Regulation of cholesterol synthesis pathway. Cholesterol Synthesis. Cholesterol biosynthesis. Regulation of HMG CoA reductase activity

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1 Cholesterol Synthesis Main function: ation of steroid nucleus Substrate: cytoplasmic acetyl CoA Endproduct: cholesterol Location: cytoplasm Regulation of cholesterol synthesis pathway HMG CoA reductase catalyzes the rate-limiting step. The synthesis and the activity of the HMG-CoA reductase enzyme is controlled in the liver cell. Cholesterol biosynthesis cyto.acetyl CoA isopentenyl (5C) HMG CoA NAD:H mevalonate Cholesterol synthesis pathway CH 3 -C ~ S-CoA c. acetyl CoA CH 3 -C= acetoacetyl CoA CH 2 -C ~S-CoA geranyl (10 C) farnesyl (15C) cholesterol squalene (30C) HMG-CoA CH 3 -C-CH 2 -C CH 2 -C ~ S-CoA HMG CoA reductase CH 3 -C-CH 2 -C CH 3 -C-CH 2 -C CH 2 -C ~ S-CoA CH 2 -CH 2 HMG-CoA mevalonate 2 NAD:H 2 NAD H + Regulation of HMG CoA reductase activity cholesterol and mevalonate directly inhibit HMG-CoA reductase activity insulin binding indirectly stimulates HMG-CoA reductase activity glucagon binding indirectly inhibits HMG-CoA reductase activity

2 Inhibition of HMG CoA reductase synthesis 1 cholesterol esters in blood bind to Low Density Lipoprotein LDL-chol. 2 LDL-cholesterol complex binds LDL receptor protein in liver cell membrane. liver cell Inhibition of HMG CoA reductase synthesis 3. LDL-cholesterol-ester complex is transported into liver cell by LDL receptor protein in liver cell membrane. 4. LDL-chol.ester drops off LDL receptor protein and binds to cytoplasmic receptor protein. Control of enzyme synthesis LDL membrane receptors LDL-cholesterol cytoplasmic receptor protein Control of enzyme synthesis 5. Cholesterol derivative and c. recept. protein enter nucleus, bind to DNA and prevent RNA polymerase from transcribing the gene coding for HMG-CoA reductase. Controlling enzyme synthesis Hormonal regulation of cholesterol synthesis Glucagon binds to receptor in liver cell membrane, stimulating cam ation LDL-cholesterol binds to cyto. receptor protein and enters nucleus cholesterol binds to DNA; inhibits transcription of gsene coding for HMG CoA reductase cam activates RTEIN KINASE which inactivates rate-limiting HMG CoA reductase enzyme, decreasing cholesterol synthesis

3 Hormonal regulation of cholesterol synthesis Insulin binds to its receptor protein in liver cell membrane, and stimulates irs-1 ation. irs-1 activates HMG CoA reductase enzyme, increasing rate of cholesterol synthesis Hormone action insulin binds glucagon binds cam irs-1 G AT active HMG CoA reductase inactive protein kinase inactive Glucagon binding results in cam ation active cam rotein kinase inactive HMG CoA reductase HMG ~ S-CoA mevalonate + 2 NAD:H 2 NAD + HMG ~ S-CoA 2 NAD:H no product Insulin binding decreases [cam] in cell insulin binds G irs-1 adenyl cyclase AT cam phosphodiesterase AM Insulin binding to cell stimulates cholesterol synthesis active protein kinase inactive HMG CoA reductase HMG ~ S-CoA mevalonate 2 NAD:H 2 NAD +

4 Activated isoprenes Activated isoprenes mevalonate isopentyl pyrophosphate --~- --~- dimethylallyl pyrophosphate isopentyl pyrophosphate --~- --~- dimethylallyl pyrophosphate Condensation of activated isoprenes Derivatives of cholesterol pathway intermediates --~- --~- geranyl ~ + --~- ubiquinone retinal (Vit. A) cholecalciferol (Vit.D) menadione (Vit. K) cholesterol cholesterol ester CH 3 - ( CH ) 14 - C - 2 cholesterol palmitate

5 Steroid hormones testosterone cholesterol CH 3 C = progesterone H H estradiol Bile acids H C= - cholic acid - bile acids are derivatives of cholic acid Bile acids - glycine is condensed through C - to produce glycocholic acid - 80% of cholesterol made in liver is converted to bile acids and stored in gall bladder H C= - + NH 3 CH 2 C - gly Function of bile acids - bile acids are secreted from liver and stored in the gall bladder liver - glycocholic acid emulsifies triglycerides in the small intestine liver Function of bile acids gall bladder stomach small intestine Function of bile acids fatty acids in blood stream cause gall bladder to contract releasing bile liver gall bladder stomach Fatty acids absorbed into blood through stomach wall stimulate gall bladder to contract, releasing bile. - glycocholic acid (bile acid) emulsifies triglycerides small intestine

6 Gall stones - gall stones are cholesterol & bile acids - stones pass into hepatic duct liver - passage of large gall stones is extremely painful hypercholesterolemia (too much cholesterol in blood stream) High cholesterol levels may be due to: 1. defective gene for LDL receptor protein - affected individuals are slow to clear cholesterol from blood stream 2. other factors: smoking, age, inactivity normal liver cell chol.-ldl hypercholesterolemic liver cell LDL receptor protein chol.-ldl chol.-ldl chol.-ldl chol.-ldl Atherosclerosis atherosclerosis is the ation of plaques in arteries and arterioles plaques are complex deposits of cholesterol esters and dead cells embedded in walls of artierioles Atherosclerosis damaged regions in arteriole walls trigger inflammatory response plaques at these inflamed areas more often in persons with high blood cholesterol plaques and remain when circulation of blood is sluggish laque ation healthy vessel LAQUE damage & inflammation of arteriole wall 90% blocked

7 entose shunt (phosphogluconate pathway) Main function: ation of NAD:H and pentose 4 Location in cell: enzymes found in cytoplasm Regulation: 1st enzyme, glu-6- DHase catalyzes rate-limiting step entose shunt Substrate: glucose End-product: depends on cell needs in adipose cells, NAD:H is required for lipid synthesis in rapidly dividing cells, pentose - 4 s are required for DNA synthesis H HC- H :H g NAD + H HC- NAD:H G-6- DHase = H HC-= 6-phosphoglucolactone 6-phosphogluconolactone (Lactonase) =.. H::H C= H -C- H-C-H H -C- H -C- H -C--= 6-phosphogluconate rxn probably occurs spontaneously in cell 6-hosphogluconate DHase - - C= H -C- H-C - H H -C- H -C- H -C--= NAD + = C = NAD:H H H -C- =C H -C- H -C- H -C--= ribulose-5- Hereditary deficiency of G-6- DH at least 2 different G-6- DHase isozymes in humans one isozyme is absent in many persons whose ancestors lived in malarial regions (S. Italy, parts of Africa, S.E. Asia) these individuals are asymptomatic until large demand for NAD:H

8 NAD:H provides reducing power in r.b.c. G-6- DHase g-6- + NAD + NAD:H 6-phosphogluconate NAD:H NAD + oxidant oxidant.h.h (acetyl salicylate) (reduced acetyl salicylate) Classes fatty acids triglycerides phosphoglycerides steroids sphingolipids LIIDS Components acetyl units 3 f. a. + glycerol 2 f.a. + glycerol- acetyl units sphingosine + f.a. glu AA malate malate glu g-6- f-6- glycogen r-5- Carbon skeleton gly. f-1,6-di 3-G DHA gly. DHA E pyr pyr acetyl Co A AA citrate pyr malate isocitrate AA succinate G succ.coa glu AA malate malate glu g-6- f-6- glycogen f-1,6-di NAD:H r-5-3-g DHA gly. phosphitidate c. acetyl CoA c.citrate E pyr pyr m. acetyl Co A AA citrate pyr malate isocitrate AA succinate G succ.coa Glucagon glycogen c. acetyl CoA glu g-6- NAD:H r-5- c.citrate cam f-6- f-1,6-di gly. DHA 3-G DHA gly. AA E pyr pyr acetyl Co A AA citrate malate pyr malate isocitrate malate AA succinate G succ.coa Insulin glycogen c. acetyl CoA glu glu g-6- NAD:H r-5- c.citrate f-6- gly. f-1,6-di DHA 3-G DHA gly. AA E pyr pyr acetyl Co A AA citrate malate pyr malate isocitrate malate AA succinate G succ.coa