk for heart disease and you have high cholesterol levels, you and your doctor may consider one of many cholesterol-lowering drugs approved for use that are on the market today. http://mayoclinic.com/health/high-blood-cholesterol/DS00178/DSECTION=9 37

Diet Reduce your intake of fats and cholesterols. Increase your intake of fruits and vegetables. Add more fiber. Eat low-fat or fat-free dairy products. Avoid eating too many calories. There are many ways that an altered diet, or even slightly altered diet, may help lower cholesterol. You should start limiting your intake of trans and saturated fats and cholesterol-containing foods. The best dietary action you can take to help lower your cholesterol is to decrease your intake of saturated fats. It may mean having a smaller slab of steak at dinner, cooking with egg whites only instead of the whole egg, or skipping the fried foods or dessert. Your doctor or dietitian can make suggestions on choices you can make that fit your lifestyle. Increase your intake of fresh fruits and vegetables, getting 5 servings a day. You should also switch to low-fat or fat-free dairy products. How many of you like the taste of skim milk the best? Adding more fiber to your diet may also help lower your cholesterol, as studies have revealed starting your day off with a bowl of Cheerios can lower your cholesterol. 38

Exercise 30 minutes a day 4+ times a week Improve your physical activity levels while improving your cholesterol levels. It is recommended that adults get 30 minutes of moderate exercise at least 4 times a week, if not every day. Moderate exercise means that you are breathing more heavily, but you don’t have to be in a full out run and breathing hard. You can get creative in the way you incorporate exercise by walking, jogging, swimming, biking, or playing a sport you enjoy. It also may be helpful to realize your 30 minutes of exercise each day does not have to be all at once! It can be broken up into smaller increments. For example, you could go for a 10 minute walk with a co-worker on your lunch break, and then go on a 20 minute bike ride with your family when you get home from work. 39

Cholesterol Drugs Talk to your doctor, and follow his/her advice. Several drugs are available that work in different ways to help improve a person’s cholesterol. Your doctor may prescribe a cholesterol-lowering drug if you are at increased risk for heart attack or stroke. Drugs may also be considered after cholesterol levels remain high after months of improved diet and exercise habits. The most important thing you can do when taking cholesterol-lowering drugs is to follow your doctor’s advice. Never stop taking your medicine without first consulting your doctor, even if it is making you feel bad or you think you are experiencing side effects. 40