IBHS 527 lecture 3

• 1. fatty acids
• 2. triglycerides
• 3. phospholipids/glycolipids
• 4. eicosanoids/prostaglandins
• 5. steroids

• 1. cell membranes - affect fluidity
• 2. energy source/ storage
• 3. insulation/protection - for internal organs
• 4. hormones
• 5. chemical messengers

• lipid catabolism (breaking down)
• Triglycerides --> glycerol + 3 fatty acids

• 1. glycerol
• 2. 3 fatty acids

glycerol --> pyruvic acid (PA) --> acetyl-CoA --> goes into TCA cycle --> make NADH and FADH₂

3 fatty acids --(beta-oxidation)--> acetyl-CoA --> enters TCA cycle --> lots of ATP

• 1. lipids
• 2. carbohydrates

• 18 carbon fatty acid = net 144 ATP molecules
• compact storage = hard to access = cannot produce ATP quickly (slow)
• used in absence of glucose

• 3 * 6 carbon sugars = net 108 ATP molecules
• less compact storage = easy to access = can produce ATP quickly
• use preferentially

• lipid synthesis (creating)
• glycerol (dihydroxyacetone phosphate) + fatty acids (acetyl-CoA from lipids, amino acids, and carbohydrates) = triglycerides

• FALSE. you CAN'T synthesize everything.
• ex: essential fatty acids required for prostaglandin synthesis and cell membranes must be acquired through diet (plant-based fatty acid)

• 1. synthesis
• 2. dietary

• endogenous - 1.0 g/day
• 1. liver: HMG-CoA reductase (rate-limiting step)
• 2. bile: 95% of bile reabsorbed
• 3. HDL: scavenged from blood stream

• exogenous - 0.5 g/day
• 1. meat, eggs, dairy
• 2. 80% of serum cholesterol
• 3. high saturated fats --> into elevated serum cholesterol

• easily diffuse across membranes because they are lipophilic
• bound to albumin in blood
• utilized for energy in glucose starved cells

• large lipid-protein complexes that houses triglycerides and cholesterol that insoluble (aggregate)
• cannot diffuse across membranes due to large size

• composition of lipoproteins:
• 1. surface (hydrophilic) due to:
• a) phospholipids (PL)
• b) apoproteins (APO)
• -increase solubility of lipids in circulation
• -determine cellular destination of lipids based on protein
• -stimulate or inhibit enzymes involved in lipid metabolism
• 2. inside (hydrophobic)
• a) triglycerides (TG) and cholesterol (Chol)
• b) fat soluble vitamins

based on shape and lipid:protein ratio

• 1. chylomicrons - largest
• 2. very low density lipoproteins (VLDL)
• 3. intermediate density lipoproteins (IDL)
• 4. low density lipoproteins (LDL)
• 5. high density lipoproteins (HDL) - smallest
• *densities of lipoproteins depend on their relative amounts of protein and lipids
• 

• composition:
• 90% triglycerides, 4% cholesterol, 5% phospholipids, 1% protein
• origin:
• produced by intestinal epithelial cells (enterocytes)
• function:
• carry absorbed lipids from GI tract (ditet) into the blood stream via lymph capillaries (lacteals)

dietary lipids (fatty acids and cholesterol absorbed through the brush border of the small intestines) + pancreatic lipase + bile salts --> in the endoplasmic reticulum of intestinal epithelial cells, lipid products (lipoproteins, cholesterol, triglycerides) are assembled into chylomicrons --> enter lacteal ("milky") --(lipoprotein lipase) --> breakdown of chylomicrons --> TGs to muscles and adipose tissue; cholesterol to liver

• enzyme on capillary epithelium in adipose, muscle, or liver tissue
• process:
• apoproteins (APO) on chylomicron surface --> allows correct delivery of chylomicron to tissue and lipase activation --> lipase turns triglycerides to glycerol and fatty acids --> glycerol and fatty acids enter cell for use; chylomicron remnant (CR) which is primarily cholesterol travels to hepatocytes (liver)

• composition:
• 60% triglycerides, 15% cholesterol, 15% phospholipids, 10% proteins
• origin:
• -triglycerides synthesized by liver and from conversion of excess carbohydrates
• -cholesterol synthesized by liver and from degraded chylomicron remnants
• function:
• primary source of triglycerides for the body and transport the lipids (mainly TG) from the liver to the tissues

released into circulation --> (1) apoproteins on the surface target the VLDLs to muscle and adipose tissue (2) activate lipoprotein lipase in capillary walls to remove triglycerides from VLDL --> VLDL remnants/intermediate density lipoprotein (IDL)

• composition:
• 35% triglycerides, 30% cholesterol, 20% phospholipids, 15% proteins
• origin:
• VLDL remnants
• function:
• transport lipids from blood stream to the liver and circulation

transported from bloodstream --> (1) ~50% of IDL converted to LDL by lipoprotein lipase removing TGs, (2) ~50% binds to LDL receptor on liver via apoproteins which then enters cell via receptor mediated endocytosis --> (a) removal of TGs = degraded into LDLs, (b) addition of TGs = recycled into VLDLs --> both released into circulation

• composition:
• 10% triglycerides, 50% cholesterol, 20% phospholipids, 20% proteins
• origin:
• IDL process
• function:
• main carrier of endogenous cholesterol from liver to tissues

• circulation -->
• (1) 75% LDL binds to LDL receptors in the liver via apoprotein (specific) --> receptor mediated endocytosis --> degraded (components recycled/consumed), (2) 24% bind to LDL receptors in the peripherals --> degraded/consumed for cell metabolism and maintenance --> excess cholesterol diffuses out of cells to INC. serum (blood) cholesterol, (3) 1% becomes oxidized --> enters endothelium of blood vessels --> start of atherosclerosis which is "bad"

• composition:
• 5% triglycerides, 20% cholesterol, 25% phospholipids, 50% proteins
• origin:
• self assemble in the plasma from (a) free cholesterol (lecithin-cholesterol acyl transferase [LCAT] esterifies free cholesterol, (b) lipoprotein fragments
• function:
• transports cholesterol from tissues to liver ("good" as a scavenger)

apoprotein specific, receptor-mediated endocytosis in the liver --> cholesterol is (a) consumed (into cell membrane or make LDLs) or (b) excreted in the bile --> HDLs released back into blood stream

• 1. liver cells synthesize VLDLs for discharge into the bloodstream
• 2. in peripheral capillaries, lipoprotein lipase removes many of the triglycerides from VLDLs, leaving IDLs; the triglycerides are broken down into fatty acids and monoglycerides
• 3. when IDLs reach the liver, additional triglycerides are removed, and the protein content of the lipoprotein is altered. This process creates LDLs, which are transported to peripheral tissues to deliver cholesterol.
• 4. LDLs leave the bloodstream through capillary pores or cross the endothelium by vesicular transport
• 5. once in the peripheral tissues, the LDLs are absorbed by means of receptor-mediated endocytosis. The amino acids and cholesterol then enter the cytoplasm
• 6. the cholesterol not used by the cell (in the synthesis of lipid membranes or other products) diffuses out of the cell
• 7. the cholesterol then reenters the bloodstream, where it is absorbed by HDLs and returned to the liver
• 8. in the liver, the HDLs are absorbed and their cholesterol is extracted. Some of the cholesterol that is recovered is used in the synthesis of LDLs; the rest is excreted in bile salts
• 9. the HDLs stripped of their cholesterol are released into the bloodstream to travel into peripheral tissues and absorb additional cholesterol

• 1. LDL and IDL bind to LDL receptor (-R)
• 2. LDL-R cluster in clathrin coated pits on cell membrane
• 3. LDL-R vesicles pinch off and internalized = coated vesicles --> clathrin shed and recycled, LDL-R recycled
• 4. endosome fuses with lysosome
• 5. LDL disassembled into amino acids (apoproteins), cholesterol and triglycerides which is used for metabolism and maintenance of the cell
• 6. cholesterol esterified by acyl-CoA cholesterol acyltransferase (ACAT)
• 7. cholesterol stored in the endoplasmic reticulum (ER)
• 8. increased intracellular cholesterol causes:
• (a) INC. ACAT
• (b) DEC. synthesis of HMG-CoA reductase
• (c) DEC. synthesis of LDL-R (don't need anymore)
• *net effect: decreased storage, decreased production, decreased uptake

• INC. serum (blood) cholesterol
• 2 ways:
• 1. high fat/cholesterol diet
• 2. familial hypercholesterolemia

• -chylomicron remnants take cholesterol to the liver
• -high intracellular cholesterol levels (causes DEC. LDL receptors which causes INC. serum cholesterol)
• *desirable level is <200 mg/dl so anything above is at high risk

• 2 pros (the good):
• 1. important component of cell membranes
• 2. precursor of:
• a) bile salts (for digestion of fats and lipids)
• b) steroid hormones (corticosteroids, mineralocorticoids, sex hormones)
• c) vitamin D₃
• 2 cons:
• 1) cardiovascular disease
• 2) gallstones (gallbladder)

• arteri/o = artery
• -sclerosis = hardening

• 1. focal calcification
• 2. atherosclerosis
• *can lead to: hypertension, occlusion, hemorrhage, thrombosis, embolus

• cause:
• smooth muscle degeneration in tunica media followed by Ca²⁺ deposition
• trigger:
• age, diabetes mellitus, atherosclerosis

• athero = porridge; yellow fatty plaque
• sclerosis = hardening
• cause:
• lipid deposits in tunica media and damage to endothelial lining
• trigger:
• elevated lipids, diabetes, high blood pressure, smoking
• * complications:
• 1. brain = stroke, TIA
• 2. heart = angina, heart attack
• 3. male organ = erectile dysfunction
• 4. legs = peripheral artery disease

endothelial compromise --> fatty streaks and/or LDL infiltration --> endothelium responds - oxidizes LDL, release cytokines --> infiltration of monocytem/macrophages - ingest oxidized LDL --> foam cells --> foam cells attach to endothelia and release (1) cytokines - more monocytes/macrophage, (2) growth factors - smooth muscle proliferation --> foam cells slowly die, release Ca²⁺ stores = calcification --> cells start phagocytosins lipids = fatty plaque --> endothelium damaged, collagen exposed - platelet adhesion and aggregation = clotting

improper amounts of lipids or ratios of lipids

elevated levels of lipid (cholesterol)

cholesterol = LDL + HDL + triglycerides/5

• * goal:
• 1. decrease LDL, TG, total cholesterol
• 2. increase HDL
• treatments:
• a) Therapeutic Lifestyle Changes (TLC)
• b) statins
• c) cholesterol absorption blockers
• d) Niacin
• e) Bile acid sequestering agents

• 1. Decrease total fat, saturated fat and cholesterol consumption
• -13-20% of calories in American diet from saturated fat even though recommended 7%
• -350 -450 mg/day cholesterol in American diet even though recommended < 200 mg/day
• -nutritionally balanced, "low fat", "low cholesterol" diet
• -exercise
• -weight loss

• inhibit HMG-CoA reductase
• -DEC. cholesterol synthesis
• -INC. LDL receptor synthesis
• -INC. HDL
• ex:
• 1. Atorvastatin (Lipitor)
• 2. Simvastatin (Zocor)
• 3. Rosuvastatin (Crestor)

• inhibits absorption of dietary cholesterol
• ex:
• 1. Ezetimibe (Zetia)
• -less cholesterol inserted into chylomicrons
• 2. Ezetimibe + Simvastatin (Vytorin)
• -less cholesterol inserted into chylomicrons
• -DEC. synthesis of cholesterol

• decreased TG breakdown in adipose tissue
• -reduces available fatty acids for uptake by liver:
• a) DEC. fatty acids in liver
• b) DEC. TG synthesis in liver
• c) leads to decreased VLDL (and LDL)
• -inhibits HDL breakdown and lead to increase HDL by 15-35%
• ex:
• 1. immediate release Niacin (Niacor)
• 2. extended release Niacin (Niaspan)
• 3. Simvastatin (INC. HDL) + Niacin (Simcor)

• reduced enteroheptic recycling of bile acids
• -large polymeric cation exchange resins
• -bind bile acids and prevent reabsorption
• -resin + bile acids (contain cholesterol) excreted
• -more cholesterol used to make new bile
• ex:
• 1. Cholestyramine (Questran)
• 2. Colestipol (Colestid)
• 3. Colesevelam (Welchol)
• *unpopular use because of side effects:
• -GI distress
• -excretion of vitamins (lose vitamins = acidic proile)
• -INC. LDL receptor synthesis

• autosomal dominant deficiency of functional LDL receptors
• -heterozygotes (1:500): 50% of normal LDL receptors (~3x increase in serum/blood cholesterol at birth)
• -homozygotes: (1:1*10⁶): complete lack of LDL receptors (~6x increase in serum/blood cholesterol level at birth)

• 1. xanthomas = yellowish deposits cholesterol
• -tendons (heterozygous)
• -skin (homozygous)
• 2. early onset atherosclerosis (coronary, cerebral, peripheral)
• 3. MI (heart attack) before 20 years of age (homozygous)
• 4. INC. duration of cholesterol in blood
• -normal: 2.5 days
• -familial hypercholesterolemia: 4.5 days

• heterozygotes:
• 1. statins (requires at least one functional copy of LDL-4 gene)
• -DEC. endogenous cholesterol
• -produce more LDL receptors (DEC. serum/blood cholesterol)
• 2. bile acid sequestrants
• 3. Niacin
• homozygotes:
• 1. large doses of bile acid sequestrants
• 2. LDL pheresis
• -clearing LDL by blood filtration
• 3. liver transplant
• -liver cells with LDL receptors (about 75% of cholesterol can be harvested !! remember how the body processes LDL - slide on lipoprotein:LDL!!