Abstract
The bifunctional enzyme soluble epoxide hydrolase (sEH) is found in all regions of the brain. It has two different catalytic activities, each assigned to one of its terminal domains: the C-terminal domain presents hydrolase activity, whereas the N-terminal domain exhibits phosphatase activity. The enzyme’s C-terminal domain has been linked to cardiovascular protective and anti-inflammatory effects. Cholesterol-related disorders have been associated with sEH, which plays an important role in the metabolism of cholesterol precursors. The role of sEH’s phosphatase activity has been so far poorly investigated in the context of the central nervous system physiology. Given that brain cholesterol disturbances play a role in the onset of Alzheimer’s disease (AD) as well as of other neurodegenerative diseases, understanding the functions of this enzyme could provide pivotal information on the pathophysiology of these conditions. Moreover, the sEH phosphatase domain could represent an underexplored target for drug design and therapeutic strategies to improve symptoms related to neurodegenerative diseases. This review discusses the function of sEH in mammals and its protein structure and catalytic activities. Particular attention was given to the distribution and expression of sEH in the human brain, deepening into the enzyme’s phosphatase activity and its participation in brain cholesterol synthesis. Finally, this review focused on the metabolism of cholesterol and its association with AD.
Highlights
Cholesterol metabolism in the brain is independent of peripheral tissues due to the blood-brain barrier (BBB) that impairs the entrance of the protein-bound lipid into the central nervous system (CNS)
We provide a compilation of Soluble epoxide hydrolase (sEH) distribution and expression in the human brain and deepen the discussion on the enzyme’s N-terminal phosphatase activity and its involvement in the synthesis of cholesterol
Throughout the years, human sEH has been poorly studied in the context of CNS physiology, mainly the role of its phosphatase domain and its possible influence on brain cholesterol metabolism
Summary
Cholesterol metabolism in the brain is independent of peripheral tissues due to the blood-brain barrier (BBB) that impairs the entrance of the protein-bound lipid into the central nervous system (CNS). Brain tissues contain large amounts of cholesterol, up to 25% of the body’s cholesterol content (Dietschy, 2009) whose metabolism and complex homeostasis regulation in the CNS remain unclear (Zhang and Liu, 2015). Changes in this metabolism are related to neurodegenerative pathologies, such as Alzheimer’s disease (AD), Parkinson’s disease, and Huntington’s disease, as well as to age-related cognitive decline (Petrov et al, 2016; Loera-Valencia et al, 2019). Considering the abundance of cholesterol in the CNS, it is important to further investigate the role of sEH in the brain cholesterol pathway
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