[CRBS Seminar] Non vesicular cholesterol transport in the control of cholesterol homeostasis

Abstract:

Intestinal cholesterol absorption is an important contributor to systemic cholesterol homeostasis.  Niemann-Pick C1 Like 1 (NPC1L1) assists in the initial step of dietary cholesterol uptake.  However, how cholesterol moves downstream of NPC1L1 is unknown.  Here we show that Aster-B and Aster-C are critical for non-vesicular cholesterol movement in enterocytes. Loss of NPC1L1 diminishes accessible plasma membrane (PM) cholesterol in enterocytes and abolishes Aster recruitment to the intestinal brush border.  Enterocytes lacking Asters accumulate cholesterol at the PM and display evidence of endoplasmic reticulum (ER) cholesterol depletion.  Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia.  Aster pathway can be targeted with a small molecule inhibitor to manipulate dietary cholesterol uptake.  These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption.