Lipid Metabolism Flashcards
What is the function of fatty acids?
metabolic fuel, precursors for eicosanoids, building block for phospholipids and sphingolipids. They are amphpithic. In blood they are boundto albumin and in cells bound to fatty acid binding proteins or as esters of coenzyme A. They are saturated and most commonly exist as cis isomer
What is the function for triglycerides?
storage form and major transport form of fatty acids They are neutral fats and hydrophobic.
What is the function of ketones?
soluble metabolic fuels for skeletal muscle, heart, kidney and brain. Most important are acetoacetate and beta-hydroxybutyrate
What is the function of cholesterol?
structural component of plasma membrane; precursor of steroid hormones, Vitamin D, and bile acids. Contain steroid nucleus. Most cholesterol exists as cholesterol esters
What is the function of phospholipids?
major building block of membranes; storage site for polyunsaturated fatty acids; component of signal transduction pathways. There are two alcohols that are linked through a phosphate bond.
What is the function of sphingolipids?
structural component of membranes; surface antigens. It has one amino group and two hydroxyl groups. The amino group is linked via an amide bond to a long chain saturated fatty acid and the terminal hydroxyl group can be linked to a variety of compounds.
Describe digestion in mouth and stomach
2 lipases: lingual lipase and gastric lipase
substrate: triglycerides
products: fatty acids and diglycerides
Describe intestinal digestion.
emulsification - bile salts
pancreatic lipase (requires colipase, a small protein for optimal activity)
substrate:triglycerides and diglycerides
products: 2-monoglyceride and fatty acids
cholesteral esterase
substrate: cholesterol esters
product: cholesterol and fatty acids
phospholipidase A2
substrate: phospholipid
product: lysophospholipid and fatty acids
Describe absorption and reesterification of dietary lipids.
Once inside cell, triglycerides and cholesterol esters are reformed, packaged into chylomicrons and secreted into lymphatics
Describe chylomicron assembly
Hydrophobic shell of nascent chylomicron contains apo B48, phospholipid, and unesterified cholesterol. Triglyceride and cholesterol esters are found inside. Most triglycerides are assembled in enterocyte
Describe chylomicron secretion
Released by exocytosis into lymphatics and carried to thoracic duct where they join at the right atrium to the general circulation. Here they acquire apco C-II and apo-E from HDL
Describe chylomicron metabolism
increases hours after meal and requires 6 to 8 hours to return to basal levels. Contains lipoprotein lipase that hydrolyzes triglycerides in chylomicron. This enzyme requires apo-C for activity. The fatty acids that are released diffuse into tissues to be oxidized or stored
What are the conditions that lead to lipid malabsorption?
bile salt deficiency
pancreatic enzyme deficiency
defective chylomicron synthesis
What are the effects of lipid malabsorption?
deficiency in fat soluble vitamins: Vit K (clotting), A (nightblindness) D (osteoporosis) E (anemia
Describe the general structure of a lipoprotein
consists of a core containing triglycerides and cholesterol esters
has a surface coat containing apoproteins, phospholipids, and unesterified cholesterol
What is the order based on separation by centrifugation and electrophoresis of the lipoproteins
centrifugation (most dense to least): HDL, LDL, VLDL, chylomicrons
electrophoresis (most positive to negative): HDL, VLDL, LDL, chylomicrons
What are some of the properties of the lipoproteins?
chylomicron- least protein, most triglycerides
VLDL: more lipid than protein but not as much as chylomicron
LDL most cholesterol and cholesterol esters
HDL: most protein, least lipid, least percentage triglyceride, most percentage phospholipid
what is source and function of chylomicrons?
source: intestines
function: transport dietary triglycerides to peripheral tissues
What is the source and function of VLDLs?
source: liver
function: transport triglycerides to peripheral tissues
What is the source and function of IDLs?
Source: plasma VLDLs
Function: triglyceride transport, precursor of LDL
What is the source and function of LDLs?
Source: plasma IDLs
Function: transport cholesterol to peripheral tissues
What is the source and function of HDLs?
Source: liver and intestines
Function: reservoir or apoproteins, reverse cholesterol transport
What is the major functions of each apoprotein class?
Apo A: reverse cholesterol transport
Apo B: Recognition of LDL receptors
Apo C: Regulation of Lipoprotein Lipase
Apo E: Recognition of Remnant receptors
Describe the exogenous pathway of lipoprotein metabolism.
Transport of dietary lipids from the gut to the other tissues as chylomicrons: production of chylomicron remnants that are taken up by the liver.
lipoprotein lipase is bound by GAGs to luminal wall of capillaries especially in adipose, muscle and cardiac tissue. It hydrolyzes triglycerides to fatty acids and glycerol, causing chylomicron to shrink to chylmicron remnants. The synthesis of LPL by adipocytes is stimulated by insulin. The enzyme is activated by Apo C.
Describe the endogenous pathway of lipoprotein metabolism
synthesis of VLDL by the liver; metabolism of VLDL to IDL to LDL that are taken up by the liver and other tissues
VLDLs are synthesized only by liver and assembled in ER. The VLDLs transport endogenous lipids (triglycerides and cholesterol esters) from liver to extrahepativ tissues. Only apoprotein on nascent VLDLs is apoB100. Others are attained from HDL in circulation.
Describe reverse cholesterol transport pathway
Removal of cholesterol from peripheral tissues by HDL; Esterification and transfer to chylomicron remnants and IDL and transport to the liver
What is the fate of chylomicron remnants?
the remnants become smaller, apo C-II is returned to circulating HDLs, leaving apB48 and apo E in surface monolayer. The remnants bind to receptors on liver and are taken up by receptor mediated endocytosis. Apo E binds to remnant receptor, wheras both apo E and apoB48 are required for binding of remnants to LDL receptors
What is the effect of lipoprotein lipase on VLDLs
TRiglyceride in VLDLs is hydrolyzed, resulting in progressive shrinking to IDLs. As they become smaller, Apo C-II passed back to HDL, which leaves IDLs that have little affinity for LPL
What is the fate of IDLs?
taken up by liver or metabolized by hepatic lipase to LDLs
75% are internalized by liver following interaction of Apo E binding to remnat receptors and apoB-100 to LDL receptors. The more internalized, less in circulation, lower risk of atherosclerosis.
About 25% of the IDLs are converted to LDLs by hepatic lipase, which hydrolyzes both triglycerides and phospholipids. This also results in the return of apo E to the circulating HDL pool
Describe metabolism of LDL
interaction of apoB100 with LDL receptor -> endocytosis. REceptors returned to plasma membrane and endosome fuses with lysosomes, where LDL particle is hydrolyzed. The rates of cholesterol uptake (LDL uptake) and cholesterol synthesis are coordinated by cellular concentration of unesterified cholesterol.
About 75% of plasma LDL cleared by LDL receptor pathway. 25% removed by low affinity receptors known as scavenger receptors found on macrophages. Scavenger receptors have a low affinity for LDL, but a high affinity for oxidized LDL. The synthesis of scavenger receptors, unlike that of LDL receptors, is not regulated by the cellular concentration of cholesterol. As cholesterol accumulates, macrophages are converted to foam cells, which continue to form until they become part of an atherogenic plaque.
Describe the HDL metabolism of reverse cholesterol transport.
HDL synthesis occurs mostly in liver, though small amounts in intestinal cells. nascent HDL are disclike, with empty space inside with apo A, C and E on the surface.
HDL serves as circulating respository of apoproteins. Apo C and E exchanged readily, but not A.
The pathway of reverse cholesterol transport results in net transfer of cholesterol from peripheral tissue to liver, where it can be processed for excretion. Pathway is mediated by HDL, although HDL does not carry much cholesterol back to liver
What are the four steps in reverse cholesterol transport.
Uptake of cholesterol by HDL
Esterification of HDL Cholesterol
Transfer of Cholesterol Esters from HDL to Lipoprotein Remnants
Transfer of HDL cholesterol esters to tissues via scavenger receptor
Describe uptake of cholesterol by HDL
Lipid poor HDL interacts with surface of cells, resulting in translocation of unesterified cholesterol from cell to surface of HDL. Binding HDL to surgace of cells requires A-1. The rate controlling step in reverse cholesterol transfer is transfer of cholesterol and phospholipids from cell to lipid poor HDL, mediated by an ATP-binding cassette transporter (ABCA1)
Describe the esterification of HDL Cholesterol
The cholesterol that has been picked up is converted to cholesterol ester by lecithin cholestrol acyl transferase (LCAT) an enzyme in plasma and loosely associated with HDL. Activity of LCAT is stimulated by apo A1. The cholesterol esters formed in this reaction can be transferred either to core of HDL or other lipoprotein remnants.
Describe the transfer of cholesterol esters from HDL to Lipoprotein Remnants
IDLs, LDLs and chylomicron remnants have empty space in core created by lipoprotein lipase catalyzed hydrolysis of triglycerides. Cholesterol esters can be transferred into this space in a reaction mediated by cholesterol ester transfer protein (CETP) or apoD. Since remnants contain apo B and apo E, they can be readily cleared by liver, following binding of LDL and remnant receptors. This is indirect pathway of reverse cholesterol transport.
Describe transfer of HDL cholesterol esters to tissues via scavenger receptor B1.
HDL binds to scavenger receptor but is not endocytose, cholesterol esters are transferred to cell. Scavenger receptor B1 is expressed on liver, steridogenic tissues, and macrophages in atherosclerotic plaques. This is the direct pathway of the reverse cholesterol transport
