How active cholesterol coordinates cell cholesterol homeostasis: Test of a hypothesis

Area of Science:

• Cell Biology
• Biochemistry
• Molecular Biology

Background:

• Cholesterol homeostasis is crucial for cellular function.
• The precise mechanisms by which cells regulate intracellular cholesterol levels are complex and not fully understood.
• Existing models do not fully explain the coordination of diverse regulatory elements.

Purpose of the Study:

• To propose and test a model for cellular cholesterol homeostasis.
• To elucidate the role of membrane cholesterol complexes in regulating cellular sterol levels.
• To identify the signaling functions of excess cellular cholesterol.

Main Methods:

• Literature review of fourteen homeostatic proteins in enterocytes.
• Analysis of the proposed model's consistency with existing experimental data.
• Hypothesis testing regarding the effects of active cholesterol on gene expression and protein activity.

Main Results:

• Membrane cholesterol forms complexes with phospholipids, determining resting levels.
• Excess cholesterol, termed 'active cholesterol,' acts as a negative feedback signal.
• Active cholesterol inhibits cholesterol uptake and synthesis (via SREBP-2 targets like HMGCR, LDLR, NPC1L1) and promotes esterification (via ACAT) and oxysterol synthesis.
• Oxysterols further reduce cholesterol by degrading HMGCR and activating LXR, which upregulates cholesterol transporters.

Conclusions:

• The proposed model provides a framework for understanding cellular cholesterol coordination.
• Active cholesterol plays a key role in sensing and signaling cellular cholesterol levels.
• This regulatory network, involving active cholesterol, oxysterols, and transcription factors like LXR and SREBP-2, maintains cellular sterol balance.