1. Contact me at kgahern@davincipress.com / Friend me on Facebook (kevin.g.ahern) 2. Download my free biochemistry book at http://biochem.science.oregonstate.edu/biochemistry-free-and-easy 3. Take my free iTunes U course at https://itunes.apple.com/us/course/biochemistry/id556410409 4. Check out my free book for pre-meds at http://biochem.science.oregonstate.edu/biochemistry-free-and-easy 5. Course video channel at http://www.youtube.com/user/oharow/videos?view=1 6. Check out all of my free workshops at http://www.youtube.com/playlist?list=PLlnFrNM93wqyTiCLZKehU1Tp8rNmnOWYB&feature;=view_all 7. Check out my Metabolic Melodies at http://www.davincipress.com/ 8. My courses can be taken for credit (wherever you live) via OSU's ecampus. For details, see http://ecampus.oregonstate.edu/soc/ecatalog/ecourselist.htm?termcode=all&subject;=BB 9. Course materials at http://oregonstate.edu/instruct/bb451 Glycerolipid and Sphingolipid Metabolism III 1. SREBP (Steroid response element binding protein) is a protein that plays a role in controlling whether or not HMG-CoA reductase is made. I will use the name SREBP generically to refer to the protein and as SREBP-ER to refer to it in the endoplasmic reticulum and as SREBP-G to refer to it in the Golgi. I also define the three components of the SREBP as "R" -regulatory (binds to SCAP), "M" - membrane portion, and "D" - DNA binding portion. SRE refers to a region of DNA bound by the D portion of SREBP. 2. When cholesterol levels in the cell fall, the SREBP-ER complex moves to the Golgi Complexe. A serine protease in the Golgi cleaves SREB-G to release the MD regions These migrate in the membrane to a metalloprotease, which clips MD to free the D region from the M region. The D region then travels through the cytoplasm and enters the nucleus, where it binds to the promoter region in front of the HMG-CoA Reductase and other genes with an SRE.. This causes HMG-CoA Reductase to be synthesized and cholesterol synthesis can then begin. 3. Cholesterol in the body is either there as a result of 1) synthesis; 2) diet; or 3) storage/recycling. 4. In the digestive system, bile acids and mechanical agitation of the stomach help emulsify fats. 5. In the intestines, hydrolysis of fatty acids from fats by lipases (pancreatic lipase), yield soapy like substances that help emulsify lipids for transport across the intestinal wall. 6. After movement across the intestine, lipids are packaged in chylomicrons. They move through the lymph system into the capillaries where they get stuck. 7. Action of lipoprotein lipase in the capillaries removes some of the fat from the chylomicrons and they shrink in size and exit the capillaries and move to the liver. They are taken up there and released, when needed as VLDLs. These travel the blood system and get converted to IDLs and ultimately LDLs. Note that cholesterol ONLY gets into cells via receptor-mediated endocytosis of the LDL at the target cell. 8. The liver is involved in sensing the body's need for lipids via LDL receptors. If it senses lipids are needed, VLDLs are packaged by the liver and released these get degraded by lipases and other enzymes to IDLs and LDLs. If the liver LDL receptor cannot detect LDLs in the blood, it continues to release more lipids in lipoprotein complexes, thus elevating the LDL concentration in the blood. 9. Defects in liver LDL receptors, such as found in familial hypercholesterolemia (a genetic disease) are a leading cause of high blood cholesterol. Other factors to consider include dietary cholesterol, cholesterol synthesis rate, and efficiciency of recycling cholesterol. Statins are drugs that inhibit HMG-CoA Reductase and reduce cholesterol by inhibiting its synthesis. 10. LDLs are referred to as "bad" cholesterol, because they are associated with formation of atherosclerotic plaques. These may form as a result of free radical (reactive oxygen) species which oxidize unsaturated fatty acids in LDLs. The immune system may attack these and form the basis of an atherosclerotic plaque. 11. HDLs, by contrast, are referred to as "good cholesterol", because they are associated with reducing levels of cholesterol. HDLs are reduced in smokers, but are increased in response to exercise. Omega 3 or omega-4 fatty acids from fish oils appear, in some cases, to reduce serum cholesterol levels. 12. If a person has high cholesterol, the first approach is to see if levels can be brought down by dietary changes. If they cannot, then drugs are used to stop 1) endogenous synthesis and/or 2) recycling. 13. Endogenous synthesis drugs target HMG-CoA Reductase. These drugs are called Statins (for example, lovastatin) and they stop the pathway that leads to cholesterol.

• published: 29 Jan 2014
• views: 304