What are fatty acids?
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)
What are unsaturated fatty acids?
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)
Waht is the cardioprotective effects of omega 3 acids?
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
How are lipids digested?
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)
How are fatty acids synthesized?
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
What affect does insulin have in converting glucose to acetyl CoA in liver?
promotes many steps:
--PFK-2/PFK-1: PFK2 dephosphorylated
--pyruvate dehydrogenase: dephosphorylated
What enzymes of fatty acid synthesis are affected by insulin?
--acetyl CoA carboxylase: dephosphorylated, activated
--fatty acid synthase: induced
What is the citrate shuttle?
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
What is the function of Acetyl CoA carboxylase?
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
What is the function of fatty acid synthase?
palmitate is the only fatty acid that human can make de novo
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
Can fatty acyl CoA be elongated and desaturated?
yes by enzymes in SER
cytochrome b5 can desaturate
--can't introduce double bonds past position 9 in fatty acid
What are triglycerides?
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
What are the sources of glycerol 3 P for triglyceride synthesis?
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
What are glycerophospholipids?
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
What are lipoproteins?
tiglycerides and cholesterol are trnasported in blood as LP
desnity increases with percentage of protein
least to most dense:
chylomicrons < VLDL < IDL < LDL < HDL
What is a cholesterol ester?
What arethe steps of lipoprotein metabolism?
What are chylomicrons?
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
What is the function of ilpoprotein lipase?
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
What are very low density lipoproteins (VLDL)?
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
What are the steps of chylomicron and VLDL metabolism?
What are VLDL remnants?
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
What is a low density lipoprotein (LDL)?
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
How are cholesterol levels acquired and regulated?
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
How is LDL endocytosed?
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
What is a high density lipoprotein (HDL)?
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
What is lecithin-cholesterol aceyltransferase (LCAT, PCAT)?
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
What is choelsterol ester transfer protein (CETP)?
HDL cholestserol esters picked up in periphery can be distributed to other lipoprotein particles such as IDL converting them to LDL
--enzyme facilitates transfer
What is the scavenger receptors (SR-B1)?
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
What is atherosclerosis?
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
What is the orle of vitamin E?
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
What is type 1 hypertriglyceridemia?
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
What is a less severe hypertriglyceridemia?
in diabetes, alcoholism, and G6PHD
increae in BLDL and chylomicrons
decreased glucose uptake in adipose tissue
overactive hormone sensitive lipase
underactive lipoprotein lipase
What is hyperlipidemia secondary to diabetes?
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
What is type II hypercholesterolemia?
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
What is abetalipoproteinemia?
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
How is choelsterol metabolized?
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
How do you treat hypercholesterolemia?
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
What can the farnesyl pyrophosphate intermediate be used for?
--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)
What are the side effects of statin drugs?
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