ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 12.11 | DOI: 10.1530/ey.16.12.11

ESPEYB16 12. Type 2 Diabetes, Metabolic Syndrome and Lipid Metabolism Lipid Metabolism (4 abstracts)

12.11. Aster proteins facilitate nonvesicular plasma membrane to ER cholesterol transport in mammalian cells

Sandhu J , Li S , Fairall L , Pfisterer SG , Gurnett JE & Xiao X et al.



Cell. 2018; 175(2): 514–29 e20.
URL: http://www.ncbi.nlm.nih.gov/pubmed/30220461

Summary: The enigma of how cholesterol is transported within cells has been solved in these experimental mouse models and structural imaging studies by the discovery of the proteins Aster A, B and C, which serve as a molecular bridge for the transfer of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER).

Comment: Newly synthesized cholesterol is transported from the ER to the PM; this occurs via nonvesicular pathways by several lipid transfer proteins. In parallel, cholesterol that is obtained from extracellular sources is transported back from the PM to the ER, where it is esterified or converted to oxysterols, bile acids and steroid hormones.1 However, until now it was not known how cholesterol is transported from the PM to the ER. Three proteins were discovered, named Aster-A, -B and -C (Greek for ‘star’), which have a role in cholesterol trafficking. These proteins have remarkable similarity to the sterol-binding START (steroidogenic acute regulatory protein domain, which regulates cholesterol transfer within the mitochondria) but have higher affinity.

In a series of elegant studies, the authors determined the crystal structure of the Aster proteins, characterized the mode of their binding, and then determined their functional importance in cholesterol trafficking and homeostasis. First, they showed that Aster proteins are recruited in response to cholesterol levels. In standard lipid-poor conditions, the Aster proteins are located throughout the ER. Upon addition of cholesterol to the media, the Aster proteins quickly redistribute to ER tubules and form bridges from the PM to the ER, and the sterol-binding ASTER domain extracts cholesterol from the PM and moves it down the concentration gradient to the ER.

The authors subsequently showed that antisense oligonucleotide against Aster-A causes a delayed response to exogenous cholesterol, as demonstrated by higher levels of SREBP targets, and reduced cholesterol ester synthesis, both of which can be explained by a reduction in cholesterol transport from the PM to the ER. Finally, Aster-B knockout mice by CRISPR/Cas9 editing were established. Aster-B is the only Aster protein expressed in the adrenal gland, a tissue that relies on uptake of HDL cholesterol to generate steroid hormones and cholesterol esters. Remarkably, in the adrenal glands of the knockout mice, levels of the cholesterol esters were dramatically reduced and lipid droplets were completely lacking. Serum corticosterone levels were also reduced.

Future studies should investigate the importance of Aster proteins in diseases associated with alterations in cholesterol metabolism, including dyslipidemia, atherosclerosis, neurodegeneration and sexual development.2

References: 1. Rapoport T and Sever N: In F1000Prime, 22 Oct 2018; 10.3410/f.734007092.793551775.

2. Kutyavin VI, Chawla A. Aster: A New Star in Cholesterol Trafficking. Cell. 2018; 175(2): 307–9.

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