DHCR24, also known as 24-dehydrocholesterol reductase, is an enzyme encoded by the DHCR24 gene. As an oxidoreductase that depends on flavin adenine dinucleotide (FAD), DHCR24 is involved in cholesterol production. Its functions extend beyond a single metabolic pathway.
Primary Function in Cholesterol Production
DHCR24’s primary function is in the final step of cholesterol biosynthesis. It catalyzes the conversion of desmosterol into cholesterol by reducing the delta-24 double bond in the sterol side chain. It also participates in another pathway by converting lanosterol into 24,25-dihydrolanosterol, with cholesterol being the end product of both processes.
Cholesterol is a waxy, fat-like substance the body needs for various functions. It is a component of cell membranes, providing structure and regulating what enters or leaves the cell. Cholesterol also serves as a precursor for steroid hormones, including sex hormones like estrogen and testosterone, and adrenal hormones. It assists the liver in producing bile, which aids fat digestion and absorption of fat-soluble vitamins.
Wider Biological Roles
Beyond its central role in cholesterol synthesis, DHCR24 exhibits other functions. It protects cells from oxidative stress. Specifically, it can reduce caspase 3 activity, which is involved in programmed cell death induced by oxidative stress.
DHCR24 influences processes such as cell differentiation and proliferation. It is involved in neuroprotection, safeguarding nerve cells, and its expression is sometimes reduced in neurons affected by Alzheimer’s disease.
Impact of DHCR24 Dysfunction
When the DHCR24 enzyme does not function correctly, it can lead to various health issues. Genetic mutations in the DHCR24 gene are linked to a rare, inherited condition called desmosterolosis. This disorder is characterized by a deficiency in cholesterol production and an accumulation of desmosterol, the precursor DHCR24 typically converts to cholesterol. Individuals with desmosterolosis often present with neurological problems, including brain abnormalities such as malformation of the corpus callosum and loss of white matter, along with developmental delays in speech and motor skills.
Other symptoms of desmosterolosis include growth restriction, muscle stiffness (spasticity), stiff joints (arthrogryposis) affecting hands and feet, and short stature. Facial dysmorphism, such as a small lower jaw, cleft palate, and unusual eye movements like nystagmus or strabismus, may also be observed. The impact of reduced cholesterol production is often more severe before birth due to the rapid increase in cell numbers during embryonic development, affecting the proper formation of cell membranes and myelin.
Beyond desmosterolosis, altered DHCR24 activity has implications in other health conditions. Reduced expression of the DHCR24 gene has been noted in the temporal cortex of patients with Alzheimer’s disease. Conversely, overexpression of DHCR24 has been observed in adrenal gland cancer cells, and its role in promoting tumor progression through pathways like reactive oxygen species (ROS), p53, Ras, and PI3K-AKT is being investigated. DHCR24 dysfunction can contribute to a broader spectrum of diseases beyond genetic disorders.
Current Research and Future Directions
Ongoing scientific investigations are exploring DHCR24 for its potential as a therapeutic target and biomarker. Researchers are examining its role in various diseases, including cancer, Alzheimer’s disease, and non-alcoholic fatty liver disease (NAFLD). For instance, inhibiting DHCR24 activity leads to an accumulation of desmosterol, which can activate liver X receptors (LXR), a promising strategy for treating NAFLD without causing unwanted side effects like hyperlipidemia.
New insights are emerging regarding DHCR24’s regulation and its interactions with other biological pathways. The enzyme’s activity is regulated transcriptionally by sterols, sex steroids, and hormones like adrenocorticotropic hormone and thyroid hormone. Post-translational modifications, such as phosphorylation, and epigenetic factors like methylation and acetylation, also influence DHCR24 expression and activity. Understanding these regulatory mechanisms could pave the way for novel therapeutic approaches.