Section 7. Lipid Metabolism

1. Section 7. Lipid Metabolism Steroids 11/11/05

2. Membrane Properties • The distribution of lipids and proteins is asymmetric. • Membranes have flexible and dynamic structures. • The bilayer is fluid: lateral diffusion and protein structural fluctuations occur readily. • “Flip-flops” are rare, because the polar head group is “insoluble” in the non-polar bilayer. • Bilayer fluidity is increased by higher temperature, shorter acyl chains, more double bonds, [cholesterol]. Fig. 12.30 Fig. 12.31 1

3. Vesicle Membrane Fusion • Vesicles occur in intra- and extracellular locations. • They can fuse with cell membranes, from either side, moving the vesicle contents into or out of the cell. • On the right, vesicles filled with acetylcholine fuse with the axon cell membrane delivering the acetylcholine into the synaptic cleft. (Stryer 4th) 2

4. Endocytosis and Exocytosis • Endocytosis is the incorporation of material into a cell by the creation of a vesicle from the cell membrane. • Exocytosis is the movement of material out of cell by vesicle fusion with the cell membrane (see previous slide). 3

5. Cholesterol • Membrane constituent. • Synthetic precursor for steroid hormones, bile salts and vitamin D. • Human synthesis starts with acetyl CoA. (Stryer 4th) 4

6. Cholesterol Biosynthesispart 1 • The committed step is the synthesis of mevalonate by 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase). • Synthesis is in the cytosol. 5

7. Cholesterol Biosynthesispart 2 • 18 acetyl CoA are used to make 1 cholesterol. • A mixed oxidase catalyzes the production of squalene epoxide. 6

8. Activity: HMG CoA reductase is inhibited by phosphorylation, by an AMP-dependent kinase. Transcription: Low intracellular [cholesterol] activates production of sterol regulatory element binding protein (SREBP), which migrates to the nucleus and binds the sterol regulatory element (SRE) to increase transcription of HMG CoA reductase and related genes. Translation: High [cholesterol] inhibits translation of HMG CoA reductase mRNA. Proteolytic degradation of HMG CoA reductase is activated by cholesterol and other sterols in the membrane. HMG CoA reductase is a membrane-bond enzyme found mainly in liver and intestine cells. It is the primary control site for cholesterol synthesis. Regulation of Cholesterol Synthesis 7

9. Cholesterol Products • Cholesterol is the starting material for all steroids. 8

10. Vitamin D Synthesis UV light • Humans synthesize “vitamin” D, but often need it in the diet for regulation of calcium and phosphorous metabolism. • Notice the sunshine-requiring step. • DHCC is the active hormone. 89

11. LipoproteinComplexes • Cholesterol, cholesterol esters and triacylglycerol are transported in the blood as constituents of several different lipoprotein complexes. • Low density lipoprotein (LDL) is shown. • The density of lipoprotein complexes increases with the amount of protein they contain. • There are more than ten proteins, which vary among the complexes. Fig. 26.26 10

12. Lipid Transport LIPOPROTEINMAJOR CORE LIPIDAPPARENT ROLECELL ENTRY (Primary Apoproteins) chylomicron dietary TAG TAG to cells lipoprotein (B-48, C, E) lipase chylomicron dietary C C to liver receptor remnant (B48, E) endocytosis VLDL endogenous TAG TAG from liver lipoprotein (B-100, C, E) to cells lipase IDL endogenous TAG TAG to cells lipoprotein (B-100, E) lipase LDL endogenous CE cholesterol receptor (B-100) to cells endocytosis HDL endogenous CE cholesterol (A) from necrotic cells to LDL C=cholesterol, CE=cholesterol ester, TAG=triacylglyceride V, very; L, low; I, intermediate; H, high; D, density; L, lipoprotein 11

13. Distribution of Triacylglycerol and Cholesterol • Uptake by lipoprotein lipase (fatty acids from TAG and DAG) or receptor-mediated endocytosis (lipoproteins). 12

14. Intracellular Cholesterol Fig. 12.40 • Increased [cholesterol] reduces cholesterol uptake and synthesis (inhibits HMG CoA reductase), and increases esterification by acyl CoA:cholesterol acyltransferase (ACAT) for storage. 13

15. LDL Receptor Structure and Function • Receptor in coated pit binds LDL. • The complex is moved into the cell by receptor-mediated endocytosis. • The endocytic vesicle fuses with lysosomes in cytosol. • This releases LDL constituents to cytosol. • The LDL receptor returns to coated pit location on plasma membrane. • Cell [cholesterol] determine LDL receptor levels. • LDL receptors determine blood [cholesterol]. Fig 27-23. Stryer 4th 14

16. LDL receptor: “mosaic protein” Fig 26.18 Epidermal growth factor-like, blade and O-linked glycosylated domains keep receptor positioned away form membrane surface. Fig 26.20 Fig 26.19 15

17. Atherosclerosis, inflammation, endothelial cells • Oxidation of LDL fatty acids produce oxLDL (various possible structures). • Oxidized LDL correlates strongly and in a graded fashion with atherosclerosis. • HDL may reduce oxLDL. • OxLDL are taken up by endothelial cells to remove them from the blood. • They accumulate at these sites of inflammation which also bind macrophages, C-reactive protein and oxLDL antibodies. • These atherosclerotic lesions heal, but occlude vascular channels and have the potential to break off into the blood stream. 16

18. Drugs in the statin group inhibit HMG CoA reductase activity by competitive binding (Kd ~ 1 nM). Reduced intracellular cholesterol increases LDL receptor synthesis, which decreases blood LDL. Bile salt recycling can be reduced by dietary positively charged non-digestible polymers. This decreases the uptake of dietary cholesterol and may increases the conversion of cholesterol to bile salts. Therapeutic Interventions 17

19. Next topic: Section 8: Amino acid metabolism