1 / 53

Lipid metabolism 3-4 internet

Lipid metabolism 3-4 internet. Cholesterol. Essential molecule *Modulates membrane fluidity *Precursor of -steroid hormones - bile acids All cells can synthesize it. Synthesis of cholesterol. Condensation of 3 acetate.

emerya
Télécharger la présentation

Lipid metabolism 3-4 internet

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Lipid metabolism 3-4 internet

  2. Cholesterol Essential molecule *Modulates membrane fluidity *Precursor of -steroid hormones - bile acids All cells can synthesize it

  3. Synthesis of cholesterol Condensation of 3 acetate Acetate(C2)èmevalonate(C6) • isopentenyl pyrophosphate (C5) è squalene (C30)èCholesterol (C27) Polymerization of 6 isoprene units Cyclization plus oxidation and methyl removal

  4. Formation of mevalonate in the synthesis of cholesterol Enzyme is cytosolic distinct from the mitochondrial isoenzyme! Committed and rate-limiting step Enzyme is an integral protein in the ER

  5. Formation of activated isoprenes in the synthesis of cholesterol DIMETHYL-ALLYL PYROPHOSPHATE

  6. Formation of squalene in the synthesis of cholesterol Isopentenyl-pyrophosphate (C5) Geranyl pyrophosphate (C10) Farnesyl-pyrophosphate (C15) squalene (C30) + Farnesyl PP squalene

  7. Formation of cholesterol from squalene Contains rings multistep

  8. Formation of cholesterol esters 3 3 CH3 - (CH2)n

  9. Cholesteryl esters In tissues: Acyl-CoA + cholesterol cholesteryl esters + CoASH acyl-CoA – cholesterol acyltransferase (ACAT) (localized in the endoplasmic reticulum) Liver Intestine Adrenal cortex Arterial wall – accumulate in atherosclerosis

  10. Cholesteryl esters In the plasma: Phosphatidylcholine + cholesterolcholesteryl ester + lysophosphatidyl choline Lecithin-cholesterol acyltransferase (LCAT) LCAT is produced in the liver - secreted into the plasma in a lipoprotein – acts on the surface of HDL – cholesterol esters are trapped within the lipoprotein

  11. Hydrolysis of cholesteryl esters cholesteryl esterase Present: in many tissues -in lysosomes –acid pH -in the endoplasmic reticulum - neutral pH in the pancreatic juice

  12. Regulation of cholesterol synthesis high level of cholesterol inhibits de novo synthesis of cholesterol

  13. Regulation of cholesterol synthesis The gene of HMG-CoA reductase and genes of other enzymes in the uptake and synthesis of cholesterol and unsaturated fatty acids are controlled by sterol regulatory element-binding protein (SREBPs) -gene regulation only by the amino-terminal domain of SREBP high cholesterol cholesterol binds to SCAP (SREBP cleavage-activating protein) -cholesterol sensor- SREBP is bound to SCAP – SREBP is inactive low cholesterol SREBP – SCAP complex migrates to Golgi in vesicles - cleavage by two proteases - release of amino-terminal domain into the cytosol -entry into the nucleus- activation of transcription of target genes

  14. Regulation of cholesterol synthesis Covalent modification of the enzyme (phosphorylation-dephosphorylation unknown mediator

  15. Digestion and absorption of lipids Adult human digests: ~60-150 g lipid/day 90 % of the ingested lipids: triacylglycerols Problem: poor water solubility limited accessibility to digestive enzymes

  16. Digestion and absorption of TG involve: -enzymatic hydrolysis -emulsification -uptake of the products by epithelial cells -TG resynthesis and packaging into chylomicrons -chylomicron release into the lymphatic system

  17. Hydrolysis of triacylglicerol Pancreatic lipase - major enzyme for TG hydrolysis - products are fatty acids and 2-monoacyl-glycerol - colipase (12kDa) binds to lipase and prevents inhibition of lipase by bile acids - acts on bile acid micelles Lingual and gastric lipase - acts in the stomach - 30 % of total TG hydrolysis - slow – surface is limited - some dispersion of lipids -aided by stomach peristaltics

  18. Pancreatic enzymes for digestion of lipids Lipase -Triacylgycerol Products: fatty acids (R1-COOH R3-COOH) 2-monoacyl-glycerol Lipid esterase – requires bile acids -Cholesterol esters, monoacylglycerol Phospholipases– requires bile acids

  19. Bile salts • Biological detergents • Polar derivatives of cholesterol • Synthesized in the liver, secreted into the bile with phospholipids and cholesterol and released into the small intestine • Form micelles accommodating phospholipids and fatty acids – mixed micelles water-insoluble cholesterol is accommodated (“solubilized”) excess cholesterol – stone formation in the gallbladder Effects of bile acids: -Detergents- solubilize dietary lipids

  20. Bile acids Cholesterol Tauro ~ Glyco ~ -Side chain oxidation -double bound reduced - +OH Tauro ~ Glyco ~ Cholic acid Primary bile acids Chenodeoxycholic acid taurine glycine Glycocholic acid Taurocholic acid Conjugation to glycine or taurine Glycochenodeoxycholic acid Taurochenodeoxycholic acid

  21. Glycocholic acid Taurocholic acid Glycochenodeoxycholic acid Taurochenodeoxycholic acid Primary bile salts Na, K salts From liver to gall bladder upon hormonal stimulus Small intestine - detergent *Deconjugation *OH - 7’ Secondary bile acids Deoxycholic acid Litocholic acid Secondary bile salts Na, K salts

  22. The enterohepatic circulation of bile salts

  23. Transporters for the enterohepatic circulation of bile salts

  24. Absorption fatty acids – diffusion transporter (for long chain fatty acids) cholesterol – channel ABC transporters to pump cholesterol back to the lumen Medium and short chain fatty acids enter capillaries, long chain fatty acids are used to TG synthesis and chylomicron formation in intestinal epithelial cells Chylomicrons enter lymph vessels – travel to the systemic venous system – TG (long chain fatty acids) reach adipose tissue and muscle before coming into contact with the liver – FA metabolized and stored (liver is protected from lipid overload)

  25. Transport of lipids Problem: hydrophobic lipids in an aqueous environment Solution: More insoluble lipids (triacylglycerols & cholesterol esters) associated with more polar ones (phospholipids, cholesterol) and proteins LIPOPROTEIN COMPLEX

  26. Transport of lipids • FFA – free fatty acids • Unesterified long-chain fatty acids (less than 5 % of the total lipids) TRANSPORT - NOT BY LIPOPROTEINS

  27. Metabolism of plasma FFA Adipocytes Triglicerides HORMONE SENSITIVE LIPASE FFA FFA / ALBUMIN Liver Extrahepatic tissues OXYDATION (ENERGY) SYNTHESIS OF TISSUE LIPIDS SYNTHESIS OF TISSUE LIPIDS KETONE BODIES

  28. FFA – FREE FATTY ACIDS Source: *Lipolysis of TG in adipose tissue *Lipoprotein lipase during uptake of TG from plasma into tissues Transported in albumin binding 0.1 - 2 meq/mL 6-16 mg/100 ml

  29. FFA – FREE FATTY ACIDS Level: Low – fully fed condition High –fully fasting state vigorous excersise uncontrolled diabetes Between meal Falls - after eating Rises - prior to the next meal

  30. Lipoproteins Generally: in the central core: nonpolar lipids (triglicerides and cholesterol ester) surrounded by phospholipids, unesterified cholesterol and apoproteins Nonpolar groups Interact with lipids in the central core Polar groups Interact with water and ions of the plasma Amphipathic molecules LDL receptor: recognize B-100 apoprotein (or apo E)

  31. Transport of triglycerides from the intestine to the extrahepatic tissues and the liver. CHYLOMICRONS Adipose, Muscle, Heart

  32. Chylomicron & VLDL Chilomicron clearance from the blood is rapid Half time < 1 hour Adipose tissue Heart Muscle LIPOPROTEIN LIPASE Bound to heparan sulfate on the wall of capillaries

  33. LIPOPROTEIN LIPASE -Phospholipids & apo C-II are cofactors Chylomicrons & VLDL provide both the substrate (TG) and cofactors (PL, apo C-II) • in heart • Km for TG low • in adipose tissue (activated by insulin) • Km is 10 times greater (in starvation TG heart enzyme remains saturated; the same during lactation in mammary gland

  34. Transport of triglycerides from the liver to the extrahepatic tissues. VLDLTransport of cholesterol. LDL, HDL

  35. VLDL released from the liver (Apo B100) - precursor of LDL too in tissues lipoprotein lipase IDL (relatively rich in cholesterol) IDL disappears from the blood within 2-6 hours In the liver - it binds to LDL receptors -affinity for apo E is higher than for B100 - endocytosis by the liver rest in the circulation apo E Converted to LDL VLDL

  36. Extrahepatic tissues VLDL Cholesterol Cholesterol esters Nascent HDL TG LCAT LCAT PL ApoA ApoC Lipids Lipids HDL2 HDL3 Apoproteins Apoproteins TG/Cholesterol á Uptake by the liver E, C VLDL Chylomicron

  37. TRANSPORTS OF CHOLESTEROL FROM TISSUES TO THE LIVER Nascent HDL – secreted by the liver (and the intestine) PL bilayer + apo C, apo A Lecithin-cholesterol acyl-transferase (LCAT) - Cholesterol esters are formed - move into the hydrophobic interior of PL - bilayer pushes apart until spherical - pseudomicellar HDL is formed Esterified cholesterols transferred from HDL to chylomicron, VLDL, IDL by cholesterol ester transfer protein HDL

  38. TRANSPORT OF CHOLESTEROL BY HDL TG TG TG

  39. LDL receptor Recognizes Apo B-100 Apo E - the clearance of LDL from the plasma (also that of IDL - recognition factor is ApoE) (VLDL - no binding to B-100 or E receptor, as apo C-III inhibits binding) On binding to the receptor endocytotic vesicles are formed

  40. LDL receptor The expression of the LDL receptor is regulated by the need of the cell for cholesterol Down-regulated – when sufficient cholesterol is available Up-regulated – when the cell requires additional cholesterol

  41. LDL receptor • LDL receptors • Liver • Ovary • Adrenal cortex • Cholesterol metabolism is controlled by cholesterol released from LDL

  42. Regulation of cholesterol level in humans • Plasma cholesterol – in lipoproteins Normal cholesterol concentration: 3.1 – 5.7 mmol/L (120-220 mg/100 ml) (65 % is esterified) After an overnight fasting no CHYLOMICRONS 70 % of cholesterol in LDL

  43. Regulation of cholesterol level in humans Cholesterol free diet → 10 to 25 % decrease in plasma cholesterol concentration (larger decrease only through inhibition of cholesterol biosynthesis) Dietary cholesterol restriction is recommended for everyone especially for patients with hypercholesterolemia > 5.2 mmol/L greater tendency to atherosclerosis Saturated fatty acids → plasma cholesterol concentration increases

  44. Regulation of cholesterol level in humans STATINS – inhibitors of HMG-CoA reductase * Reduce the plasma cholesterol concentration by 30 % - 50 % * Minimum toxicity * Cardioprotective effect

  45. Regulation of cholesterol level in humans • The main route of cholesterol metabolism is the conversion to bile acids • 0.8 mmol/day of bile acids are lost (constant level in the body: 15-30 g) Bile acid – binding resin • Decreases bile acid reabsorption →increases the loss of cholesterol

  46. Regulation of cholesterol level in humans • Dietary restriction of cholesterol • Bile acid – binding resin • Cholesterol synthesis inhibitor Cholesterol for bile acid synthesis is provided by LDL →Plasma cholesterol concentration decreases

More Related