Aster-dependent non-vesicular transport facilitates dietary cholesterol uptake

Abstract

Intestinal cholesterol absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1), the target of the drug ezetimibe (EZ), 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, bridging NPC1L1 at the plasma membrane (PM) and ACAT2 in the endoplasmic reticulum (ER). Loss of NPC1L1 diminishes accessible 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 ER cholesterol depletion, including decreased cholesterol ester stores and activation of the SREBP-2 transcriptional pathway. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, we show that the 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.

T cell cholesterol transport is a metabolic checkpoint that links intestinal immune responses to dietary lipid absorption

“…In liver, Aster-A and Aster-C together facilitate HDL-cholesterol uptake and biliary excretion (6). In the intestinal epithelium, Aster-B and Aster-C are required for dietary cholesterol uptake (15). However, Aster-A mRNA expression in SI is 26.3-and 7.6-fold lower than Aster-B and Aster-C respectively (15), and it does not respond to dietary fat intake (Fig.…”

“…We have shown previously that, in cells such as hepatocytes and enterocytes, Aster proteins mobilize the 'accessible' pool of cholesterol from plasma membrane (PM) to ER (6,15). Their function in lymphocytes, however, is undetermined.…”

“…Given its important role in cellular homeostasis several recent studies have focused on cellular and external cues that regulate the size of the accessible cholesterol, such as uptake of lipoprotein-derived cholesterol, activation of sphingomyelin degradation, and exposure to infection-elicited defense molecules (5)(6)(7)(8)(9)(10)(11). Potential fates of excess PM accessible cholesterol include movement to the ER for esterification or efflux to extracellular lipoprotein acceptors (6,(12)(13)(14)(15). However, the roles of this bioactive pool in PM itself are poorly defined.…”

“…Increased accessible PM cholesterol facilitates the recruitment of the GRAM domain of Asters to PM and the formation of PM-ER contact sites, through which the ASTER domain channels excess cholesterol to the ER (12). Aster family proteins are required for the efficient internalization, storage, and utilization of diet-and lipoprotein-derived cholesterol in various metabolic and steroidogenic organs (6,12,15,21). Their function in other cell types remain to be elucidated.…”