Cardiovasculaire Geneeskunde.nl

Transintestinal cholesterol excretion: moving from mouse to man

Slides (presentatie) - Mar. 25, 2010

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

Deze inhoud is bedoeld voor medische professionals. Om dit te bekijken is registratie noodzakelijk. Registreer gratis voor onbeperkte toegang tot ons educatief materiaal.

Deel deze pagina met collega's en vrienden: