H 3 CCCCCCCCCCCCCCC COO H 3 CCCCCCCCCCCCCCC COO H 3 CCCCCCCCCCCCCCC COO H 3 CCCCCCCCCCCCCCC COO H 3 CCCCCCCCCCCCCC C 4 C COO- C 2 H 3 CCCCCCCCCCCCCC C 4 C COO- C 2 H 3 CCCCCCCCCCCCCC C 4 C COO- C 2 Palmitic acid H 3 CCCCCCCCCCCCCCC COO

Cholesterol Cholic acid

Cholesterol exogenous (dietary) cholesterol delivered to liver via chylomicron remnants. endogenous cholesterol synthesized primarily in the liver from AcCoA (extrahepatic tissues also synthesize cholesterol) in the liver, cholesterol is either converted to bile salts or to cholesterol esters and packaged into VLDLs. Peripheral tissues obtain most of their exogenous cholesterol from LDLs and convert it back to cholesterol for use in membranes or store in cholesterol ester droplets. LDLs deliver cholesterol to the tissues – HDLs circulate it back to the liver. Excess cholesterol is disposed of by the liver as bile salts. Average serum cholesterol ~175mg/100ml

Lipid transport triacylglycerides, cholesterol, phospholipids dietary lipid transport –chylomicron endogenous lipid transport (VLDL, IDL, LDL, HDL)

pancreatic lipases intestinal lumen triacylglycerols FFA + monoacylglycedrols bile acids cholesterol micelles epithelial cells triacylglycerols absorbed by intestinal epithelial cells and reconverted to triacylglycerols Packaged into chylomicron Released into lymphatic system and then via capillaries to blood stream chylomicron acted upon by lipases on cell walls of capillaries in tissues FFA taken up by tissues energy production reconversion to TAGs in adipocytes for storage hormone sensitive lipases FFA released to circulatory system and combine with albumin for delivery to tissues Dietary uptake and distribution of fatty acids

Why do we need lipoproteins? Triacylglycerides (TAGs) + cholesterol (Chol) are nonpolar molecules → insoluble in H 2 O TAG + Chol must be packaged within a polar shell in order to be transported through the blood to the various tissues This is accomplished by combining nonpolar lipids w/ amphipathic lipids →(a polar water-soluble terminal group attached to an H 2 O -insoluble hydrocarbon chain)

Lipoproteins & Apolipoproteins Lipoproteins (LP)  function: transport of cholesterol + esterified lipids in blood  structure: 1) polar shell ---single phospholipid (PL) layer: head groups directed outward -Chol -apolipoproteins 2) nonpolar lipid core -hydrophobic TAG(triacylglycerol) -cholesteryl ester (CE)

Apolipoproteins Provide structural stability to Lp Serve as ligands for interaction w/Lp receptors that help determine disposition of individual particles Act as cofactors for enzymes involved in plasma lipid and Lp metabolism

There are many types of apolipoproteinsa ApoproteinLipoproteinsFunction(s) Apo B-100 VLDL, IDL, LDL1) Secretion of VLDL from liver 2) Structural protein of VLDL, IDL, and HDL 3) Ligand for LDL receptor (LDLR) Apo B-48Chylomicrons, remnants Secretion of chylomicrons from intestine; lacks LDLR binding domain of Apo B-100 Apo EChylomicrons, VLDL, IDL, HDL Ligand for binding of IDL & remnants to LDLR and LRP Apo A-IHDL, chylomicrons1) Major structural protein of HDL 2) Activator of LCAT Apo A-IIHDL, chylomicronsUnknown Apo C-I Chylomicrons, VLDL, IDL, HDL Modulator of hepatic uptake of VLDL and IDL (also involved in activation of LCAT) Apo C-II Chylomicrons, VLDL, IDL, HDL Activator of LPL Apo C-IIIChylomicrons, VLDL, IDL, HDL Inhibitor of LPL activity

Lipoprotein Structure

Lipoproteins hydrophobic core (TAGS, cholesterol esters) hydrophilic surface (P-lipids, cholesterol, and apolipoproteins) Function transport of lipids in blood Types of lipoproteins (classified according to density) very low density (VLDL) intermediate density (IDL) low density (LDL) high density (HDL) Protein content increase, lipid decreases as density increases. % TAGS % Protein Chylomicron VLDL IDL LDL HDL 85% 2% 8% 33%

Lipoproteins: Relative Size and Density nm

Lipoproteins Chylomicron: 85% TAG, 4% chol., 8% protein nm formed in intestinal epithelial cells deliver exogenous TAGS to tissue ApoCII activates lipases in capillary cell walls releasing FFA to tissue chylomicron remnants return to liver where they bind to ApoE receptor and are taken up 1/2 life in blood minutes

VLDL: 50% TAGs, 22% choles., 10% protein nm formed in liver deliver endogenous lipids to other tissues (mainly muscle and fat cells) ApoCII activates lipases in capillary cell walls releasing FFA to tissue converted to IDLs and LDL as lipids are released

IDL: (31% TAGs, 29% choles., 18% protein) formed from VLDLs as lipids removed some IDLs return to liver rest converted to LDLs by further removal of lipids Lipoproteins

LDL: “bad” cholesterol 10% TAGs, 45% choles., 25% protein nm formed as lipids removed from VLDLs and IDLs. all apolipoproteins lost except ApoB100 bind to LDL receptor via ApoB100 and taken up by endocytosis by hepatic and other tissues (50-75% taken up by liver). Primary mode of cholesterol delivery to tissues. Synthesis of LDL receptor is inhibited by high levels of intracellular cholesterol and stimulated by low levels of cholesterol. Therefore, cholesterol uptake is closly matched to intracellular cholesterol levels.

HDL: “good” cholesterol 8% TAGs, 30% choles., 33% protein nm formed in liver scavenge cholesterol from cell surfaces and other lipoproteins and deliver it to liver. Convert cholesterol to cholesterol ester bind to “scavenger receptor” on liver cell surface - cholesterol esters taken up and HDLs released and reenter circulation. Lipoproteins

Intestine Liver Dietary lipids chylomicron Peripheral tissues Dietary lipids chylomicron LDLs Triacylglycerols FFA monoacylglycerols Cholesterol Cholesterol esters Triacylglycerols cholesterol Cholesterol esters VLDLs HDL HDLs

Intestine Liver Dietary lipids chylomicron Peripheral tissues Dietary lipids chylomicron Triacylglycerols FFA monoacylglycerols Cholesterol Cholesterol esters Fig Distribution of endogenous lipids The Exogenous Pathway LPLs activated by ApoCII Chylomicron remnants acquire ApoE, CII and others ApoE/LDLR mediated uptake

Liver Peripheral tissues LDLs Triacylglycerols FFA monoacylglycerols Cholesterol Ester Cholesterol Triacylglycerols cholesterol Cholesterol esters VLDLs IDLs Fig Distribution of endogenous lipids The Endogenous Pathway acquire ApoE, CII and others LPLs activated by ApoCII LDLR/ApoE LDLR/ApoB100

Distribution of endogenous lipids The HDL Pathways Transport of excess cholesterol from peripheral tissues back to liver for excretion in bile HDLs act as acceptors for excess chol, Apo, PL derived from CM, VLDL and LDL HDLs synthesized by both liver and intestine

Liver Peripheral tissues LDLs Triacylglycerols FFA monoacylglycerols Cholesterol Ester Cholesterol Triacylglycerols cholesterol Cholesterol esters VLDLs HDL HDLs IDLs CEs TAGs Fig Distribution of endogenous lipids The HDL Pathways scavenger receptor uptake of cholesterol VLDL Choles.