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Transintestinal Cholesterol Excretion: Moving from Mouse to Man
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Transintestinal Cholesterol Excretion: Moving from Mouse to Man.
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Figure 26.21
An atherosclerotic
plaque.
A plaque (marked by an
arrow) blocks most of the
lumen of this blood
vessel. The plaque
is rich in cholesterol.
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Simplified scheme of cholesterol homeostasis
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The first step in reverse cholesterol transport (RCT) is cholesterol efflux from peripheral cells
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Reverse cholesterol transport
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RCT Paradigm
The only pathway for cholesterol to leave the body is hepatobiliary secretion either as free cholesterol or after conversion in the form of bile salt.
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Cholesterol balance (µmol/day.100 g body wt) in FVB mice
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Cholesterol balance (µmol/day.100 g body wt) in FVB mice
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Cholesterol fluxes (mg/day.70 kg body wt) in man
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Cholesterol balance (µmol/day.100 g body wt) in FVB mice
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Abcb4 (mdr2) and Abcg8 -/- mice show strongly decreased biliary cholesterol secretion
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Van de Velde et al Gastroenterology 2007
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ABCG5/G8 knock-out humans show decreased fecal neutral sterol excretion
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Conclusion
Passage through the liver is not the only pathway for cholesterol to leave the body!
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Intestine perfusion
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Isolated intestinal perfusion
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Slide 18
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Intestinal cholesterol secretion
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Cholesterol fluxes (µmol/day.100 g body wt) in FVB mice
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Summary I
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What is the origin of secreted cholesterol ?
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Q
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Presence of phospholipid is the dominant factor for induction of cholesterol secretion
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Dietary PC stimulates neutral sterol secretion in man
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Q
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Important genes in intestinal cholesterol trafficking
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High fat diets affect transintestinal cholesterol transport (TICE)
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PPARΔ ACTIVATION INDUCES TRANSINTESTINAL CHOLESTEROL SECRETION
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Expression of important genes in intestinal cholesterol trafficking does not correlate with TICE
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PPARΔ activation increases expression of Rab9
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Possible role of RAB9 in TICE
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Summary II
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Q
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Use of stable isotopes to determine body cholesterol fluxes
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Cholesterol flux from plasma to feces
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Cholesterol Absorption
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Cholesterol Synthesis
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Validation of the approach in mouse models
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Abcg5-/- mice
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Q
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Experimental Setup
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Fractional enrichment in bloodspots of IV and orally administered cholesterol
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Cholesterol absorption in Humans
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Slide 45
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Fractional enrichment in bloodspots of IV and orally administered cholesterol
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Simplified model of cholesterol fluxes
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Simplified model of cholesterol fluxes
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THE SYSTEMS BIOLOGY APPROACH
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Simplified model of cholesterol fluxes
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Simplified model of cholesterol fluxes
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Determination of isotope enrichments in blood, bile and feces using SAAMII modelling and flux balance analysis yields:
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Fecal neutral sterol excretion
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LXR agonist strongly stimulates TICE
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Absence of cholesterol transporter ABCG5 decreases TICE
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Summary III
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Next Steps
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