Lipid

Aka: Lipid, Cholesterol, Total Cholesterol, Sphingolipid, Lipoprotein, Chylomicron, Glycolipid

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II. Definitions

  1. Lipids
    1. Organic molecules containing Hydrocarbons
    2. Poorly soluble in water, but soluble in organic solvents
    3. Examples include free Fatty Acids, Triglycerides, phospholipids
  2. Cholesterol
    1. Lipid precursor for steroid Hormones, bile acids and Vitamin D
  3. Triglyceride
    1. Lipid composed of three molecules of Fatty Acid esterified to Glycerol
    2. Triglycerides are a non-polar fat synthesized from Carbohydrates or ingested
    3. Triglycerides are High Energy Molecules that are stored for later use in animal adipose cells (fat cells)
  4. Lipoprotein
    1. Serum Proteins that solubilize hydrophobic lipids (Triglycerides, Cholesterol esters)
      1. Key to lipid transport through the blood stream
    2. Contain two components
      1. Spherical hydrophobic core (Cholesterol, Triglycerides)
      2. Hydrophilic shell (phospholipids, apolipoproteins)
    3. Classified by density (Chylomicrons, VLDL, LDL, HDL)
      1. In general, Lipoproteins transport Cholesterol and Triglycerides to and from the liver and other tissues
      2. Chylomicrons and VLDL transport both Triglycerides and Cholesterol esters
      3. Low Density Lipoproteins (LDL) primarily transports Cholesterol
      4. High Density Lipoproteins (HDL) is a Cholesterol scavenger
        1. Returns excess Cholesterol and LDL remnants back to the liver
  5. Sphingolipid
    1. Similar to Triglycerides (but with a Serine backbone and other slight structural changes)
    2. Includes sphingosine and ceramides, of which sphingomyelin is a key component of myelin nerve sheath

III. Physiology: Lipid Metabolism

  1. FatMetabolism.png
  2. See Fat Metabolism
  3. Fats are a high energy (9 kcals/g), long term energy source
  4. Intestinal Digestion and Absorption of fats
    1. Duodenal bile salts emulsify fats into small droplets
    2. Enzymatic breakdown by intestinal and pancreatic agents
      1. Lipase (intestinal, pancreatic) lyse Triglycerides to monoglycerides and free Fatty Acids
      2. Esterases lyse Cholesterol to free Cholesterol and free Fatty Acids
      3. Phospholipases lyse phospholipids to free Fatty Acids and lysophospholipids
    3. Small micelles form from fat breakdown products and bile acids
    4. Micelles carry fats to intestinal epithelial cell brush border for absorption
      1. Bile salts allow for absorption of polar lipids
    5. Bile salts are reclaimed by enterohepatic circulation
      1. Bile salts absorbed in ileum are transported back to liver via portal circulation
  5. Intestinal Epithelial cell Processing of Fats
    1. Re-forming of lipids
      1. Triglycerides re-form from free Fatty Acids and monoglycerides
      2. Cholesterol esters re-form from free Fatty Acids and Cholesterol
      3. Phospholipids re-form from free Fatty Acids and lysophospholipids
    2. Chylomicrons
      1. Form from Apoproteins combined with Triglycerides, Cholesterol to phospholipids
      2. Chylomicrons move from intestinal epithelial cells into Lymphatic System
      3. Triglycerides are carried by Chylomicrons to Muscle and fat cells
        1. Triglycerides are lysed into free Fatty Acids by capillary Lipoprotein Lipase
        2. Free Fatty Acids are then absorbed by Muscle and fat cells
        3. Triglycerides reform from free Fatty Acids within Muscle and fat cells (esterification)
    3. Other Lipoproteins (VLDL, LDL, HDL)
      1. Form from Cholesterol processing in the liver

IV. Physiology: Lipid Functions

  1. Energy Source
    1. Fatty Acids are stored for later energy use, bound to Glycerol, as Triglycerides within fat cells
      1. Fatty Acids are synthesized by adding, in repeated cycles, 2 carbon atoms (acetyl CoA)
      2. Fatty Acid synthesis occurs in the cytoplasm of most cells to supply numerous uses including cell wall
    2. Fatty Acids are burned as fuel in the Kreb Cycle (TCA Cycle)
      1. Fatty Acids are degraded (oxidized) by removing, in repeated cycles, 2 carbon atoms (acetyl CoA)
      2. Energy from each extracted acetyl coA enters the Kreb Cycle
      3. Each Kreb Cycle generates NADH and FADH2 (total energy 17 ATP)
    3. Fats offer high energy stores (9 KCals/g) compared with Carbohydrates and Proteins (4 kcals/g)
      1. Triglycerides are non-polar and bind less water (more compact than Carbohydrates, Proteins)
      2. Each triglcyeride contains 3 Fatty Acids, each with 16 to 18 carbons (fueling 24-27 Kreb Cycles)
  2. Cell Membrane Components
    1. Cholesterol, Glycolipids and phospholipids are important components of cell membranes
  3. Cholesterol Derivatives
    1. AdrenalFunction.png
    2. CholesterolDerivedSteroidHormones.png
    3. Cholesterol
      1. Cholesterol is a sterol ring structure (four interlinked aromatic rings) critical in physiology
      2. Cholesterol may either be ingested or synthesized
      3. Cholesterol synthesis (primarily in the liver)
        1. Acetyl CoA is converted to isoprene (5 carbon structure)
        2. Isoprene is combined with other isoprene molecules to form 10, 15 and 30 carbon rings
        3. Cholesterol (27 carbons) is among many Isoprenoids (isoprene derived molecules)
          1. Others Isoprenoids include all fat soluble Vitamins (A, D, E and K) and Coenzyme Q
    4. Steroid Hormones are derived from Cholesterol with unique side chains at the C17 carbon
      1. Pregnenolone (21 carbons) is derived from Cholesterol
        1. Sex Hormones, mineralcorticoids and Glucocorticoids are all formed from Pregnenolone
      2. Sex Hormones
        1. Testosterone (primarily synthesized in the Testes)
        2. Estrogen and Progesterone (primarily synthesized in the ovary)
        3. Dehydroepiandrosterone and Androstenedione (androgens synthesized in the Adrenal Cortex)
      3. Mineralcorticoids (e.g. Aldosterone, synthesized in the Adrenal Cortex)
      4. Glucocorticoids (e.g. Cortisol, synthesized in the Adrenal Cortex)
    5. Other Cholesterol derivatives and related Isoprenoids
      1. Bile Acids (derived from Cholesterol)
      2. Fat Soluble Vitamins (Vitamin A, Vitamin D, Vitamin E, Vitamin K)
      3. Coenzyme Q
  4. Fatty Acid Derivatives (esp. Arachidonic Acid Derivatives)
    1. FattyAcidDerivatives.png
    2. General
      1. Basic structure is a 5 carbon ring "head" with two 6 to 9 carbon chain "legs"
      2. Functions vary by specific molecule, but function in general is summarized here
    3. Thromboxanes
      1. Increase Platelet aggregation
    4. Leukotrienes
      1. Leukocyte chemotaxis
    5. Prostacyclin
      1. Inhibits Platelet aggregation
      2. Vasodilates
    6. Prostaglandins
      1. Contracts Smooth Muscle (e.g. Vasoconstriction, bronchoconstriction, uterine contraction)
      2. Increases inflammatory response as well as pain and fever
  5. Lipoproteins
    1. Serum Proteins that solubilize hydrophobic lipids (Triglycerides, Cholesterol esters)
      1. Key to lipid transport through the blood stream
      2. Altered Lipoprotein metabolism may result in Hyperlipidemia and increased Cardiovascular Risk
    2. Contain two components
      1. Spherical hydrophobic core of Cholesterol ester or Triglycerides
      2. Hydrophilic shell of phospholipids, Cholesterol and apolipoproteins
    3. Classified by density
      1. Chylomicrons
        1. Lipoproteins carrying Triglycerides and Cholesterol esters from the Small Intestine via Lymphatics to central circulation
        2. Transport Triglycerides to the fat cells and Muscle, and remaining Cholesterol to the liver
      2. Very Low Density Lipoproteins (VLDL)
        1. Similar to Chylomicrons (which have the same density), carrying both Triglycerides and Cholesterol esters
        2. Very light (0.93 to 1.006 g/ml), large (30-80 nm) Lipoproteins whose cores are primarily Triglycerides
        3. Surface is a phospholipid and Cholesterol monolayer with embedded apolipoprotein B, E and C
        4. Transport Triglycerides from the liver to Muscle and fat cells
          1. First Triglycerides and Apo C are off-loaded
          2. Next VLDL becomes intermediate density Lipoprotein (IDL)
          3. Next LDL Cholesterol forms
      3. Low Density Lipoproteins (LDL)
        1. Cholesterol laden particles for transport from liver, throughout the body (see Cholesterol function above)
        2. Small (18-25 nm) and light (1.019 to 1.063 g/ml) Lipoproteins
        3. Primarily contain a core of Cholesterol esters and a lower concentration of Triglycerides
        4. LDL transports Cholesterol esters from the liver throughout the body
        5. Phospholipid monolayer surface contains a single Apolipoprotein A100
      4. High Density Lipoproteins (HDL)
        1. HDL is synthesized in the liver as empty, non-lipid bound Proteins (apolipoprotein A1)
          1. Start as the smallest (4-13 nm) and most dense (>1.063 g/ml) Lipoproteins, without a Cholesterol core
        2. HDL is a Cholesterol scavenger returns excess Cholesterol and LDL remnants back to the liver, for bile synthesis
        3. HDL also transports apolipoproteins C2 and E to and from Triglyceride rich Lipoproteins
        4. Lecithin-Cholesterol acyl transferase (LCAT) enzyme is bound to HDL
          1. LCAT converts free Cholesterol into more hydrophobic Cholesterol esters
          2. Cholesterol esters, in turn, are sequestered into Lipoproteins
  6. Sphingolipids
    1. Sphingolipids.png
    2. Similar to Triglycerides with 2 exceptions
      1. Serine backbone (with a NH2 at the middle carbon) instead of a Glycerol backbone
      2. First carbon group is a COOH instead of CH2-OH
    3. Sphingosine
      1. Analogous to a monoglyceride, with the first Serine carbon attached to a Fatty Acid (palmitoyl CoA)
    4. Ceramide
      1. Analogous to a diglyceride, with the first 2 Serine carbon chains attached to Fatty Acids
      2. Ceramide serves as a base for many molecules with different attachments at the third carbon
        1. Sphingomyelin (Choline at the third carbon), a key component of the Myelin Sheath of nerves
        2. Glycolipids (sugar-lipid combinations)
          1. Cerebroside (Glucose or Galactose at the third carbon)
            1. Sulfatides contain Galactose with an attached sulfate
          2. Ganglioside (Oligosaccharide, with multiple linked sugars at the third carbon)
            1. Also contain sialic acid (N-acetyl neuraminic acid, NANA), an 11-carbon amino-sugar
          3. Globoside
            1. Similar to Gangliosides, but without sialic acid

V. Precautions

  1. Total Cholesterol <175 mg/dl in elderly: Increased mortality
    1. Schupf (2005) J Am Geriatr Soc 53:219-26 [PubMed]

VI. Components

  1. LDL Cholesterol
  2. VLDL Cholesterol
  3. HDL Cholesterol

VII. Patient Education

  1. Mnemonic: Lower L-DL, Higher H-DL

VIII. References

  1. Goldberg (2001) Clinical Biochemistry, Medmasters, Miami, p. 17-23
  2. Guyton and Hall (2006) Medical Physiology, 7th Ed, Elsevier Saunders, Philadelphia, p. 829-58

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