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JK_LIPID_MET_CHOLESTEROL_SYN_REGULATION_22.pdf
- 1. Prof. Dr. Jariya Kalsoom Regulation of cholesterol synthesis 10/15/22 0 Prof. dr. jariya
- 2. Prof. Dr. Jariya Kalsoom ﺑ ﺴ ﻢ ﷲ ا ﻟ ﺮ ﺣ ﻤ ﻦ ا ﻟ ﺮ ﺣ ﯿ ﻢ ا ﻟ ﻠ ّٰ ﮭ ُ ﻢ َ ا ء ِ ﻧ ﱢ ﯽ ا َ ﺳ ﺎ َ ﻟ ُ ﮏ َ ﻋ ِ ﻠ ﻤ ﺎ ً ﻧ ﺎ َ ﻓ ِ ﻌ ﺎ ً و َ ر ِ ز ﻗ ﺎ ً ط َ ﯿ ﺒ ﱢ ﺎ ً و َ ﻋ َ ﻤ َ ﻼ ً ﻣ ُ ﺘ َ ﻘ َ ﺒ ﱠ ﻼ ً O Allah, I ask you for beneficial knowledge, pure sustenance, and acceptable deeds. 10/15/22 1
- 3. Prof. Dr. Jariya Kalsoom
- 4. Prof. Dr. Jariya Kalsoom Waiting room • A middle aged man on statin therapy regularly consumes grape fruit juice in breakfast • Task: • Comment on SREBP-SCAP-INSIG Complex status in his cells
- 5. Prof. Dr. Jariya Kalsoom WAITING ROOM • A middle aged manager at food outlet regularly consumes sizzling desi ghee parathas with beef nihari and fried eggs tossed in butter • Task: • Comment on biochemical ventures towards atherogenesis by his habits. 10/15/22 4
- 6. Prof. Dr. Jariya Kalsoom Waiting room • An old woman with high blood cholesterol levels is being treated with lovastatin. • Tasks: • Comment on SREBP-SCAP-INSIG Complex in her cells 10/15/22 5 Jariya Ja riy a
- 7. Prof. Dr. Jariya Kalsoom Waiting room • A man regularly consumes whole wheat cereals in breakfast and ispagulla husk at bed time • Task: • Comment on his SREBP-SCAP-INSIG Complex in his cells 10/15/22 6
- 8. Prof. Dr. Jariya Kalsoom Mortuary 10/15/22 7 Cause of death: Cardiac arrest Age: 18 years Diagnosis: Phytosterolemia/sitosterolemia Task: Comment on her SREBP during her life time
- 9. Prof. Dr. Jariya Kalsoom Waiting room • A middle aged man with high total cholesterol is prescribed statin therapy • Task: • Comment on SREBP- INSIG-SCAP complex in his cells before start of therapy • Comment on SREBP in him after 3 months of regular statin therapy 10/15/22 8 LFTs Jariya
- 10. Prof. Dr. Jariya Kalsoom Waiting room: • A medical student regularly stops at drive thru for double cheese burger on his way to college as his breakfast • Task: • Comment on his HMG- CoA and LDL-Receptors 10/15/22 9
- 11. Prof. Dr. Jariya Kalsoom
- 12. Prof. Dr. Jariya Kalsoom Feedback inhibition Mevalonate Cholesterol 10/15/22 11
- 13. Prof. Dr. Jariya Kalsoom -P- -P- -P- -P-O + 3 Acetyl-CoA Mevalonate C6 Isopentenyl diphosphate C5 Squalene Cholesterol C27 Isopentenyldiphosphate + Dimethylallyldiphosphate Steroids Bile acids 3ATP↝3ADP CO2↝Pi Farnesyl diphosphate ↝ PPi ↝3CH3 Stage 1 Stage 2 Stage 3a Stage 3b Stage 4 Jariya Jariya Mevalonate HMG-CoA reductase
- 14. Prof. Dr. Jariya Kalsoom Sterol-dependent regulation of gene expression 10/15/22 13
- 15. Prof. Dr. Jariya Kalsoom
- 16. Prof. Dr. Jariya Kalsoom Jariya Jariya Sterol regulatory element binding proteins ER membrane DNA binding domain DNA binding domain DNA binding domain Regulatory domain Regulatory domain Regulatory domain N-terminal C-terminal Cleavage site For Proteolytic enzymes in Golgi ER lumen
- 17. Prof. Dr. Jariya Kalsoom Chromosome 22 Chromosome 17 SREPB 1a & SREBP 1c Identical except for length of N-terminal domain due to Alternative splicing SREBP-1a Rapidly dividing cells Intestine Spleen SREBP-1c Liver Adipose tissue Skeletal muscle Induced by insulin SREBP-2 Expressed constitutively in all cells Two two major proteins required for Regulation of lipid synthesis Lipogenesis Cholesterol synthesis Regulates both Lipogenesis Cholesterol synthesis
- 18. Prof. Dr. Jariya Kalsoom Chromosome 22 Chromosome 17 SREPB 1a & SREBP 1c SREBP-2 Increase expression of enzymes for NADPH Synthesis Malic enzyme [citrate shuttle] Glucose-6-phosphate dehydrogenase & 6-phosphogluconolactone [HMP shunt]
- 19. Prof. Dr. Jariya Kalsoom Active SREBP SRE SRE SRE LDL Receptor gene HMG-CoA synthase gene HMG-CoA reductase gene Increased levels of enzymes for mevalonate synthesis Increased flux through cholesterol biosynthetic pathway Increased levels of intracellular cholesterol Increased levels of LDL-receptor proteins on cell surface
- 20. Prof. Dr. Jariya Kalsoom Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Legend : SREBP SREBP SREBP2 SCAP LDL Receptor gene HMG-CoA synthase gene HMG-CoA reductase gene Golgi
- 21. Prof. Dr. Jariya Kalsoom Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Legend : SREBP SREBP SREBP2 SCAP LDL Receptor gene HMG-CoA synthase gene HMG-CoA reductase gene Golgi Low cholesterol Ca++
- 22. Prof. Dr. Jariya Kalsoom Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Legend : SREBP SREBP SREBP2 SCAP LDL Receptor gene HMG-CoA synthase gene HMG-CoA reductase gene Golgi Low cholesterol Ca++
- 23. Prof. Dr. Jariya Kalsoom Jari ya Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Legend : SREBP SREBP SREBP2 SCAP INSIG LDL Receptor gene HMG-CoA synthase gene HMG-CoA reductase gene Golgi High cholesterol
- 24. Prof. Dr. Jariya Kalsoom Jariya ER lumen INSIG ER Inactive complex Insulin induced gene-1 protein SREBP Cleavage Activating Protein
- 25. Prof. Dr. Jariya Kalsoom Jariya ER lumen INSIG ER
- 26. Prof. Dr. Jariya Kalsoom Jariya ER lumen INSIG ER
- 27. Prof. Dr. Jariya Kalsoom Jariya Cholesterol binding region ER lumen INSIG ER Jariya ER
- 28. Prof. Dr. Jariya Kalsoom Sterol-accelerated Enzyme degradation 10/15/22 27
- 29. Prof. Dr. Jariya Kalsoom 10/15/22 28 Ubiquitination Cytosol Lumen INSIG ER ER P r o t e a s o m e
- 30. Prof. Dr. Jariya Kalsoom Sterol-independent phosphorylation/dephosphorylation 10/15/22 29
- 31. Prof. Dr. Jariya Kalsoom Hormonal regulation 10/15/22 30
- 32. Prof. Dr. Jariya Kalsoom • Increased activity: • Insulin • Thyroid hormone • Decreased activity: • Glucagon • Glucocorticoids 10/15/22 31
- 33. Prof. Dr. Jariya Kalsoom Insulin Protein Phosphatase Pi Glucagon AMP activated Protein kinase ↝ P Inactive HMG-CoA P P Inactive HMG-CoA P
- 34. Prof. Dr. Jariya Kalsoom Jariya V V V V V V V V V V V V V Jariya P S R B P - 1 - c P P P SRE U ACC
- 35. Prof. Dr. Jariya Kalsoom MCQs • SCAP-INSIG complex retains SREBP in ER membrane when cholesterol is: a. High b. Low c. Borderline d. Absent
- 36. Prof. Dr. Jariya Kalsoom • SCAP-INSIG complex dissociates and allows SREBP to move to golgi when cholesterol is: a. High b. Low c. Borderline d. Absent
- 37. Prof. Dr. Jariya Kalsoom Revisiting the waiting room 10/15/22 36
- 38. Prof. Dr. Jariya Kalsoom Waiting room • A middle aged man on statin therapy regularly consumes grape fruit juice in breakfast • Task: • Comment on SREBP in his cells
- 39. Prof. Dr. Jariya Kalsoom Key: • Furanocoumarins Cyt P450 CYP3A4 Statin build up Low intra cellular cholesterol INSIG SCAP Complex will end their collaboration
- 40. Prof. Dr. Jariya Kalsoom Waiting room • An old granny with high blood cholesterol levels is being treated with lovastatin. • Tasks: • Comment on INSIG- SCAP complex in her cells 10/15/22 39 Jariya Ja riy a
- 41. Prof. Dr. Jariya Kalsoom Key: • Low intra cellular cholesterol • SCAP-INSIG complex active • Loss of INSIG inhibition on translocation of SREBP to golgi • LDL-receptor synthesis 10/15/22 40
- 42. Prof. Dr. Jariya Kalsoom Low cholesterol Ap o B1 00 Ap o B1 00 A p o B 1 0 0 Ap o B1 00 Ap o B1 00 Amino acids Fatty acids Cholesterol pool Acetyl CoA Mevalonate HMG-CoA Reductase Statin drugs Cholesterol biosynthesis J a r i y a SREBP activation LDL-receptor protein biosynthesis Endoplasmic reticulum Golgi Clathrin coated pit with LDL-receptors Clathrin recycling Key:
- 43. Prof. Dr. Jariya Kalsoom Waiting room • A man regularly consumes whole wheat cereals in breakfast and ispagulla husk at bed time • Task: • Comment on his SCAP-INSIG complex 10/15/22 42
- 44. Prof. Dr. Jariya Kalsoom 10/15/22 43 key Intestinal Lumen Jariya Lacteals ABCG5 ABCG8 NPC1L1 Cholesterol Cholesteryl ester Emulsion droplet Micelle Chylomicrons
- 45. Prof. Dr. Jariya Kalsoom key • Low cholesterol • SREBP-INSIG-SCAP complex likely to be active 10/15/22 44
- 46. Prof. Dr. Jariya Kalsoom WAITING ROOM • A middle aged manager at food outlet regularly consumes sizzling desi ghee parathas with beef nihari and fried eggs tossed in butter • Task: • Comment on biochemical ventures towards atherogenesis by his habits. 10/15/22 45
- 47. Prof. Dr. Jariya Kalsoom key • Small VLDL with more cholesterol • Slow utilization 10/15/22 46
- 48. Prof. Dr. Jariya Kalsoom Mortuary 10/15/22 47 Cause of death: Cardiac arrest Age: 18 years Diagnosis: Phytosterolemia/sitosterolemia Task: Comment on her INSIG-SCAP complex during her life time
- 49. Prof. Dr. Jariya Kalsoom Jariya ER lumen INSIG ER Key
- 50. Prof. Dr. Jariya Kalsoom
- 51. Prof. Dr. Jariya Kalsoom