Lipids & Lipoproteins Part 1 Lecture 12.

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1 Lipids & Lipoproteins Part 1 Lecture 12

2 Introduction Lipids are a diverse group of compounds that have many biological functions They have 2 primary purposes in living Organisms Storage of excess calories Composed mostly of carbon hydrogen (rich source of energy) Structural role: Integral part of cell membrane Because of their unique structural design

3 Lipids The term lipid applies to a class of compounds that are soluble in organic solvents and nearly insoluble in water Some lipids contain non lipid groups (phosphoryl, amino, sulfate) They are carried in the body by lipoproteins Subdivided into 4 main groups based on their chemical structure Fatty acids Cholesterol Triglycerides Phospholipids

4 Fatty Acids Linear chains of carbon and hydrogen
Terminate in -COOH carboxyl group Short chain = 4-6 carbons Medium = 8-12 carbons Long chain > 12 carbons Diet is mostly long chains with even number of carbons ss

5 Fatty Acids In plasma, only a relatively small amount of fatty acids exists in the free or unesterified form, Most of which is bound to albumin. The majority of plasma fatty acids are instead found as a constituent of triglycerides or phospholipids Fatty acids are covalently attached to the glycerol backbone of triglycerides and phospholipids by an ester bond that forms between the carboxyl group on the fatty acid and the hydroxyl group (—OH) on glycerol

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7 Triglycerides Glycerol backbone with FA attached by ester bonds
Each FA can be different Triglycerides with saturated FA (no kinks) pack tightly → solid at room tempt Triglycerides with unsaturated FA typically oils at room temp Glycerol Triglyceride

8 Triglycerides Most plant-derived FA are highly unsaturated
Corn, sunflower, and peanut oils Most animal-derived saturated FA Usually solid at room temp Triglycerides → No charged groups or polar hydrophilic groups Hydrophobic Not soluble in water

9 Triglycerides Sources of Triglycerides:
Exogenous source: Dietary Endogenous : Liver and tissue storage Triglycerides transported by Chylomicrons (exogenous) and VLDL (endogenous) Energy source when plasma glucose is decreased Triglycerides catabolism is regulated by: lipase, Epinephrine, and cortisol

10 Phospholipids Similar in structure to triglycerides
Two FA – usually C long One commonly saturated; one unsaturated Third position has phospholipid head group Several types of phospholipid head groups Choline, serine, ethanolamine, inositol

11 Phospholipids Phosphatidylcholine
Have a choline head group Most common in lipoproteins and cell membranes Phospholipids are Amphipathic lipid molecules Hydrophobic FA and hydrophilic head group In Cell membrane Polar hydrophilic faces outward toward aqueous environment Hydrophobic FA face inward away from water

12 Cholesterol Unsaturated steroid alcohol - amphipathic
4 ring structures (A, B, C, D) with single side R chain Hydrophilic OH on A ring 4 rings and side chain internal, OH external

13 Cholesterol Primarily animal source
Plants have other sterols Cholesterol not used as fuel source Not readily catabolized by cells Converted by liver to bile salts Promote fat absorption in bowel Converted to steroid hormones glucocorticoids mineralocorticoids (for example, aldosterone), and sex hormones—androgens, estrogens, and progestins

14 Cholesteryl Ester Hydroxyl group bonded to FA
Therefore no polar group → very hydrophobic Generally found in center of lipid droplets with triglycerides

15 Lipoproteins Phospolipids Cholestrol Apolipoprotein
Lipids need to be transported to tissues and organs to perform their metabolic functions Triglycerides & cholesteryl esters are hydrophobic There should be a form of hydrophilic compound Lipids are transported by a series of micelles called lipoproteins Triglycerides & cholesteryl esters Phospolipids Cholestrol Apolipoprotein

16 Lipoproteins General structure: spherical 10 - 1200 nm
Lipoproteins composed of lipids & proteins (apolipoprotein) Cholesterol and phospholipids on surface monolayer Triglycerides and cholesterol esters in center Main role is delivery of lipids

17 Lipoproteins Size correlates to lipid content
Larger particles have more lipid core Relatively more triglycerides & cholesterol esters Larger lipid to protein ratio Lighter in density Various lipoproteins were separated by ultracentrifugation into different density fractions: Chylomicrons, Very Low Density Lipoproteins (VLDL), Low Density Lipoproteins (LDL), High Density Lipoproteins (HDL)

18 Lipoproteins Characteristics CHYLOS VLDL LDL HDL Density (g/mL)
<0.93 Molecular weight (kD) (0.4-30) · 109 (10-80) · 106 2.75 · 106 ( ) · 105 Diameter (nm) 80-1,200 30-80 18-30 5-12 Total lipid (% by weight) 98 89-96 77 50 Triglyceride (% by weight) 84 44-60 11 3 Total cholesterol (% by weight) 7 16-22 62 19

19 Apolipoproteins Apolipoproteins primarily on surface of lipoprotein particle Maintain structural integrity Recognition of cell surface receptors Activators & inhibitors of various enzymes that modify lipoprotein particles Amphipathic helix Hydrophobic aa residues interact with lipids Hydrophilic aa resides interact with aqueous environment

20 Apolipoproteins Apo A-1 Apo B Apo C Apo E Apo (a) major protein of HDL
two forms: apo B-100 and apo B-48 Primary protein of LDL, VLDL and chylomicrons Apo C Chylomicrons, VLDL, HDL Apo E Chylomicrons, LDL, VLDL, HDL Apo (a) lipoprotein (a)

21 Chylomicrons Contain apo B-48 lipoprotein
Largest and least dense – up to 1200nm Large size reflect light – post-prandial serum turbidity Float to the top – “cream” layer

22 Chylomicrons Produced by intestine, where they are packaged with absorbed lipids Triglycerides and cholesteryl esters hydrolyzed by lipases Leaves chylomicron remnant → recycled by liver Therefore primary purpose is transport of dietary lipid to liver and peripheral cells

23 VLDL Contains apo B-100, apo E & Apo C
Rich in endogenously derived triglycerides from liver to cells Reflects light – fasting serum turbidity Excess carbohydrates in diet, saturated FA and trans FA increases hepatic synthesis of triglycerides → hepatic synthesis VLDL

24 LDL Contains apo B-100 and apo E
More cholesterol rich than other apo-B lipoproteins Formed from lipolysis of VLDL LDL taken up by cells through receptor Part of reason behind atherosclerosis

25 LDL Up to 8 subclasses – The LDL subclasses differ largely in their content of core lipids; the smaller particles are denser and have relatively more triglycerides than cholesteryl esters. Recently, there has been great interest in measuring LDL subfractions, because small, dense, LDL particles have been shown to be more proatherogenic and may be a better marker for coronary heart disease risk.

26 LDL Significantly smaller than VLDL – can infiltrate in vessel walls
Oxidized, taken up by macrophages Macrophages with too much lipid become foam cells foam cells are the predominant cell type of fatty streaks - precursor of atherosclerotic plaques

27 Lipoprotein (a) LDL-like molecule Contain apo (a) linked to apo B-100
Very heterogeneous in both size and density due to number of peptide sequences in apo (a) portion Elevated Lp (a) increased risk for premature coronary heart disease domains of Lp(a) have a high level of homology with plasminogen (a protein that promotes clot lysis) Compete with binding – increase clotting Lp(a) is similar in structure to a protein called plasminogen. Plasminogen is important in helping the body dissolve blood clots. Believe or not, our bodies are constantly making and dissolving microscopic blood clots in a delicate balance of two blood clotting systems. If Lp(a) competes for binding spots for this blood clot dissolver, the blood system balance may favor forming blood clots. Most heart attacks are caused by a blood clot in a heart artery at a site of atherosclerosis. Lp(a) may also stimulate our immune cells to deposit cholesterol into heart artery walls thereby promoting the development of atherosclerosis. Evidence suggests that Lp(a) may be more firmly retained in the arterial wall than LDL. Furthermore, Lp(a) transports oxidized phospholipids whose plasma levels are strongly correlated with the severity of coronary artery disease.

28 HDL Smallest and most dense Synthesized by liver and intestine
Exist as either disk-shaped particles or, more commonly, spherical particles Nascent- newly secreted HDL – active in removal of excess cholesterol from peripheral cells

29 HDL Discoidal HDL acquires additional lipids, cholesterol esters & triglycerides to form core region = spherical HDL Spherical HDL predominate in plasma HDL transport lipids back to the liver from peripheral tissues

30 Lipoprotein Pathways There are four major pathways involved in lipoprotein metabolism as shown in figure. Lipid absorption pathway, Exogenous pathway & Endogenous pathway All depend on apo B-containing lipoproteins Transport dietary and hepatic derived lipid to peripheral cells Transport energy to cells but also cholesterol If too much – cholesterol accumulates Peripheral cells cannot catabolize Hydrophobic cannot diffuse away

31 Lipid Pathways LCAT= lecithin –cholestrol acyltransfera-se
CETP= cholesteryl ester transfer protein CETP LCAT= lecithin –cholestrol acyltransferase CETP= cholesteryl ester transfer protein

32 Lipid Absorption Average person takes in 60-130 grams of fat per day
Mostly triglycerides Pancreatic lipase cleaves FA Triglycerides → mono or diglycerides Cholesteryl esters → free cholesterol These amphipathic molecules form large aggregates with bile acids into micelles in intestine

33 Lipid Absorption Micelles contact intestinal villi and are absorbed – passive and active transport Smaller FA (<10 carbons) absorbed directly into portal circulation Larger fragments converted back into triglycerides & cholesteryl ester Packaged chylomicrons with apo B-48 > 90% absorption effectiveness for triglycerides but only 50% for cholesterol

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35 Exogenous Pathway Newly synthesized chylomicrons secreted into lymphatic ducts → thoracic duct → blood Interact with lipoprotein lipase Hydrolyzes triglycerides Free FA and triglycerides = energy for cells Excess – reesterified for storage Mobilized with hormone sensitive lipase (epinephrine and cortisol ) the thoracic duct (aka left lymphatic duct) is an important part of the lymphatic system—it is the largest lymphatic vessel in the body. Lacteal: the lymphatic vessels of the small intestine that absorb digested fats.

36 Exogenous Pathway Lipid and apolipoproteins transferred onto HDL leaving chylomicron remnants Chylo-remnants taken up by liver via apo E and liver receptor Liver breaks them down further to FA, triglycerides, cholesterol, and amino acids

37 Endogenous Pathway Triglycerides in liver packaged into VLDL (from dietary recirculation from adipose tissue) Only small fraction synthesized de novo VLDL lipolysis similar to chylomicrons Loss of core lipids - Dissociation of particle Transfer to other particles VLDL remnants - half are converted to LDL, half taken up by liver

38 Lipid Pathways LCAT= lecithin –cholestrol acyltransfera-se
CETP= cholesteryl ester transfer protein CETP LCAT= lecithin –cholestrol acyltransferase CETP= cholesteryl ester transfer protein

39 Endogenous Pathway LDL primary transport of exogenous cholesterol to cells LDL receptors very efficient Endocytosed & degraded Triglycerides for energy or stored Free cholesterol membrane biosynthesis Excess cholesterol → cholesteryl ester & stored

40 Endogenous Pathway Biosynthesis enzymes for cholesterol down-regulated when excess cholesterol in cells Target for cholesterol-statin drugs Abnormal LDL receptor function → hypercholesterolemia → premature atherosclerosis 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase) 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase)

41 Reverse Pathway HDL is thought to remove excess cellular cholesterol by 2 mechanisms Aqueous diffusion pathway Small amount of cholesterol diffuses away from cells Converted to cholesteryl ester by LCAT (lecithin cholesterol acyltransferase) About ½ transferred to LDL and taken back to liver By Cholesterol ester transfer protein (CETP) Excreted into bile or converted to bile acids

42 Reverse Pathway ABCA1 transporter pathway
ATP binding transporter group Pumps ligands across cell membrane The exact substrate for the ABCA1 transporter is not known It is believed that the transporter modifies the plasma membrane by transferring a lipid Then, Apo A1 removes excess cholesterol from the plasma membrane Recently, ABCG1 & ABCG5 are other ABC transporters that also collect cholesterol