Q: What is the fate of proteins attached to the lipid glycosylphosphatidylinositol? A: Proteins with the attached phospholipid, associated sugars, and ethanolamine are destined for the cell surface. Q: In what form are fatty acids (FA) transported in the body? Why can't they be transported as triglycerides? A: Free FA's travel in plasma bound to albumin. Triglycerides are too hydrophobic. Q: How are trglycerides transported throughout the body. A: They are packaged (with cholesterol and proteins (apoprotines)) by hepatocytes and enterocytes into lipoproteins. They are then secreted into plasma or lymph. Q: T or F Once a lipoprotein is excreted from the liver, it undergoes no interaction until it reaches the target tissue, thus maintaining it's pure nature. A: F While in the plasms, lipoprotins exchange components changing their size and shape. The conformation of apolipoproteins also changes until they fit into cellular receptors wherin the whole particle is taken up by cells. Q: T or F Lipoproteins are THE most abundant type of plasma protein. A: F They are the third most abundant. Albumin is 1st with immunogloblins next. Almost all bloodborne lipid is found in some lipoprotein. Q: Name the 5 classes of lipoproteins A: Chylomicrons, VLDL, IDL, LDL, HDLs. Densities are from relative proportion of apoprotein to lipid in each one. So decreasing triglyceride content, increases density. Q: Which lipoprotein has the most triglyceride? A: Chylomicrons 90%, then VLDLs 60% that's why it is low density. HDLs have 5% Q: which lipoprotein has the most protein? A: HDLs 45% that's why they are high density. VLDLs 10% Chylomicrons 1% Q: Which lipoprotein has the most phospholipid? A: HDLs 30% VLDLs 15% with chylomicrons 4% Q: Which lipoprotein has the highest concentration of cholesterol? How about chol ester? A: Looking at the lipoproteins in order of density, the middle ones have the most of cholesterol (IDL 10%) and chol ester (LDL 40% IDL 30%). The high and low densities (including chylomicrons1% and 4%) have low cholesterol (5% and 3%) and cholesterol ester. Q: Besides density, what else distinguishes lipoproteins and what are the 4 major classes? A: Apoproteins. A,B,C,E and also a protein called apo(a). Q: What is the function of the apolipoproteins? A: Rather than determining lipid concentration, they determine metabolic disposition of the lipoprotein. So a metabolic abnormality are related to defects in apoptroein synthesis or their receptors. Q: where are the different lipoproteins synthesized? A: VLDLs are synth. only in liver. LDLs are made from loss of tryglycerides froom VLDLs. HDLs are made in intestine and liver doing reverse transport of cholesterol from the tissues to bile for excretion. High HDL levels make you resistent to atherosclero Q: Where are the apoproteins synthesized? A: Intestines can only make apoB48 and traces of apoA. Liver makes them all (apo A, B, C, and E). Q: What is significant about the apoBs? A: apoBs do not exchange with other lipoproteins in the blood. ApoBs are very large proteins intrinsic to the lipoprotein monolayer and fulfill a mandatory structuaral role in chylomicrons and VLDLs. Q: What is the sole transport vehicle for dietary triglycerides? A: Chylomicron, composed only of dietary lipid Q: what do apoproteins do for the lipoprotein? A: Some apoproteins interact with cellualr receptors. Some serve as activators and inhibitors of enzymes involved in lipoprotein metabolism. Q: Describe the structure of lipoproteins listing the components with their locatons. A: Hydrophobic core of cholesterol esters and triglycerides. The outer layer is made of amphipathic phospholipids, free cholesterol, and proteins (apoproteins). Q: T or F apoB is right on the surface of the lipoprotein so it can easily be transferred? A: F some proteins are easily exchanged (like apoC) but apoB is deeply embedded into the particles and thus not easily exchanged. Q: T or F All FA's are transported from the intestine to chyle? A: F Short or medium FA's (c4-c12) are absorbed directly into intestinal epithelium and enter the portal blood, bind albumin and go to the liver. Long FA's are packaged into chylomicrons, go into lymph (making chyle) and are delivered to the blood. Q: What form is FA's in our diet and what enzymes break it down? A: Triacylglycerols (TAGs) are the major fat in our diet. They are metabolized to free FA's and glycerol by 3 lipases: lingual, gastrol, and pancreatic. (They are then reconverted to TAGs and packaged into cylomicrons) Q: You know very well the pathway of TAG's being broken down into free FA's and glycerols and then reformed in epithelial cells and packaged into chylomicrons. So where and when are these triacylglycerols digested again, or do they just enter adipocytes? A: Lipoprotein lipase (LPL) on blood capillary endothelial cells digests the TAGs of the chylomicrons to FAs and gylcerol. Q: Compare apoB48 and apoB100. A: ApoB48 is found in the intestine and is part of chylomicrons. It is made from the same gene as apoB100 but the mRNA undergoes editing to generate a stop codon giving a proten 48% the size of apoB100. ApoB100 is found in the liver and makes part of VLDLs Q: When do chylomicrons become "mature" chylomicrons? A: After they enter the blood via the thoracic duct, they accept proteins from HDL and then are they 'mature'. HDL transfers apoE and apoC2 Q: What is the function of the two apoproteins that are transferred to chylomicrons? (what are the apoproteins?) A: apoE is recognized by membrane receptors, particularly those on liver cells so these cylomicrons can enter by endocytosis for digestion by lososomes. apoC2 acts as an activator of LPL (LPL digests triacylglycerols of the chylomicrons. After LPL action, Q: What are the proteins in VLDL, and where is it made. A: apoB100 is the main apoprotein with some C and E. VLDL transports triglycerides and cholesterol from the liver to periphery Q: What is required for lipoprotein assembly. A: MTP Microsomal transfer protein Q: How are the cholesterol pool of the liver derived? A: 1)endocytosis and lysosomal digestion of lipoproteins and 2) synthesis from acetyl CoA. Q: Trace the fate of VLDLs after they leave the liver. A: VLDL is converted to IDL Q: What happens to VLDL after it leaves the liver? A: TAGs are digested by lipoprotein lipase (LPL) in VLDLs. It also gives back apoC2 to the HDL transforming VLDL to IDL. TAGs of IDL are degraded, apoE is transfered to HDL and LDL is formed. LDL has no aopC2 or E, low in TAGs and high in CE Q: What are the main apoproteins? A: apoA, apoB, apoC, apoE, and apo(a), or Lp(a) Q: Which apoprotein controls the metabolism of chylomicrons? A: apoB48 Q: What is the function of apoC? A: It's and enzyme activator and inhibitor (not a structural component like most apoproteins) apoC2 is a lipase cofactor. Q: What is the function of apoE? A: It plays and essential role in metabolism of remnant particles. (receptor recognition) Q: What is the function of apoB100? A: VLDL synthesis and secretion, LDL receptor binding. apoB100 is on LDLs (>98%), IDLs, and VLDLs. Q: Compare abetalipoproteinemia with hypobetalipoproteinemia. A: In abeta there is an absence of plasma lipoproteins due to mutations in the microsomal triglyceride transfer protein (MTP) gene. In hypo plasma lipoprotein levels are low due to mutations in apoB. Q: MTP and apoB physically interact during lipoprotein biogenesis and MTPs lipid transfer activity is required for lipoprotein assembly. Describe MTP activity during this process. A: MTP enhances rate of lipid transfer between vesicles by a shuttle mechanism. The MTP molecule interacts with a memebrane, extracts lipid molecules, dissociates from the membrane and then delivers lipids to a second membrane or lipoprotein particle. Q: What step is rate limiting for VLDL synthesis? A: MTP Q: MTP has been found to be associated with human longevity. Explain A: Genetic variants that impact lipid metabolism also impact human lifespan. People whose lipid profiles have higher levels of HDL and lower levels of LDL exhibit significantly lower risks of heart disease and stroke. Q: Where is HDL synthesized? A: Synthesized in a nascent form in the liver and to a minor extent in the gut. Q: What are the main apoproteins of HDL? A: apoAI and apoAII, although it also contains apoCand apoE, which it exchanges with other lipoproteins. Q: Describe HDL when it is secreted into the blood. A: small, discoid in shape, and are nearly devoid of cholesterol ester and triacylglycerols. Q: Describe what happens to HDL as it picks up cholesterol from other lipoproteins and from cell membranes. A: The cholesterol is converted to cholesterol esters by the LCAT reaction (which is stimulated by apoAI). The HDL particles fill with cholesterol esters and triacyglycerol and become large and spherical in shape. Q: What does HDL do with the particles it picks up? A: The cholesterol esters are ultimately returned to the liver. "reverse cholesterol transport" Q: HDL transfers apoCII and apoE to chylomicrons and VLDL. What does ApoCII do? A: SpoCII stimulates the degradation of the triacylglycerols by activating LPL producing chylomicron remnants and IDL (from VLDL). Q: HDL transfers apoCII and apoE to chylomicrons and VLDL. What does ApoE do? A: ApoE serves as a ligand for receptors on liver cell membranes that are involved in the uptake of chylomicron remnants and IDL. Q: What two diseases do mutations in the human LCAT gene result in? A: Familial LCAT deficiency (FLD) and fish eye disease (FED). Q: What happens and why in patients with fish eye disease? A: FED patients have a partial deficiency of LCAT function leading to the development of corneal opacities. Q: Describe the disease state of patients with FLD. A: Total deficiency of LCAT function, corneal opacities, mild anemia, proteinuria, and/or renal dysfunction. Glomerulosclerosis, the major cause of morbidity and mortality, may lead to renal failure in the 4th or 5th decade of life. Q: Describe the role of LPL (lipoprotein lipase) in lipoprotein metabolism. A: Binds to heparan sulfate proteoglycans on the surface of the vascular endothelial cells. May hydrolyze up to 10g of triglycerides per hour. Can also anchor lipoproteins to the cell surface and to the extracellular matrix. (HL, hepatic lipase, is associated with liver plasma membranes) Q: What is CETP and where is it expressed? A: Cholesterol Ester Transfer Protein, hydrophobic glycoprotein expressed primarily by the liver, spleen, and adipose tissue. Q: What is the primary role of CETP and how is it accomplished? A: transfer of neutral lipids such as cholesterol esters and triglycerides between lipoproteins. It catalyzes the transfer of CE from HDL to apo B-containing lipoproteins (VLDL, LDL), and also transfers TG and sometimes CE in the opposite direction from VLDL to HDL. Q: Describe the proatherogenic and antiatherogenic roles of CETP. A: High levels of plasma VLDL, then CETP mediated CE transfer results in high levels of CE rich VLDL. The high levels of CE-rich LDL's that result then contribute to atherosclerosis. High levels of HDL results in reverse cholesterol transport facilitated by CETP. Q: What is the structure of lipoprotein (a)? A: cholesterol-phopholipid core and a closely associated protein called apoB100. Q: How does Lp(a) differ from LDL? A: each Lp(a) particle contains one copy of an additional proein of the apoprotein 9a) family bound to apoB100 by a single disulfide linkage. Q: What are the 3 things Lp(a) is implicated in doing? A: implicated in the delivery of cholesterol to injured blood vessels, blockade of plasmin generation on fibrin and cell surfaces, and stimulus for smooth muscle cell proliferation. Q: What is familial hypercholesterolemia? A: Inherited condition in which too much LDL circulates in the blood. Q: What is Tangier disease? A: Rare, recessive disorder characterized by a reduced efflux of cholesterol from cells resulting in macrophages becoming engorged with cholesterol esters. They have NO HDL due to a defect in an ATP binding cassette transporter gene which encodes the cholesterol-efflux regulatory protein (CERP). Mature HDL is not formed and apoAI is rapidly destroyed. Q: What are the symptoms associated with Tangier disease? A: symptoms range from orange tonsils to coronary heart disease. Q: Describe HDL biosynthesis. A: Assembly of nascent HDL from apolipoprotein-AI, and phospholipid and free cholesterol discs, secreted from the liver and intestine. Q: What happens to cholesterol in mature HDL? A: free cholesterol is esterified to form cholesterol ester which can be either transferred to LDL or delivered to the liver and sterol-metabolizing tissures. Cholesterol is removed from the tissues and cholesterol engorged macrophages are discouraged from accumulating in the artery wall. Normal cells pump out free cholesterol at a rate of 0.1% per minute. Q: Where is apoE abundant and what is it's function? A: In the brain, serves as the principal lipid transport vehicle in CSF, plays a key role in repair by redistributing lipids to regenerating axons. Q: What disease has apoE4 been implicated in? A: sporadic and familial alzheimers' desease, also associated with poor clinical outcome in patients with acute head trauma and stroke. Q: It has been hypothesized that the apoE isoform differentially affect amyloid plaque formation. How is this done? A: lipidated apoE3 binds to the Abeta peptide with a 20 fold higher affinity than lipidated apoE4. The increased binding of apoE3 could enhance the clearance of the Abeta peptide, preventing the accumulation of the neurotoxic Abeta species. ApoE4 has been shown to result in the formation of insoluble, high-molecular-weight complexes with the Abeta peptide.