CHM4116 - LipidMetabolism

• Triacylglycerols are broken down by lipases, and the products are absorbed by the intestine. Lipoproteins transport lipids between the intestines, liver, and other tissues
• Triacylglycerols

  • Water insoluble
  • triesters of fatty acids
• Digestive enzyme - water soluble
• Triacylglycerol digestion takes place at lipid water interfaces, and its rate depends on the surface area of the interface, which is increased by the mixed contraction and relaxation movements of the intestine combined with the emulsifying action of bile acids
• Bile acids

  • amphipathic detergent-like molecules that act to solubilize fat globules by dispersing them into micelles
  • are cholesterol derivatives synthesized by the liver and secreted as glycine or taurine conjugates into the gallbladder for storage.
  • Afterwards, they are secreted into the small intestine, where lipid digestion and absorption of digestion products mainly takes place
• Micelles - poorly soluble substance such as fatty acids and water come into contact
• The esterification of fatty acids in triacylglycerols are the principal storage form of energy for most organisms

  A) Lipases

  B) Phospholipases

  C) Phosphatidylcholine

  D) Glycerophosphorylcholine

  
• Interfacial activation - enzymatic activity of pancreatic lipase increases when it contacts the lipid-water interface
• Lipases

  • act at the lipid-water interface
  • Pancreatic lipase (triacylglycerol lipase) catalyzes hydrolysis of triacylglycerol at their 1 and 3 positions to form sequentially 1,2-diacylglycerols and 2-acylglycerols, together with Na+ and K+ salts of fatty acids
  • Requires mixed micelles of phosphatidylcholine, bile acids, and pancreatic coliapse
• Pancreatic colipase - 90-residue protein that forms a 1:1 complex with lipase
• The active site of the pancreatic lipase, which is contained in the enzyme's N-terminal domain, contains a catalytic triad that closely resembles that in serine proteases
• Colipase

  • binds to the C-terminal domain or lipase such that the hydrophobic tips of its three loops extend from the complex
  • forms three hydrogen bonds to the open lid, thereby stabilizing it in that conformation
• Phospholipases

  • catalyzes reactions at interfaces
  • contains a hydrophobic channel that provides the substrate with direct access from the phospholipid aggregate surface to the bound enzyme's active site
• Bile acids and fatty acid binding protein facilitate the intestinal absorption of lipids

  • The mixture of fatty acids and mono- and diacylglycerols produced by lipid digestion is absorbed by the cells lining the small intestine (intestinal mucosa)
  • Bile acids are required for the efficient intestinal absorption of the lipid soluble vitamins A, D, E, and K
• Inside the intestinal cells, fatty acids form complexes with intestinal fatty acid-binding protein (1-FABP)
• 1-FABP

  • a cytoplasmic protein that increases the effective solubility of the water-insoluble substances (fatty acids)
  • also protects the cell from their detergent like effects
  • a monomeric, 131-residue protein that consists largely of 10 antiparallel strands stacked in two approximately orthogonal sheets
• Lipids are transported as liporoteins

  • Lipoproteins - globular micelle-like articles that consist of a nonpolar core of triacylglycerols and cholesteryl esters surrounded by an amphiphilic coating of protein, phospholipid, and cholesterol
• 5 classes of Lipoproteins

  1. Chylomicrons
  2. Very low density lipoproteins (VLDL)
  3. Intermediate density lipoproteins (IDL)
  4. Low density lipoproteins (LDL)
  5. High density lipoproteins
• Chylomicrons

  • intestinal mucosal cells convert dietary fatty acids to triacylglycerols and package them, along with dietary cholesterol and are converted to lipoproteins
  • these are then released into the intestinal lymph and are transported through the lymphatic vessels before draining them into large veins which are afterwards distributed to the body through the bloodstream
• VLDL, IDL, LDL

  • synthesized by the liver to transport endogenous (internally produced) triacylglycerols and cholesterol from the liver to the tissues
• HDL

  • transport cholesterol and other lipids from the tissues back to the liver
• Lipoprotein densities increase with decreasing particle diameter because the density of their outer coating is greater than that of their inner core (HDL to Chylomicrons)
• Apolipoproteins coat lipoprotein surfaces, the protein components of lipoproteins are known as apolipoproteins or just apoproteins
• At least 9 lipoproteins are distributed in different amounts in the human lipoproteins

  • Each LDL particle contains apolipoprotein B-100 (apoB-100)
  • A 4536-residue monomer and one of the largest monomeric proteins known
  • Has a hydrophobicity approaching that of integral membrane proteins
  • It appears to cover at least one half of the particle surface
• Other lipoproteins unlike apoB-100 are water soluble and associate rather weakly with lipoproteins.

  • Has a high helix content which increases when incorporated to lipoproteins
• Apolipoprotein A-1 (apoA-1)

  • Occurs in chylomicrons and HDL
  • a 243-residue, 29-kD polypeptide
  • consists largely of tandem 22-residue segments of similar sequence
• VLDL, which transport endogenous triacylglycerols and cholesterol are also degraded by lipoprotein lipase in the capillaries of adipose tissue and muscle
• The glycerol backbone of triacylglycerols as it was resynthesized back from the released fatty acids is transported to the liver or kidneys and converted to Dihydroxyacetone phosphate
• After giving up triacylglycerols, the VLDL remnants, appear in the circulation first as IDL, then LDL. About half of the VLDL, after degradation to IDL and LDL, are taken up by the liver.
• Cell Take up LDL by Receptor Mediated Endocytosis

  • Animal cells require cholesterol, an essential component of cell membranes and produced from synthesis of taking up LDL which is rich in cholesterol and cholesteryl esters
• Receptor mediated endocytosis - a general mechanism whereby cells take up large molecules, each through a corresponding specific receptor
• May cell-surface receptors recycle between the plasma membrane and the endosomal compartment as does the LDL receptor, even in the absence of ligand
• Defects in the LDL receptor system lead to abnormally high levels of circulating cholesterol with the attendant increased risk of heart disease because it prevents the release of LDL cholesterol in the blood
• HDL transport cholesterol from the tissues to the liver

  • they remove cholesterol from the tissues
  • Assembled in the plasma from components largely obtained through the degradation of other lipoproteins
  • A circulating HDL particle acquires its cholesterol by extracting it from cell-surface membranes
• The cholesterol is converted to cholesteryl esters by the HDL-associated enzyme lecithin-cholesterol acyl-transferase (LCAT), which is activated by Apo-1. HDL therefore function as cholesterol scavengers
• The liver is the only organ capable of disposing of significant quantities of cholesterol.
• An HDL particle binds to a cell surface receptor SR-BI (scavenger receptor class B type I), and selectively transfers its component lipids to the cell. The lipid depleted HDL particle then dissociates from the cell and re-enters the circulation to be converted to bile acids
• Fatty acid oxidation - Catabolism, and a cyclic pathway which involves 4 reactions in the mitochondria

  • Fatty acyl CoA - from the cytosol and transported to mitochondria when primed and Beta oxidized
  • Acyl-CoA dehydrogenase with FAD
  • Enoyl-CoA hydratase with H2O
  • L-Hydroxyacyl-CoA dehydrogenase with NAD+
  • Thiolase

  The product produces Acetyl CoA and fatty acyl CoA is shortened by two carbons to proceed to cycles
• The lipases that will cut triacylglycerol in adipose tissue are hormone dependent such as glucagon and epinephrine. Utilizing glucagon, when glycogen runs out, fatty acids takes place
• Fatty acids are catabolized by an oxidative process that releases free energy