Chapter 15

Question 1

What are fatty acids?

Answer 1

long chain carboxylic acids

carboxyl carbon=number 1

carbon number 2=alpha carbon

saturated fatty acids have no double bonds

palmitate: primary end product of FA synthesis (C16:0)

Question 2

What are unsaturated fatty acids?

Answer 2

one or more double bonds

can synthesize a few; most come from essential fatty acids in diet

–transported as triglycerides from intestine in chylomicrons

–ex. inolenic acid and linoleic acid (important membrane phospholipids to maintain nomral fluididty of cell membrane)

omega: position of last double bond relative to end of chain

arachidonic acid: precursor for prostaglandins, thromboxanes, leukotrienes

double bonds in FA are in cis configuration

trans double bonds: unnatural , margarine; decrease membrane fluidity; Increase risk of atherosclerosis (and saturated fatty acids)

Question 3

Waht is the cardioprotective effects of omega 3 acids?

Answer 3

decreased risk of cardiovascular disease

replace some of the arachidonic acid (omega 6 fatty acid) in platelet membranes and lower production of thromboxane and the tendency of platelets to aggregate

–decrease serum triglyerides

found in cold water fish, nuts and seeds

Question 4

How are lipids digested?

Answer 4

high fat meals contain gram level amounts of triglycerides and milligram amounts of cholesterol and cholesterol esters

–intestinal lumen: bile is secreted by liver to emusify lipids

–pancreas: secretes pancreatic lipase, colipase, and cholesterol esterase that degrade lipids to 2 monoglycerides, fatty acids and cholesterol

–lipids absorbed and reesterfied to triglycerides and cholesterol esters

–packages with apoprotein B48 and other lipids into chylomicrons

–litle lipid loss in stools

–defect=steatorrhea (excessive amounts of lipids in stool)

Question 5

How are fatty acids synthesized?

Answer 5

excess dietary glucose is converted to fatty acids in liver and then sent to adipose tissue for storage

–adipose tissue syntehsizes small quantities of fatty acids

Question 6

What affect does insulin have in converting glucose to acetyl CoA in liver?

Answer 6

promotes many steps:

–glucokinase: induced

–PFK-2/PFK-1: PFK2 dephosphorylated

–pyruvate dehydrogenase: dephosphorylated

Question 7

What enzymes of fatty acid synthesis are affected by insulin?

Answer 7

–acetyl CoA carboxylase: dephosphorylated, activated

–fatty acid synthase: induced

Question 8

What is the citrate shuttle?

Answer 8

transports acetyl CoA from mitochondria to the cytoplasm for fatty acid syntehsis

acetyl CoA combines with OAA in mitochondria to form citrate

citrate transported into cytoplasm

citrate lyase forms acetyl Coa and OAA from citrate

OAA returns to mitochondria

reaction: additional source of cytoplasmic NADPH in liver and adipose tissue, supplementing that from the HMP shunt

activated by: insulin and high energy status

Question 10

What is the function of Acetyl CoA carboxylase?

Answer 10

acetyl CoA is activated in cytoplasm for incorporation into fatty acids by acetyl CoA carboxylase

–rate limiting enzyme of FA synthesis

requires biotin, ATP, and CO2

activated by insulin (dephosphorylated) and citrate

CO2 added to form malonyl CoA isn’t incorporated into FA–removed by FA synthase during addition of acetyl group to fatty acid

Question 11

What is the function of fatty acid synthase?

Answer 11

pallmitate synthase

palmitate is the only fatty acid that human can make de novo

cytoplasm

induce in liver after a meal by high carboxydrate and inulin

contains acyl carrier protein–requires vitamin pantothenic acid

–malonyl CoA is substrate used by FA synthase–only carbons from acetyl CoA portion are incorporated into FA

–FA is derived entirely from acetyl CoA

NADPH is required

–8 acetyl CoA required to make palmitate

Question 12

Can fatty acyl CoA be elongated and desaturated?

Answer 12

yes by enzymes in SER

cytochrome b5 can desaturate

–can’t introduce double bonds past position 9 in fatty acid

Question 13

What are triglycerides?

Answer 13

sotrage form of fatty acids

3 fatty acids (fatty acyl CoA) to glycerol

formed in iver and adipose tissue

liver sends triglycerides to adipose tissue packaged as VLDL

small amount of triglyceride may be stored in liver

Question 14

What are the sources of glycerol 3 P for triglyceride synthesis?

Answer 14

1. reduction of dihydroxyacetone pohsphate (DHAP) from glycolysis by glycerol 3-P dehydrogenase (enzyme in adipose tissue and liver)

–adipose tissue dependent on glucose uptake via GLUT 4 transport (stimulated by insulin ensuring good supply of DHAP for TG synthesis)

2. phosphorylation of free glycerol by glycerol kinase (enzyme only in liver)

–allows liver to recycle glycerol released during VLDL metabolism (insulin) back into new triglyceride syntehssis

–during fasting (glucagon), enzyme allows liver to trap glycerol released into blood from lipolysis in adipose tissue for later conversion to glucose

Question 15

What are glycerophospholipids?

Answer 15

used for membrane syntehsis and producing hydrophilic surface layer on lipoproteins like VLDL

–reservoir of second messengers such as diacylglycerol, inositol 1,4,5, triphosphate and arachidonic acid

structure is similar to TG except last fatty acid is raplaced by phosphate and water soluble group like choline or inositol

Question 16

What are lipoproteins?

Answer 16

tiglycerides and cholesterol are trnasported in blood as LP

desnity increases with percentage of protein

least to most dense:

chylomicrons < VLDL < IDL < LDL < HDL

Question 17

What is a cholesterol ester?

Answer 17

Question 18

What arethe steps of lipoprotein metabolism?

Answer 18

Question 19

What are chylomicrons?

Answer 19

primarily triglyceride particles and small quanity of cholesterol esters

transport dietary triglyceride to adipose tissue and muscle

have apoC-II, apoE, apoB, apoB-48

assembled from dietary TG–mainly longer chain fatty acids, including essential FA–cholesterol esters and 4 lipid soluble vitamins

core lipid is surrounded by phospholipids (increase solubility of chylomicrons in lymph and blood)

ApoB48: required for release from epithelial cells into lymphatics

–leave lymph where thoracic duct joints left subclavian vein so bypass liver

after high fat meal, chylomicrons cause serum to become turbid or milky

in blood, chylomicrons acquire apoC-II and apoE from HDL particles

in capillaries of muscle and adipose tissue, apoC-II activates lipoprotein lipase, FA released enter tissue for storage and glycerol is retrieved by liver which has glycerol kinase

remnant is picked up by hepatocytes by apoE receptor

–dietary cholesterol and remaining TG is released in hepatocyte

Question 20

What is the function of ilpoprotein lipase?

Answer 20

required for metabolism of chylomicrons and VLDL

induced by insulin

tranpsorted to the luminal surface of capillary endothelium so in direct contact with blood

hydrolyzes FA fro mTG carried by chylomicrons and BLDL

activated by apoC-II

Question 21

What are very low density lipoproteins (VLDL)?

Answer 21

primarily triglyceride particles and small quantities of cholesterol esters

transport TG (containing FA newly syntehsized from excess glucose or retrieved from mchylomicron remnants) synthesized in liver to adipose tissue and muscle

have apoC-II, apoE, apoB and apoB-100

apoB111 is added in the hepatocytes to mediate release into blood

VLDL acquire apoCII and apoE from HDL in blood

metabolized by lipoprotein lipase in adipose tissue and muscle

Question 22

What are the steps of chylomicron and VLDL metabolism?

Answer 22

Question 23

What are VLDL remnants?

Answer 23

intermediate density lipoproteins (IDL)

after TG is removed from VLDL

portion of IDL is picked up by hepatocytesthrough apoE receptor but some IDL stays in blood where they are further metabolized

transition particles between TG and cholesterol transport

can acquire cholestreol esters ransferred from HDL particles and become LDLs

Question 24

What is a low density lipoprotein (LDL)?

Answer 24

primarily cholesterol particle

most cholesterol measured inblood is associated with it

deliver cholesterol to tissues for biosyntehsis

cholesterol is required for membrane synthesis, bile acids and salts in liver, steroid synthesis

80% of LDL are picked up by hepatocytes, rest are in peripheral tissue

apoB100 is only apoprotein

endocytosis of LDL is medaited by apoB 100 receptors (LDLD receptors) clustered in areas of cell membranes lined with protein clathrin

Question 25

How are cholesterol levels acquired and regulated?

Answer 25

pathways for acquiring cholesterol: de novo synthesis, endocytosis of LDL, transfer of cholesterol from HDL via SR-B1 recpetor, and endocytosis of chylomicron remnants with residual dietary cholesterol --increased cholesterol in the hepatocytes inhibits further accumulation by repressing expression of genes for HMG-CoA reductase (rate limiting enzyme of de novo cholesterol synthesis), the LDL recptor and the SR-B1 receptor

Question 26

How is LDL endocytosed?

Answer 26

formation of coated pit to become endosome fusion of endosome with lysosome release of LDL fro LDL receptor --receptor can recyle to surface, LDL is degraded and cholesterol is released into cell

Question 27

What is a high density lipoprotein (HDL)?

Answer 27

syntehsized in liver and intestines and released as dense protein rich particle in blood contain apoA1 used for choelsterol recovery from fatty streaks in blood vessels carry apoE and apoC-II to donate to chylomicrons and VLDL

Question 28

What is lecithin-cholesterol aceyltransferase (LCAT, PCAT)?

Answer 28

activated by apoA-1 on HDL in blood adds fatty acid to cholesterol, producing cholesterol esters that dissolve in core of HDL allowing HDL to transport choelsterol from periphery to liver

Question 29

What is choelsterol ester transfer protein (CETP)?

Answer 29

HDL cholestserol esters picked up in periphery can be distributed to other lipoprotein particles such as IDL converting them to LDL --enzyme facilitates transfer

Question 30

What is the scavenger receptors (SR-B1)?

Answer 30

HDL cholesterol picekd up in periphery can also enter cells through SRB1 expressed at high levels in hepatocytes and steroidogenic tissues (ovaries, testes, adrenal glands) transfer of choelstserol into cell

Question 31

What is atherosclerosis?

Answer 31

damage to endothelium (normal turbulence of blood, elevated LDL--modified or oxidized LDL, free radicals from cigarette smoking, homocystinemia, diabetes--glycation of LDL, and hypertension) endothelial dysfunction increases adhesiveness and permeability of endothelium for platelets and leukocytes (infiltration of monocytes and T cells); damage endothelium has procagulant properties local inflammation recruits monocytes and macrophagees wtih produciotn of ROS; LDL oxidized and taken up by macrophages which can be full of choelsterol (foam cells)--produces fatty streaks as fatty streak enlarges over time, necrotic tissue and free lipid accumulates and forms an advanced plaque with fibrous cap; plaque occludes blood vessel causing ischemia, infarction in heart brain and extremities fibrous cap thins and plaque ruptures and thrombosis forms HDL may be protective by picking up cholesterol before advanced lesion forms; apoA1 activates LCAT--adds FA to cholesterol to produce CE that dissolves in HDL core HDL may then be picked up by liver thorugh apoE recpetor or deliver cholesterol through SRB1; HDL may transfer choeslterol to IDL forming LDL

Question 32

What is the orle of vitamin E?

Answer 32

oxidation of LDL at sites of endothelial damage is major stimulus for uptake by macrophages lipid soluble vitamin acts as antioxidant in lipid phase protects LDL from oxidation prevents peroxidation of membrane lipids

Question 33

What is type 1 hypertriglyceridemia?

Answer 33

absense of lipoprotein lipase excess triglyceride in blood and deposition in tissues (liver, skin pancrease) orange red eruptive xanthomas over mucous membranes and skin abdominal pain and acute pancreatitis fasting chylomicronemia produces milky tubidity in serum/plasma

Question 34

What is a less severe hypertriglyceridemia?

Answer 34

in diabetes, alcoholism, and G6PHD increae in BLDL and chylomicrons contributing factors: decreased glucose uptake in adipose tissue overactive hormone sensitive lipase underactive lipoprotein lipase

Question 35

What is hyperlipidemia secondary to diabetes?

Answer 35

hyperglycemia, hypertriglyceridemia, choelsterol levels slightly elevated recovered quickly with adminstration of insulin type V hyperlipidemia elevated serum TG in VLDL and chylomicrons in response to meal contains cabohydrates and fat, respectively insulin in adipose tissue promotes lipoprotein lipase acitivity normally by increasing transcription of its genes in diabetes, abnormally low levels of lipoprotein lipase and inability to adequately degrade serum TG in lipoproteins to facilitate uptake of fatyt acids into adipocytes

Question 36

What is type II hypercholesterolemia?

Answer 36

LDL receptor deficiency dominant genetic disease elevted LDL hcolesterol and increased risk for atherosclerosis and coronary artery disease choelsterol deposits seen as: xanthomas of the achilles tendon, subcutaneous tuberous xanthomas over elbows, xanthelasma (lipid in eyelid), corneal arcus --MI before 20 years of age

Question 37

What is abetalipoproteinemia?

Answer 37

hypolipidemia low to absent serum apoB100 and apoB48 serum TG may be near zero cholesterol exremly low chylomicron levels low, fat acummulates in intestinal enterocytes and hepatocytes essetnial fatty acids and vitamin A and E not well absorbed symptoms: steatorrhea, cerebellar ataxia, pigmentary degneration in retina, acanthocytes (thorny appearing erythrocytes), possible loss of night vision

Question 38

How is choelsterol metabolized?

Answer 38

most cell dervie their cholestrol from LDL or HDL some syntehsized from acetyl CoA in cytoplasm citrate shuttle carries mitochondrial acetyl-CoA into cytopalsm and NADPH is provided by HMP shunt and malic enzyme HMG-CoA reductase: SER, rate limiting enzyme --insulin activates (dephosphorylation) and glucagon and statin drugs (competitively) inhibits choelsterol represssion expression of HMG - CoA reductase gene and increases degradation of enzyme

Question 39

How do you treat hypercholesterolemia?

Answer 39

cholestyramine: increase elimination of bile salts and force liver t oincrease synthesis from cholesterol (lower internal level in hepatocytes) decreased cholesterol in the cell increases LDL receptor expression allowing hepatocyte to remove LDL cholesterol from the blood HMG-CoA reductase inhibtiors (lovastatin, simvastatin) inhibit de novo cholesterol syntehsiss in hepatocytes--increases LDL receptor expression

Question 40

What can the farnesyl pyrophosphate intermediate be used for?

Answer 40

--synthesis of CoQ for mitochondrial ETC --synthesis of dolichol pyrophosphate, required cofactor in N-linked glycosylation of proteins in ER --prenylation of proteins (posttranslation modification) that need to be held in cell membrane by lipid train (ex. p21ras G protein in insulin and GF pathways)

Question 41

What are the side effects of statin drugs?

Answer 41

by inhibiting HMG-CoA reductase, syntehssis of CoQ is lessened--which is needed for ETC without properly fucntion mitochodnria muscle would have decreased ability to make ATP required for muscle contraction red brown urine: spillage of myoglobin from damaged muscel cells CRP: liver protein that is secreted in inflammation correlation between elevated CRP and atherosclerosis