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Full text release has been delayed at the author's request until May 17, 2026

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Aster-C , A Novel Regulator of Cholesterol Metabolism & Homeostasis

Hohe, Rachel Carlene
http://orcid.org/0000-0002-4809-753X
http://rave.ohiolink.edu/etdc/view?acc_num=case1712756037824829

Abstract Details

2024, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Cholesterol equilibrium is meticulously orchestrated, and its proper regulation is pivotal in mitigating the risk of cardiovascular disorders. To preserve this delicate balance, cholesterol must activate sensing mechanisms at organelle membranes within the cell’s interior. The recently discovered Aster protein family (Aster-A, -B, and -C) partakes in nonvesicular cholesterol import to organelles from the plasma membrane (PM). Despite their high coding sequence homology, each Aster protein exhibits distinct tissue expression patterns, conferring unique functions. This work elucidates their nuanced roles in regulating whole-body cholesterol flux. It scrutinizes how existing therapeutics modulate cholesterol flux, emphasizing their effects on key proteins that are known regulators of cholesterol homeostasis. The introductory chapter reviews the intended and off-target effects of these existing therapeutics. Aster proteins are then introduced as novel modulatory nodes in cholesterol regulation. Aster-C, prominently expressed in sterol- regulatory tissues like the liver and testis, presents an intriguing target, especially in potential therapeutic applications for dyslipidemia-associated disease pathology. The body chapter delves into Aster-C’s role in whole-body homeostasis, unveiling its contribution to cholesterol balance and revealing modest effects on bile acid metabolism under low- cholesterol dietary conditions. Aster-C knockout prompts upregulation in the messenger ribonucleic acid (mRNA) levels of paralogs Aster-A and -B in murine liver tissue, suggesting nuanced roles and potential redundancy with other Aster proteins. Comparative nalysis with existing literature indicates that Aster-C’s hepatic transcription is inducible by FXR stimulation. These findings, intersected with our own research on the Aster-C knockout-induced disruption of bile acid homeostasis, suggest an integral role for Aster-C in mediating the rate of reverse cholesterol transport within hepatic tissue. Overall, we deconstruct cholesterol metabolism, identify existing therapeutic interventions, and then propose potential benefits of targeting Aster proteins as novel nodes by which the rate of reverse cholesterol transport can be stimulated. Ultimately, we aim to explore novel therapeutic applications in Aster modulation by potentiating clinical relevance in our future directions section. Herein, we hope to broaden perspectives on inter-tissue cholesterol homeostasis dynamics by emphasizing the need for further investigations into the role of Aster proteins in cholesterol trafficking.
Jonathan Mark Brown (Advisor)
Christopher Hine (Committee Chair)
Scott Cameron (Committee Member)
Phillip Ahern (Committee Member)
Jonathan Smith (Committee Member)
183 p.
Biology; Medicine; Molecular Biology
cholesterol; cardiovascular; Aster; plasma membrane; endoplasmic reticulum; non-vesicular transport; homeostasis; Aster-C; dyslipidemia; hyperlipidemia; bile acids; mRNA; FXR; LXR; membranes; lipids; statins; sterols; oxysterols

Recommended Citations

Citations

  • Hohe, R. C. (2024). Aster-C , A Novel Regulator of Cholesterol Metabolism & Homeostasis [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1712756037824829

    APA Style (7th edition)

  • Hohe, Rachel. Aster-C , A Novel Regulator of Cholesterol Metabolism & Homeostasis. 2024. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1712756037824829.

    MLA Style (8th edition)

  • Hohe, Rachel. "Aster-C , A Novel Regulator of Cholesterol Metabolism & Homeostasis." Doctoral dissertation, Case Western Reserve University, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=case1712756037824829

    Chicago Manual of Style (17th edition)

case1712756037824829
© 2024, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
Release 3.2.12