BPS 334 Lecture 34: Lipid Metabolism Notes

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University of Rhode Island
Biomedical and Pharmaceutical Sciences
BPS 334

How Does Dietary Cholesterol Get into the Enterocyte? 1. Exogenous cholesterol and triglycerides are simultaneously absorbed from the intestinal lumen by different mechanisms 2. Cholesterol is taken up from micelles across a regulatory channel named Niemann-Pick- C1-like 1 protein (NPC1L1) 3. A fraction of the cholesterol is pumped back into the lumen by ABCG5/G8, a geterodimeric ATP-dependent plasma membrane protein. Therefore, this cholesterol is not getting absorbed so there is not hypercholesterol 4. The remainder of the cholesterol is converted to cholesteryl esters by ACAT. This cholesterol ester is VERY important in the formation of chylomicrons and VLDL 5. Triglycerides are taken up as fatty acids and monoglycerides which are re-esterified to triglycerides by diglyceride acyltransferase (DGAT) 6. Once triglycerides and cholesteryl esters are packaged together with ApoB48, the chylomicron particle is exocytosed into the lympathics for transport to the circulation via the thoracic duct. Chylomicrons: formed in the intestine and transport dietary triglycerides. Cholesteryl esters in chylomicrons are derived mainly (75%) from biliary cholesterol, with the remainder contributed by dietary sources VLDL: formed in the liver and transport triglycerides that are synthesized endogenously Lipid Metabolism Pathway Overview: (exogenous and endogenous pathway) 1. Ingested fat passes through the stomach and continues on to the duodenum where it is then emulsified by bile 2. Bile salts are synthesized from cholesterol precursor in the liver and stored in the gallbladder. 3. Before dietary lipids can be absorbed from the GI tract, they must be emulsified or solubilized in the aqueous environment of the intestinal tract and this is facilitated by the action of bile salts forming “micelles” 4. The bile salts micelles renders fats and cholesterol accessible to pancreatic lipases leading to fat digestion into free fatty acids, phospholipid end products and free cholesterol. 5. Long-chain dietary fatty acids are packaged into micelles in the small intestine 6. Micelles are then taken up by intestinal mucosal cells and used in the synthesis of chylomicrons 7. Nascent (immature) chylomicrons enter the blood at the thoracic duct. 8. HDL donates apoproteins to nascent chylomicrons (ApoCII and ApoE). HDL are synthesized primarily in the liver 9. LPL (lipoprotein lipase) is activated by ApoCII allowing triglycerides in the lipoprotein to be broken down 10. The resultant free fatty acids and diglycerides are taken into the adjacent tissue cell (for instance: adipose tissue) and either utilized or stores 11. Chylomicrons then donate ApoCII to HDL in the bloodstream and become chylomicron remnants 12. The chylomicron remnant is then taken up by the liver. ApoproteinB-48 binds to its receptor on a liver cell and the lipoprotein is endocytosed 13. The chylomicron remnant’s components are then used to synthesize a new lipoprotein: nascent VLDL 14. The synthesis of nascent VLDL involves the inclusion of apoprotein B100 15. In the blood, HDL then donates two apoproteins to the lipoprotein (ApoCII and ApoE) yielding a mature VLDL 16. LPL (lipoprotein lipase) is activated by Apoprotein CII, allowing triglycerides in the lipoprotein to be broken down 17. The resultant free fatty acids and diglycerides are taken into the adjacent tissue cell and either utilized or stored 18. VLDL then donates ApoCII to HDL in the blood-stream and becomes IDL 19. As IDL becomes less dense through the loss of triacylglycerols, they are considered LDL (remodeled at the liver and transformed into LDL) 20. The function of LDL is to deliver cholesterol to cells where it is used in membranes or for the synthesis of steroid hormones. 21. Cells take up cholesterol by receptor-mediated endocytosis. 22. LDL binds to a specific LDL receptor and is internalized in an endocytic vesicle. 23. Some of the LDL’s enter the subendothelial space of arteries, are oxidized, and then are taken up by macrophages, which become foam cells. Assembly and Secretion of ApoB-Containing Lipoproteins: dependent on the availability of apolipoprotein B and triglycerides as well as the activity of microsomal triglyceride transfer protein (MTP) 1. ApoB proteins (48 or 100) are synthesized by ribosomes and enters the lumen of the ER 2. If triglycerides are available, the apoB protein is lapidated by the action of microsomal triglyceride-transfer protein (MTP) in two steps, accumulating triglyceride as well as cholesteryl ester molecules to the core of the particle. 3. The resulting chylomicron or VLDL particle is secreted by exocytosis into the lympathics by enterocytes (Chylomicrons) or into the plasma by hepatocytes (VLDL) 4. In the absence of triglycerides, the apoB protein is degraded Editing ApoB mRNA: Key Event to Differentiate Chylomicron and VLDL Metabolism 1. The apoB gene is transcribed in both the intestine and the liver 2. In the intestine, but NOT THE LIVER, a protein complex containing apoB editing complex- 1 (apobec-1) modifies a single nucleotide in the apoB mRNA 3. As a result, the codon containing the nucleotide is converted to a premature stop codon. 4. The protein that is synthesized in the intestine (apoB48) therefore is only 48% as long as the full-length protein that is synthesized in the liver (apoB100) because there is no editing that is done to the protein in the liver. What happens Upon Completion of Hydrolysis to LPL (Chylomicrons and VLDL): 1. Upon completion of hydrolysis, chylomicrons and VLDL lose affinity for lipoprotein lipase (LPL) 2. When an HDL particle is encountered, ApoCII is transferred back to HDL particles in exchange for ApoE. 3. The resulting particles are chylomicron and VLDL remnants (IDL) 4. These remnants are small enough to enter the space of Disse. These remnant particles are then SEQUESTERED in the space of disse by binding to high-molecular-weight heparin sulfate proteoglycan (HSPG) molecules (a new tag on the molecules) 5. This is followed by action of hepatic lipase, which promotes lipolysis of some residual triglycerides in the core of the remnant lipoproteins and the release of fatty acids 6. Uptake of remnant lipoprotein particles into hepatocytes is mediated by the LDL receptor (LDL-R), the LDL-receptor-related protein (LRP), a complex formed between LRP and HSPG, or HSPG alone Formation and Clearance of LDL Particles: 1. ApoB48-containing chylomicron remnants will be completely removed from the plasma 2. Only 50% of VLDL-remnants (IDL) will be cleared by remnant-receptor pathway. The remainder of IDL is converted to LDL by hepatic lipase. a. IDL particles interact with hepatic lipase (80%) to become denser and cholesteryl ester-enriched. b. As a result, both ApoE and ApoCII lose affinity for the particle and are transferred to HDL, leaving only ApoB100. c. Binding of ApoB100 to LDL receptors on hepatocytes or other cell types promotes LDL internalization of endoyctic vesicles and fusion of the vesicles with lysosomes. d. In the liver (hepatocytes), LDL is converted into bile acids and secreted into the intestines e. In non hepatic tissues, LDL is used in hormone production, cell membrane synthesis, or stored f. In hepatic tissues, LDL receptors are recycled to the cell surface, whereas lipoprotein particles are hydrolyzed to amino acids (from ApoB100) and free cholesterol (from cholesteryl esters) g. Intrac
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