Phytosterols reverse antiretroviral-induced hearing loss, with potential implications for cochlear aging

Area of Science:

• Neuroscience
• Otolaryngology
• Biochemistry

Background:

• Cholesterol is vital for neuronal function, and its imbalance is linked to neurodegeneration.
• Cholesterol homeostasis in the inner ear and its role in age-related hearing loss remain underexplored.
• Inner ear cholesterol dynamics are critical for maintaining auditory function.

Purpose of the Study:

• To investigate cholesterol homeostasis in the aging mouse inner ear.
• To explore the role of cholesterol 24-hydroxylase (CYP46A1) in inner ear aging and hearing loss.
• To evaluate therapeutic interventions targeting inner ear cholesterol for hearing loss prevention.

Main Methods:

• Characterization of cholesterol levels and CYP46A1 expression in young and aged mouse inner ears.
• Pharmacological activation of CYP46A1 using efavirenz and assessment of auditory function (prestin, DPOAEs).
• Evaluation of dietary phytosterol supplementation effects on auditory function following efavirenz treatment.

Main Results:

• Aging mice exhibit reduced inner ear cholesterol and increased CYP46A1 expression.
• Efavirenz-induced CYP46A1 activation decreased inner ear cholesterol, reduced prestin, and impaired auditory function.
• Phytosterol supplementation counteracted the negative effects of efavirenz on auditory function.

Conclusions:

• Cholesterol homeostasis in the inner ear is crucial for maintaining auditory function during aging.
• Targeting CYP46A1 offers a potential strategy for modulating inner ear cholesterol.
• Interventions like phytosterol supplementation may mitigate hearing loss associated with cholesterol dysregulation.