Highlights Steroid Metabolism / Fat Transport
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. LDLs are called bad cholesterol because in high amounts, they can lead to formation of atherosclerotic plaques. These arise due to oxidative damage of unsaturated fatty acids in the LDL by reactive oxygen species. The immune system attacks these damaged LDLs and the resulting complex can lead to the formation of foam cells (rich in cholesterol) and finally a physical block to the flow of blood (plaque).
7. Factors increasing LDLs include smoking, obesity, and saturated fats in the diet.
8. Opposing the LDLs are the HDLs (good cholesterol). They are associated with removing cholesterol from the bloodstream and giving feedback to the liver to reduce the output of VLDLs. High levels of HDLs correlate with reduced incidences of atherosclerosis. Factors increasing HDLs include exercise and factors decreasing them include obesity and smoking.
9. SREBP (Steroid response element binding protein) is a protein that plays a role in controlling whether or not HMG-CoA reductase is made. When cholesterol is abundant, SREBP is found in the membrane of the endoplasmic reticulum linked to another protein called SCAP through the regulatory (REG) region of SREBP. When cholesterol is abundant, SCAP-SREBP-A (see video for description of SREBP-A, SREBP-B, and SREBP-C) is held in the endoplasmic reticulum's membrane by a protein called INSIG
10. When cholesterol levels in the cell fall, the SCAP/SREBA complex loses its connection to INSIG and moves to the Golgi Complex where a serine protease cleaves SREBP-A to release SREBP-B. Next, SREBP-B migrates in the membrane to a metalloprotease, which clips the DNA binding region to free SREBP-C (a transcription factor) from the membrane-bound portion. The SREBP-C has a DNA binding region then travels through the cytoplasm and enters the nucleus, where it binds to the promoter region (called SRE) in front of the HMG-CoA Reductase. This causes HMG-CoA Reductase to be synthesized and cholesterol synthesis can then begin.
11. HMG-CoA reductase can also be broken down when cholesterol is abundant. This occurs through action of another INSIG. This INSIG carries an enzyme to ubiquitinylate (put ubiquitin on) the HMG-CoA reductase. Ubiquitin is a "flag" to the cell to digest it with a protease, thus destroying it.
12. Phosphorylation of HMG-CoA reductase is also regulated by feedback inhibition (allosteric) and phosphorylation (covalent modification). Thus, HMG-CoA reductase can be regulated in multiple ways - synthesis, degradation, phosphorylation, allosterism.
13. Cholesterol is a precursor of the bile acids that are important in the digestive system for solubilizing dietary fat. Two examples include glycocholate and taurocholate.
14. Cholesterol is also a precursor of the steroid hormones. There are five groups of steroid hormones. These are all derived from pregnenolone and include Androgens (male sex hormones), Estrogens (female sex hormones,which are derived from male sex hormones), Mineralocorticoids (regulation Na/K and blood pressure), Glucocorticoids (fat/protein degradation & swelling/inflammation), and Progestagens (maintenance of pregnancy) .
15. Conversion of androgens to estrogens requires action of an enzyme known as aromatase. Since some tumors are stimulated by estrogens, such as estradiol, inhibition of them by aromatase inhibitors is a strategy of some chemotherapies.
16. Vitamin D is derived from cholesterol (ultimately). A reaction converting 7-dehydrocholesterol to Previtamin D3 requires ultraviolet light. Conversion of Previtamin D3 to Vitamin D3 occurs spontaneously. Conversion of Vitamin D3 to calcitrol requires an enzyme and the enzyme is regulated to control how much calcitrol is made. Calcitrol is the active form of vitamin D. Vitamin D is involved in regulating uptake of calcium and phosphorus, which are important for healthy bones. It may also play roles in mental health and has been shown to have anti-cancer properties.
17. Cholesterol in the body is either there as a result of 1) synthesis; 2) diet; or 3) storage/recycling. The actual levels depend on all of these.
Fatty Acid Oxidation
1. In the digestive system, bile acids and mechanical agitation of the stomach help emulsify fats.
2. 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. On the other side of the wall, they are reassembled back into fats and these are packaged in the chylomicrons.
3. Breakdown of fats occurs by action of enzymes known as lipases and these may be extracellular or intracellular.
4. Cells that store fat are known as adipocytes.
5. Fatty acid oxidation and fatty acid synthesis are almost identically the chemical reverse of each other.
6. Fatty acid oxidation proceeds in steps that mirror steps in the citric acid cycle. These include dehydrogenation, hydration, and oxidation. In the last step, a thiolytic cleavage releases acetyl-CoA and a fatty acid two carbons shorter.