A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis

Area of Science:

• Biochemistry
• Cell Biology
• Molecular Biology

Background:

• Cholesterol biosynthesis is an oxygen-dependent pathway crucial for cell membranes.
• Fungi exhibit oxygen-dependent sterol production, triggering transcriptional responses similar to hypoxia-inducible factors (HIFs).
• The existence of an analogous pathway in metazoans remains unexplored.

Purpose of the Study:

• To investigate whether a similar oxygen-sensitive pathway regulates cholesterol synthesis in mammals.
• To identify the key regulators and mechanisms involved in this pathway.

Main Methods:

• Identification of Sterol Regulatory Element Binding Protein 2 (SREBP2) as an oxygen-sensitive regulator.
• Investigation of SREBP2 degradation under hypoxic conditions.
• Identification of MARCHF6 as the ubiquitin ligase controlling SREBP2 stability.
• Analysis of cellular response to statins under hypoxia.

Main Results:

• Sterol Regulatory Element Binding Protein 2 (SREBP2), a key mammalian transcription factor for sterol production, is oxygen-sensitive.
• SREBP2 degradation occurs during hypoxia, independent of HIFs, overriding normal sterol-sensing.
• MARCHF6, activated by NADPH in hypoxia, is identified as the primary ubiquitin ligase for SREBP2.
• Hypoxia-induced SREBP2 degradation protects cells from statin-induced death by promoting exogenous cholesterol uptake.

Conclusions:

• A novel oxygen-sensitive pathway regulating cholesterol synthesis via SREBP2 degradation has been uncovered in mammals.
• This pathway explains cholesterol auxotrophy in solid organ tumors.
• The findings highlight SREBP2 as a critical target for understanding cholesterol metabolism and cancer biology.