Feedback Regulation of Cellular Lipid Metabolism

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Feedback Regulation of Cellular Lipid Metabolism
Section 18.4
Melissa Simmons
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Feedback Regulation of Cellular Lipid Metabolism

• Cellular Crisis
• Lack of Lipids to make adequate amounts of
  membranes
• Large amounts of cholesterol that crystals form
  damage cellular structures

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Feedback Regulation of Cellular Lipid Metabolism
Continued

• Regulation pathways
• Control cellular cholesterol, fatty acids,
  phospholipids metabolism
•  

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Cholesterol Biosynthetic Pathway

• First pathway shown to exhibit end-product
  regulation
• As cellular cholesterol level rises, the need to
  import cholesterol through the LDL receptor or to
  synthesize additional cholesterol goes down

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• Rate-controlling enzyme HMG-CoA reductase
• Ester-forming storage enzyme acylcholesterol
  acyl transferase (ACAT)
• When cellular cholesterol level begins to fall
  expression of the LDL receptor HMG-CoA
  reductase increases, ACAT decreases,
  conversely

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ER-to-Golgi Transport Proteolytic Activation
Control the Activity of SREBP Transcription
Factors

• Sterol Regulatory elements (SREs) 10-base pairs
• Cholesterol-dependent transcriptional regulation
  depends on SREs in the promoters of regulated
  target genes
• Interaction of cholesterol-dependent SRE-binding
  proteins (SREBPs) with the response elements
  modulates the expression of the target genes
• Begins in the ER includes two proteins, SCAP
  insig-1, with SREBPs

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SREBP

• 3 distinct domains
• N-terminal cytosolic domain composed of a basic
  helix-loop-helix (bHLH) DNA-binding motif,
  functions as a transcription factor
• Central membrane-anchoring domain, contains two
  transmembrane ? helices
• C-terminal cytosolic regulatory domain

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SCAP

• 8 transmembrane ? helices
• Large C-Terminal cytosolic domain that interacts
  with the regulatory domain of SREBP
• 5 transmembrane helices in SCAP form a
  sterol-sensing domain
• Sterol-sensing domain in SCAP binds tightly to
  insig-1, but only at high cellular cholesterol
  levels
• Cellular cholesterol levels drop, insig-1 no
  longer bonds to SCAP, in the SCAP / SREBP complex
  can move from the ER-to-Golgi
• In the Golgi, SREBP is cleaved sequentially at
  two sites by two membrane-bound proteases, S1P
  and S2P

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Members of the Nuclear Receptor Superfamily

• Contribute to cellular and whole-body lipid
  regulation
• Some Ligands for nuclear receptors are extra
  cellular molecules that diffuse across plasma
  membrane (steroid hormones)
• Ligands generated within a cell oxysterols, bile
  acids, fatty acids and their derivatives bind to
  nuclear receptor within the same cell
• When activated, these receptors stimulate or
  suppress gene expression to ensure that the
  proper physiological levels of lipids are
  maintained

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The Cell Biology of Atherosclerosis, Heart
Attacks, Strokes

• Section 18.5

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Atherosclerosis

• most common cause of heart attacks strokes
• 75 of deaths due to cardiovascular disease in
  the U.S.
• Cholesterol-dependent clogging of the arteries
• Progressive deposition of lipids, cells, and ECM
  material in the inner layer of the wall of an
  artery
• Distortion of the artery wall leads to a blood
  clot

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Structure of an Artery

• Endothelium lines the blood vessel wall, blood
  flow
• Intima amorphous collagens, proteoglycans,
  elastic fibers
• Media layer of smooth muscle cells, contraction
  controls the diameter of the vessels influences
  blood pressure
• Adventitia layer of connective tissue cells
  that form the interface between the vessel and
  the tissue

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Infection or Trauma

• WBC adhere loosely to the luminal surface of the
  artery wall roll
• WBC -gt monocytes -gt macrophages
• Macrophages fight infection, engulf destroy
  pathogens, damaged macromolecules, infected or
  dead body cells

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Arterial Inflammation Cellular Import of
Cholesterol Mark Early Stages of Atherosclerosis

• Foam cells macrophages convert the imported
  cholesterol into the ester form, they become
  filled with cholesterol ester lipid droplets
• As macrophage foam cells accumulate in an artery
  wall, form a fatty streak
• Continued accumulation of macrophage foam cells,
  proliferation of smooth muscle cells, and
  migration of these cells from the media into the
  intima.

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Continued

• Invisible fatty streak grows bigger as the
  disease progresses, forming an early
  atherosclerotic plaque
• Cells within the center of the plaque die,
  producing a necrotic core containing large
  amounts of cholesterol esters and un-esterified
  cholesterol.
• Cholesterol crystals commonly form within a more
  advanced plaque, covered by a fibrous cap
  composed of smooth muscle cells and collagen

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Atherosclerotic Plaque Can Impede Blood Flow,
Leading to Heart Attacks and Strokes

• As an atherosclerotic plaque expands, it projects
  farther into the lumen of the vessel, narrowing
  the lumen and distorting the endothelium
• Because blood flow thought the affected artery is
  reduced and disturbed, the rate of delivery of
  nutrient-rich oxygenated blood to tissues fed by
  the artery decreases
• If the endothelial lining covering a plaque
  ruptures, a large platelet and fibrin blood clot
  can form rapidly and block the artery

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Continued

• Tissues downstream of an occlusion soon becomes
  depleted of oxygen and energy sources
• Severe occlusion of a coronary artery can cause a
  heart attack
• Occlusion of an artery feeding the brain can
  cause a stroke

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LDLR-Independent Uptake of LDL (Bad Cholesterol)
Leads to Formation of Foam Cells

• The greater the concentration of LDL in the
  artery wall, the more rapidly foam cells develop
  and accumulate to form fatty streaks
• First LDLR activity is under cholesterol
  dependent SREBP-controlled feedback regulation,
  which maintains cellular cholesterol levels
  within a narrow range
• The consequent low levels of LDLR expression
  prevents massive intracellular cholesterol buildup

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Reverse Cholesterol Transport by HDL (Good
Cholesterol) Protects Against Atherosclerosis

• HDL can remove cholesterol from cells in
  extrahepatic tissues, including artery walls
  deliver the cholesterol to the liver or by
  transferring its cholesterol to other
  lipoproteins that are ligands of hepatic
  endocytic receptors.
• The excess cholesterol can then be secreted into
  the bile and eventually excreted from the body,
  reducing foam cell formation

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Continued

• HDL itself and some plasma enzymes associated
  with HDL can suppress the oxidation of LDL
• Relaxation of the smooth muscle around an artery
  results in widening of the artery lumen and
  consequently increased blood flow, thereby
  helping to prevent ischemia and tissue damage

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Two Treatments for Atherosclerosis are based on
SREBP-Regulated Cellular Cholesterol Metabolism

• An increase in LDLR activity, especially in the
  liver, can lower LDL levels and protect against
  Atherosclerosis
• Treatments that lower cellular cholesterol levels
  in the liver will increase the expression of the
  LDL receptor and lower the LDL plasma levels

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Continued

• Two approaches used to lower steady-state hepatic
  cholesterol levels
• 1.     Reducing cholesterol synthesis
• 2.     Increasing the conversion of cholesterol
  into bile acids into the liver
• Both approaches exploit the regulatory mechanisms
  for controlling cellular cholesterol

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Statins Bile Acid Sequestrants

• Statins Drugs that bind to HMG-CoA reductase
  inhibit its activity lowering cholesterol
  biosynthesis the pool of hepatic cholesterol
• Bile Acid Sequestrants insoluble resins that
  bind tightly to bile acids in the lumen of the
  intestines, forming complexes that prevent
  absorption

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