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