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  • There are three main points of regulation for cholesterol absorption into the body. When the micellar particle comes in the proximity of an enterocyte, cholesterol is transported into the enterocyte through a channel recently identified as NPC1L1. A fraction of this cholesterol is pumped back out of the enterocyte into the intestinal lumen by the complex ABCG5/G8, and the remainder is esterified by the enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT) into cholesteryl esters. Reference: Altmann SW, Davis HR Jr, Zhu LJ, Yao X, Hoos LM, Tetzloff G, Iyer SP, Maguire M, Golovko A, Zeng M, Wang L, Murgolo N, Graziano MP. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science 2004;303:1201-1204.
  • Versions of lipoproteins where the core is the non polar material, triglyceride predominantly. 84% on average, with smaller amounts of other lipids and phospholipid primarily being at the surface acting as surfactant along with the proteins. Several proteins that have these code names, collectively known as apolipoproteins, protein part of a particle known as lipoproteins. Protein constitutes only a small fraction
  • Summary of lipid digestion and absorption. Pics not proportional. Begin with oil drop, and the early stages of digestion produce smaller particles, oil drop contains the lypitic material, triglycerides cholesterol esters in small amounts. The early digestive process, produces the smaller particles, emulsion droplets, consisting of triglycerides, early digestion products, and later on these small particles are broken down into still smaller ones, known as mixed micelles, consequence of bile salts combining with these materials, further digestion is also part of this process, need to get to the stage of mixed micelles that contain the monoglycerides and fatty acids that enables them to get at the surface of the absorbing cell, enterocyte, and then these arrows indicate the components that are absorbed, bile salts are resorbed and recycled, fatty acids of small size, 12 carbons, go through these cells directly, and they are polar enough, water soluble enough that they can get directly into the blood and carried by protein albumin. Have a simple short circuit way of getting through the absorbing cell and on their way. Vast majority of fatty acids are longer, have more carbons than this. Milk has short chain hydrocarbons, special fluid designed to provide nutrition for young mammals, role is to get some nutrition there fast, and other material to show up at later time, spread out the nutrient value. These short chain hydrocarbons, role of fuel into circulation at a rapid rate. Long chain fatty acids get absorbed, undergo further chemistry in enterocyte, go back to triglycerides, still being non polar substances need a lot of help to be carried around. Be big fat globules stuck inside enterocytes. They are packaged into chylomicrons, these chylomicrons are the form that these triglycerides get out of enterocyte and ultimately into blood and lymph. Idea is to start with big insoluble particles and getting down to the stage of absorption.

    2. 2. Absorption of lipidsThe end products of lipid digestion are Fatty acids Glycerol 2-Monoacylglycerol 1- Mono acylglycerol Cholesterol Lysophonpholipid
    3. 3. Stomach gastricmobility - Small Hormonal control intesti cholecytokinin ne + Gut Endocrine cells Dietary (enlarged) lipids + bicarbonate Secretin sec (in blood) re Pancreatic tes lipase secret + e s pancreas bile secret + e s Degradation of dietary lipids Gall bladder
    4. 4.  As food enters the intestine, cholecystokinin hormon is released which signals (1) the gallbladder to release bile salts and; (2) the exocrine (pancreas) to release digestive enzymes. Within the intestine, bile salts emulsify fats, which increase their accessibility to pancreatic lipase. 4
    5. 5. Figure: Bile salts. 5
    6. 6.  Bile salts are synthesized in the liver, stored in the gallbladder, secreted into the small intestine, resorbed in the ileum, and returned to the liver via the enterohepatic circulation. Under normal circumstances, 5% or less of luminal bile salts are excreted in the stool. 6
    7. 7. Figure: Enterohepaticcirculation. The bile saltsare reabsorbedfarther down theintestinal tract andreturned to theliver by theenterohepaticcirculation. 7
    8. 8. Fate of dietary lipids: TGs: FFA + glycerol FFA: - FFA from TGs muscle (energy production) adipocytes( re esterified to TGs) Glycerol : Glycerol from TGs in liver forms glycerol 3 phosphate ( glycolysis, gluconeogenesis) Chylomicron remnants: Endocytosed into liver and are hydrolysed to their component parts and recycled by the body. - If this process is decreased due to impaired binding to the receptor on liver, they accumulate in the plasma leading to type III hyperlipoproteinemia
    9. 9.  2-monoacylglycerols are reacylated to TAG via the monoacylglycerol pathway. (1) Glycerol released in the intestinal lumen is not reutilized but passes into the portal vein; (2) glycerol released within the epithelium is reutilized for TAG synthesis via the normal phosphatidic acid pathway. 9
    10. 10.  Monoacylglycerols are poor substrates for hydrolysis, so it mean less than 25% of ingested TAG is completely hydrolyzed to glycerol and FAs. Because the micelles are soluble, they allow the products of digestion to be transported through the aqueous environment of the intestinal lumen and permit close contact with the brush border of the mucosal cells, allowing uptake into the epithelium. 10
    11. 11.  TAG are further degraded to 2-monoacylglycerols and FAs as the major end products of luminal TAG digestion. Bile salts formed in the liver and secreted into the bile, permit emulsification of the products of lipid digestion into micelles together with phospholipids and cholesterol from the bile. 11
    12. 12.  Micelles are formed within the intestinal lumen and interact with the enterocyte (intestinal absorptive cells) membrane. Lipid-soluble components diffuse from the micelle into the enterocytes. 12
    13. 13. MICELLE
    14. 14. Figure: Diffusion of FFA and2-monoglycerides into the enterocytes. 14
    15. 15.  The intestinal epithelial cells resynthesize TAG and package them into nascent (new) chylomicrons for release into the circulation. Long-chain FAs are esterified to yield to TAG in the mucosal cells and together with the other products of lipid digestion, secreted as nascent chylomicrons into the lymphatics, entering the bloodstream via the thoracic duct. 15
    16. 16.  Short- and medium-chain FAs are mainly absorbed into the hepatic portal vein as FAs. Cholesterol is absorbed and dissolved in lipid micelles, and is mainly esterified in the intestinal mucosa before being incorporated into chylomicrons. Unesterified cholesterol and other sterols are actively transported out of the mucosal cells into the intestinal lumen. 16
    17. 17. Figure: Synthesis of TAG in ER andformation of chylomicrons. 17
    18. 18. Formation and secretion of (A) chylomicron in intestinal and (B) VLDL in Hepatic cell.
    19. 19. Chylomicron Formation IntestinalLymph Enterocyte Lumen Phospholipid TriglycerideWithapoB48 Cholesteryl Ester
    20. 20. Packaging for transport Lehninger et al., apolipo- 3rd ed., Fig. 17-2 proteinschylomicrons  Particles for transport of lipids PL to liver & adipocytes  Size: 0.1–1 µm  Average composition: TG (84%) chol (2%) cholE (4%) PL (8%) apolipoproteins (2%) chol PL cholE, TG
    21. 21. Summary of lipid oil digestion & absorption drop Enterocyte lipase- colipase MG 4ATPs/TG FA TGemulsion (>10C) apolipoproteins TGdroplet MG phospholipids FA BILE SALTS lipase- colipase chylomicron chylomicron FAmixed (<12C) FA BILE albuminmicelle BILE SALTS SALTS 18
    22. 22. Lipids Are Transported in the Plasma as LipoproteinsFour Major Lipid Classes Are Present in Lipoproteins. Plasma lipids consist of TAG (16%), phospholipids (30%), cholesterol (14%), and cholesteryl esters (CE) (36%) and a much smaller fraction of unesterified long-chain FAs (4%). 22
    23. 23. Figure: Lipoproteins. 23
    24. 24. Figure: Lipoprotein. 24