Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake

Abstract

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

The nonvesicular sterol transporter Aster-C plays a minor role in whole body cholesterol balance

“…However, a recent study by the Tontonoz group ( Xiao et al, 2023 ) demonstrated that hepatocyte-specific deletion of both Gramd1a and Gramd1c (i.e., hepatocyte-specific Gramd1a and Gramd1c double knockout) have impaired movement of lipoprotein-derived free cholesterol out of the body via RCT. In further support of functional redundancy, only double knockout of both Gramd1b and Gramd1c in intestinal enterocytes, but not single deficiency, can reduce intestinal cholesterol absorption ( Ferrari et al, 2023 ). Also, the ability of Chinese hamster ovary (CHO-K1) cells to esterify LDL-derived cholesterol depends on the deletion of all three Aster proteins (A, B, and C), whereas single deletion had modest to no effect ( Trinh et al, 2021 ).…”

“…However, the cell autonomous and systemic roles of Aster-A and Aster-C in cholesterol uptake and metabolism have been more elusive. Given the tissue-specific expression patterns of Aster proteins, and unique nuclear hormone receptor-driven transcriptional control (i.e., LXR-driven transcription of Gramd1b and FXRdriven transcription of Gramd1c) (Sandhu et al, 2018;Xiao et al, 2023;Ferrari et al, 2023), it is logical to assume that each Aster protein may play unique roles in cholesterol homeostasis. Here, we have specifically addressed the role of Aster-C in tissue and systemic balance.…”

“…Therefore, the trafficking of PM cholesterol to intracellular organelles is tightly controlled to maintain cellular homeostasis. A recently identified family of ER-resident proteins called Asters (Aster-A, -B, and -C) form membrane-membrane contact sites to facilitate the transfer cholesterol away from the PM ( Sandhu et al, 2018 ; Naito et al, 2019 ; Ferrari et al, 2020 ; Ferrari et al, 2023 ; Xiao et al, 2023 ). Aster-B was first described as a liver X receptor (LXR)-stimulated cholesterol transporter that facilitates PM-to-ER sterol transfer for cholesterol ester (CE) storage in the adrenal gland ( Sandhu et al, 2018 ).…”

“…More recently, Aster-C was found to be a direct transcriptional target gene for the farnesoid X receptor (FXR) in the liver where it plays a role in reverse cholesterol transport (RCT) ( Xiao et al, 2023 ). Although there is emerging evidence of functional redundancy in some tissues, all three Asters (A, B, and C) have been implicated in both intestinal and hepatic cholesterol trafficking under certain conditions of fasting and re-feeding ( Ferrari et al, 2023 ; Xiao et al, 2023 ). However, the specific individual role for each Aster protein in regulating whole body cholesterol balance under conditions of excess dietary cholesterol is not well understood.…”