1. LIPOPROTEINS
A to Z

3. 1.Dyslipoprot(0).FLV

4. Lipid Digestion & Transport
Digestion & transport of lipids poses unique problems relating to the insolubility of lipids in water.
Lipids, & products of their digestion, must be transported through aqueous compartments within the cell as well as in the blood & tissue spaces.
Free fatty acids are transported in the blood bound to albumin

5. Within intestinal cells (and other body cells) some of the absorbed cholesterol is esterified to fatty acids, forming cholesteryl esters.
The enzyme that catalyzes cholesterol esterification is ACAT (Acyl CoA: Cholesterol Acyl Transferase).
Intestinal epithelial cells synthesize triacylglycerols, cholesteryl esters, phospholipids, free cholesterol, and apoproteins, and package them into chylomicrons.

6. Chylomicron assembly Fatty acids, 2-MAG lumen ATP ADP intestinal
Triacylglycerol
Apolipoproteins
Chylomicrons
lumen
intestinal
epithelium
lymphatics
Cholesterol

7. Chylomicrons -
Lipoprotein + lipids
TG PL Chol
~85% ~9% ~4%
released into lymph/blood ~ 50 : 50
ApoC-II activates lipoprotein lipase in capillaries
Tissues remove FFA, PL
Liver picks up chylomicron remnants

8. Formation of lipoproteins:
Intestinal epithelial cells synthesize triacylglycerols, cholesteryl esters, phospholipids, free cholesterol, and apoproteins, and package them into chylomicrons.
Chylomicrons are secreted by intestinal epithelial cells, and transported via the lymphatic system to the blood.

9. Chylomicron Metabolism

10. Formation of Chylomicrons :
Chylomicrons are secreted by intestinal epithelial cells, and transported via the lymphatic system to the blood.
Apoprotein CII on the chylomicron surface activates Lipoprotein Lipase, an enzyme attached to the luminal surface of small blood vessels. Lipoprotein Lipase catalyzes hydrolytic cleavage of fatty acids from triacylglycerols of chylomicrons.
Released fatty acids & monoacylglycerols are picked up by body cells for use as energy sources.
With removal of triacylglycerols and some proteins, the % weight that is cholesteryl esters increases.

11. As triacylglycerols are removed by hydrolysis, chylomicrons shrink in size, becoming chylomicron remnants with lipid cores having a relatively high concentration of cholesteryl esters.
Chylomicron remnants are taken up by liver cells, via receptor-mediated endocytosis (to be discussed later).
The process involves recognition of apoprotein E of the chylomicron remnant by receptors on the liver cell surface.

12. Biosynthesis of membrane lipids and steroids 1
Chylomicrons
Biosynthesis of membrane lipids and steroids 1

14. FIGURE 21-2 (part 2) Addition of two carbons to a growing fatty acyl chain: a four-step sequence. Each malonyl group and acetyl (or longer acyl) group is activated by a thioester that links it to fatty acid synthase, a multienzyme system described later in the text. 1 Condensation of an activated acyl group (an acetyl group from acetyl-CoA is the first acyl group) and two carbons derived from malonyl-CoA, with elimination of CO2 from the malonyl group, extends the acyl chain by two carbons. The mechanism of the first step of this reaction is given to illustrate the role of decarboxylation in facilitating condensation. The β-keto product of this condensation is then reduced in three more steps nearly identical to the reactions of β oxidation, but in the reverse sequence: 2 the β-keto group is reduced to an alcohol, 3 elimination of H2O creates a double bond, and 4 the double bond is reduced to form the corresponding saturated fatty acyl group. 14

15. Questions What are the lipids carried by CM? Where is CM formed?
What is the source for lipids in CM?
How does the CM release FFA?
What is the fate of the FFA and Glycerol?
Where is the LPL found?
What are the components of Remnant CM?

16. VLDL

17. As VLDL particles are transported in the bloodstream,
. Liver cells produce, and secrete into the blood, very low density lipoprotein (VLDL).
The VLDL core has a relatively high triacylglycerol content.
VLDL has several apoproteins, including apoB-100.
As VLDL particles are transported in the bloodstream,

18. Lipoprotein Lipase, is attached to the lumenal surface of small blood vessels. It catalyzes hydrolytic cleavage of fatty acids from triacylglycerols of chylomicrons.
Released fatty acids & monoacylglycerols are picked up by body cells for use as energy sources.
With removal of triacylglycerols and some proteins, the % weight that is cholesteryl esters increases.
VLDL are converted to IDL, and eventually to LDL.
VLDL  IDL  LDL

19. VLDL Assembly

20. Biosynthesis of membrane lipids and steroids 1
VLDL
Biosynthesis of membrane lipids and steroids 1

21. Control of VLDL production:
VLDL assembly is dependent on availability of lipids. Transcription of genes for enzymes that catalyze lipid synthesis is controlled by SREBP.
Availability of apoprotein B-100 for VLDL assembly depends at least in part on regulated transfer of B-100 out of the ER for degradation via the proteasome.

22. Nascent VLDL (B-100) + HDL (apo C & E) = VLDL
LPL hydrolyzes TG forming IDL
IDL loses apo C-II (reduces affinity for LPL)
75% of IDL removed by liver through Apo E and Apo B mediated receptors
25% of IDL converted to LDL by hepatic lipase

23. Biosynthesis of membrane lipids and steroids 1
VLDL
Chylomicrons
Biosynthesis of membrane lipids and steroids 1

24. CHYLO & VLDL.FLV

25. QUESTIONS Where is VLDL formed? What are the lipids Carried by VLDL?
Which lipid is delivered by VLDL?
What is the mechanism of FFA release from VLDL?
What is the fate of Remnant VLDL?
What are the lipids present in excess when VLDL becomes VLDLR?

26. LDL

27. Biosynthesis of membrane lipids and steroids 1
LDL
Biosynthesis of membrane lipids and steroids 1

28. Low Density Lipoprotein (LDL)
The lipid core of LDL is predominantly cholesteryl esters.
Whereas VLDL contains 5 apoprotein types (B-100, C-I, C-II, C-III, & E),
ONLY ONE PROTEIN, APOPROTEIN B-100, IS ASSOCIATED WITH THE SURFACE MONOLAYER OF LDL.

29. Cells take up LDL by receptor-mediated endocytosis, involving formation of a clathrin-coated pit & pinching off of a vesicle incorporating the receptor & LDL cargo.
After the clathrin coat disassembles, the vesicle fuses with an endosome
LDL is released from the receptor within the acidic environment of the endosome, and the receptor is returned to the plasma membrane.
After LDL is transferred to a lysosome, cholesterol is released & may be used, e.g., for membranes synthesis.
LDL

30. Endocytosis flv

31. LDL

32. LDL METABOLISM
Synthesis of LDL Receptor is suppressed by high intracellular cholesterol.
The decreased synthesis of LDL receptor prevents excessive cholesterol uptake by cells.
It has the deleterious consequence that excess dietary cholesterol remains in the blood as LDL.

33. Mutations affecting the LDL receptor are associated with the most common form of the disease familial hypercholesterolemia (high blood cholesterol).
Cells lacking functional LDL receptors cannot take up LDL.
As a result, the amount of circulating LDL increases, leading to enhanced risk of developing atherosclerosis.
Other hereditary hypercholesterolemias relate to genetic defects in structure of apolipoproteins.
E.g., familial defective apoprotein B100 leads to impaired binding of LDL to cell surface receptors, with elevated levels of circulating LDL.

34. ACYL-COA:CHOLESTEROL ACYLTRANSFERASE (ACAT) GENERATES CHOLESTERYL ESTERS ( LDL Metabolism )

35. LDL Receptor (apoB-E receptor)
Increased uptake of LDL-cholesterol results in:
inhibition of HMG-CoA reductase
reduced cholesterol synthesis
stimulation of acyl CoA:cholesterol acyl transferase (ACAT)
increased cholesterol storage
TG + C -> DG + CE
LDL-Receptors
HMG-CoA
reductase
Cholesteryl ester
(storage)
LDL
Receptors
ACAT
Cholesterol
LDL
LDL
Amino
acids
Endosome
Lysosome
decreased synthesis of LDL-receptors
“down-regulation”
decreased LDL uptake

36. Apo B LDL Flv Non HDLC FLV

37. HDL

38. Biosynthesis of membrane lipids and steroids 1
HDL
Biosynthesis of membrane lipids and steroids 1

39. High Density Lipoprotein (HDL)
Synthesized in liver and intestine
Reservoir of apoproteins
Reverse cholesterol transport
Apo A
Activates lecithin-cholesterol acyltransferase (LCAT)
Apo C
Activates LPL
Apo E
Remnant receptor binding

40. HDL Reverse cholesterol transport RESERVOIR OF APOPROTEINS
provides apo C and apo E to/from VLDL and chylomicrons
Reverse cholesterol transport

41. Biosynthesis of membrane lipids and steroids 1
HDL
Biosynthesis of membrane lipids and steroids 1

42. HDL FLV

43. Reverse Cholesterol Transport Delivery of peripheral tissue cholesterol to the liver for catabolism Requires HDL, apoA-I and LCAT
HDL apoprotein, A-1, activates LCAT (Lecithin-Cholesterol Acyl Transferase), which catalyzes synthesis of cholesteryl esters using fatty acids cleaved from the membrane lipid lecithin.
The cholesterol is scavenged from cell surfaces & from other lipoproteins.

44. Reverse Cholesterol Transport Delivery of peripheral tissue cholesterol to the liver for catabolism Requires HDL, apoA-I and LCAT
HDL may transfer cholesteryl esters to other lipoproteins.
Some remain associated with HDL, which may be taken up by liver & degraded.
HDL thus transports cholesterol from tissues & other lipoproteins to the liver, which can excrete excess cholesterol as bile acids.

45. Reverse Cholesterol Transport Delivery of peripheral tissue cholesterol to the liver for catabolism Requires HDL, apoA-I and LCAT
Esterification of HDL by LCAT
LCAT activated by apoA1
Transfer of CE to VLDL remnants (IDL)) and Chylomicron remnants by CETP
Removal of CE-rich remnants by liver
Converted to bile acids in liver and excreted

46. Reverse Cholesterol Transport
Peripheral
Cell
diffusion
HDL UC UC
HDL
Macrophage/ Foam cell UC
ABCA1
LCAT PL
LCAT
Nascent
HDL
HDL CE CE CE
SR-B1 =
apoA-I TG CE
Liver
UC = unesterified cholesterol
CE = esterified cholesterol
PL = phospholipid
LDLr = LDL receptor
ABC = ATP Binding Cassette transporter
VLDL
or LDL
apoB
LDLr
Chol
Bile acids
Bile to gut

47. High blood levels of HDL ("good" cholesterol) correlate with low incidence of atherosclerosis.
Bacterial & viral infections, & some inflammatory disease states decrease HDL & increase VLDL production by the liver.
These & other changes associated with inflammation can lead to increased risk of atherosclerosis if prolonged.