Lipids and Lipoproteins Flashcards
what are isoprenoids made from?
acetyl CoA
three acetyl CoAs are used to generate what?
1 IPP molecule
what serves as the building block for the synthesis of all isoprenoids?
IPP
what are some examples of what IPP can be converted into?
steroids (cholesterol), lipid-soluble vitamins, ubiquinone, and lipid anchors
what are some sources of acetyl CoA?
it is generated in the mitochondria from various pathways (oxidative decarboxylation of pyruvate, beta oxidation of fatty acids, and breakdown of amino acids)
how is acetyl CoA transported into the cytoplasm from the mitochondria?
via a citrate shuttle
what is the backbone of most steroids?
six units of IPP that form a tetracyclic sterane ring
what type of compound is cholesterol?
an allicyclic compound (there is a hydrophobic part and an amipatic part)
what is one important key identifier of a cholesterol molecule?
there is one hydroxyl group at the C3 position
cholesterol is a component of plasma membranes and a precursor of biologically active compounds such as what?
bile acids and bile salts, vitamin D, steroid hormones
what is biosynthesis of cholesterol like?
it is inversely proportional to dietary intake of cholesterol
what is the daily production of cholesterol and where does this take place?
.75-1.0 (mostly in the liver, small intestine, adrenal cortex, ovaries, testes, and skin)
the synthesis of cholesterol can divided into 2 phases- what are they?
Phase 1: generation of IPP from acetyl CoA; phase 2: generation of cholesterol from IPP
what is the rate limiting step of cholesterol synthesis?
the conversion of HMG CoA into mevalonate
what is the enzyme for the rate limiting step of cholesterol synthesis?
HMG CoA reductase
Which enzyme is impacted by statins?
HMG CoA reductase
anything that is going to impact IPP synthesis will in turn impact the synthesis of what?
prenylated proteins (e.g. Ras), Heme A, Dolichol, and ubiquinone
what is IPP converted into during cholesterol synthesis?
squalene
what is squalene converted into during cholesterol synthesis?
lanosterol
what is lanosterol converted into during cholesterol synthesis?
cholesterol
where is HMG-reductase found?
in the endoplasmic reticulum
what are the cholesterol lowering drugs?
statins
how do statins work?
they are strong competitive inhibitors of HMG CoA reductase
what is the Km for HMG CoA reductase? and what is the Ki for statins?
Km= 4 microM; Ki= 5-45 nM
what was a positive adverse effect of statin use?
transcription of LDL receptor and subsequent enhanced clearance of cholesterol via LDL-receptor mediated endocytosis
what was a negative adverse effect of statin use?
there are myotoxic side effects- statin mediated myopathy caused by depletion of muscle levels of ubiquinone (CoQ 10)- leads to impairment of mitochondria function
what are the 2 fates of cholesterol we focused on?
it is esterified to cholesterol esters by the enzyme ACAT or it is packaged into VLDL and released into the blood
what are the two types of regulation of cholesterol synthesis?
there is direct inhibition or there is covalent modification
what is direct inhibition of cholesterol synthesis?
by free fatty acids, bile acids, and oxysterols; and by statins
what is covalent modification of cholesterol synthesis?
the enzyme becomes inactive in its phosphorylated form and active in its dephosphorylated form
what phosphorylates HMG CoA reductase? and therefore inactivates it?
conditions of low energy, high AMP–> these activate AMPK; glucagon inactivates it
what dephosphorylates HMG CoA reductase? and therefore activates it
insulin
what are lipoproteins?
vehicles that transport TAGs and Cholesterol
why are TAGs, cholesterol, cholesterol esters, and fat soluble vitamins transported by lipoproteins?
they are all very hydrophobic substances, so if they were just released, they would adhere to the blood vessel wall
what is the general structure of a lipoprotein?
it has an outer shell and an inner core
what is the composition of the outer shell of a lipoprotein?
it has a monolayer of phospholipids, free cholesterol, and apolipoproteins
what is the composition of the inner core of a lipoprotein?
it is packed with TAGS, cholesterol, and cholesterol esters
how do lipoproteins contribute to lipid metabolism?
they serve as a means to transport and deliver TAGs to tissues for fuel or for storage
how do lipoproteins play a key role in cholesterol homeostasis?
lipoproteins transport the cholesterol from the site of synthesis, to sites of use, and finally to the liver for excretion
what do apolipoproteins serve as?
cell targeting signals/ ligands that bind to receptors to internalize lipoproteins
what do apolipoproteins activate?
various enzymes involved in lipoprotein metabolism and processing
what are the five different types of lipoproteins?
chylomicrons, very low density lipoproteins, intermediate density lipoproteins, low density lipoproteins (LDL), and high density lipoproteins (HDL)
how do the different types of lipoproteins vary?
based on size, density, and composition
which lipoprotein is the largest in size?
chylomicron
which is the smallest lipoprotein?
HDL
which lipoprotein has the highest density?
HDL
which lipoprotein has the smallest density?
chylomicron
what are the chylomicrons richest in?
triglycerides
what are the LDLs richest in?
cholesterol
what are the HDLs richest in?
proteins
what are chylomicrons formed from?
exogenous dietary fats
what does the specific apoprotein ApoB-48 on the chylomicron do?
it facilitates transport
what does the specific apoprotein ApoE on the chylomicron do?
it facilitates uptake into the liver
what does the specific apoprotein ApoC-II on the chylomicron do?
it activates capillary lipoprotein lipase
where are VLDLs made?
in the liver
what are VLDLs packaged with?
TAGs and cholesterol
what specific apoproteins are found on the surface of the VLDLs?
ApoB-100, ApoC-II, and ApoE
what specific apoproteins are found on the surface of the IDL?
ApoB-100 and ApoE
what apoprotein is found on the surface of the LDL lipoproteins?
ApoB-100
why is the LDL considered to be the bad cholesterol?
the LDLs are very deficient in TAGs but have a high amount of cholesterol
why are HDLs considered to be the good cholesterol?
because they have a high content of protein and phospholipids
what specific Apoproteins are found on HDLs?
ApoC-II, ApoA-I, and ApoE
what is the role of ApoC-II on the HDLs?
they activate capillary lipoprotein lipase
what is the role of the ApoA-I on the HDLs?
they activate the enzyme that esterifies cholesterol
what is the role of the ApoE on the HDLs?
they promote uptake into hepatocytes
where are chylomicrons synthesized?
in the small intestine
when they are initially synthesized, what are chylomicrons referred to as?
nascent chylomicrons
what apoprotein is found on the nascent chylomicron?
ApoB-48
how do you get a mature chylomicron?
you add ApoC-II and ApoE
what is the role of the capillary lipoprotein lipase?
it hydrolyzes TAGs into glycerol and free fatty acids
what happens once the capillary lipoprotein lipase hydrolyzes TAGs into glycerol and free fatty acids?
the mature chylomicron become a chylomicron remnant
how do you get a chylomicron remnant?
the surface only has ApoB-48 and ApoE; you lost the ApoC-II
what happens to the chylomicron remnants?
they will be taken up into the liver
as the VLDLs are navigating in the bloodstream, what occurs?
the capillary lipoprotein lipase hydrolyzes the TAGs into glycerol and free fatty acids
what happens to the VLDLs when the capillary lipoprotein lipase does its job?
the VLDLs will lose the ApoC-II and the VLDL becomes the IDL
two things can happen to the IDL. What are they?
- It can be taken up by the liver through the IDL receptors in the hepatocytes
- It can be converted to LDL
If the IDL is taken up by the liver, what happens to it?
the IDL will lose more TAGs via the action of hepatic lipoprotein lipase, and it loses ApoE and becomes LDL
what is the main function of LDL?
it will transport cholesterol and delivery to the liver and peripheral tissues via ApoB-100
each LDL particle contains a shell of phospholipids and free cholesterol and is packed with what else?
1500 cholesterol ester molecules in the core
what happens to the LDL receptor once the LDL is endocytosed and broken down by lysosomes?
the receptor is recycled
mutations that generate receptors that are unable to release the LDL cargo cause what?
familial hypercholesterolemia
where are HDLs synthesized?
in the liver and small intestine
what are HDLs initially known as when first released into the blood stream?
nascent HDL
what does nascent HDL pick up from the peripheral tissue?
cholesterol
what enzyme helps to esterify the cholesterol?
LCAT
what happens to the cholesterol esters once the LCAT does its job?
the esters enter the HDL core- making it more spherical
what happens to the HDL once the cholesterol esters enter the core?
it becomes mature
what is one important function of the HDLs?
it interacts with all of the other lipoproteins to help them mature
what does HDL donate and receive from chylomicrons?
ApoC-II and ApoE
What effect does HDL have on LDLs?
HDL scavenges and removes LDL-cholesterol from the periphery and transports it to the liver where it can be recycled and processed
What does loss of ABCA1 activity cause?
a very rare condition known as Tangier disease
what is Tangier disease characterized by?
HDL deficency, accumulation of cholesterol in macrophages, and premature atherosclerosis
What are HDL-C levels increased by?
weight loss, exercise, and smoking cessation
What is another name for Type 1 hyperlipoproteinemia?
hyperchylomicronemia
what occurs during type 1 hyperlipoproteinemia?
there is an inability to hydrolyze TAGs in chylomicrons and VLDL
what causes type 1 hyperlipoproteinemia?
either a deficiency in capillary lipoprotein lipase or ApoC-II
when does primary lipoprotein lipase deficiency manifest?
infancy
when does ApoC-II manifest?
post-adolescence
what is the marker for type I hyperlipoproteinemia?
Plasma TAG levels >1000 mg/dL
what are the clinical symptoms of type 1 hyperlipoproteinemia?
abdominal pain, acute pancreatitis, cutaneous eruptive xanthomas
what is the treatment for type I hyperlipoproteinemia?
low fat diet
what does the blood sample look like in a patient with type I hyperlipoproteinemia?
it is creamy looking
what is another name for type II hyperlipoproteinemia?
familial hypercholesterolemia
what is the cause of type II hyperlipoproteinemia?
defects in the LDL receptor resulting in defects in the uptake of LDL via receptor mediated endocytosis
what does defective uptake of LDL cause?
increased cholesterol in blood
what does excessive LDL under the endothelial cells lining the blood vessels undergo?
oxidation to form oxidized LDL (oxLDL)
what does oxLDL initiate?
an inflammatory response which leads to atherosclerosis
in type II hyperlipoproteinemia, what is there an impaired ability to do?
recognize ApoB 100 on LDL
what type of inheritance is type II hyperlipoproteinemia?
autosomal dominant
what happens to untreated homozygotes of type II hyperlipoproteinemia?
they die of CAD before their teenage years
what do heterozygotes of type II hyperlipoproteinemia respond to?
diet, statins, and bile acid binding resins
what do homozygotes for type II hyperlipoproteinemia need for treatment?
they need LDL apheresis and liver transplantation
