БИОХИМИЯ, 2022, том 87, вып. 6, с. 741–757

УДК 577.25

25‑Гидроксихолестерин как сигнальная молекула в нервной системе

Обзор

© 2022 Ю.Г. Одношивкина 1,2#, Е.А. Кузнецова 1#, А.М. Петров 1,2*alexey.petrov@kazangmu.ru

Казанский институт биохимии и биофизики, ФИЦ КазНЦ РАН, Лаборатория биофизики синаптических процессов, 420111 Казань, Россия

Казанский медицинский университет, 420012 Казань, Россия

Поступила в редакцию 25.03.2022
После доработки 10.05.2022
Принята к публикации 10.05.2022

DOI: 10.31857/S0320972522060045

КЛЮЧЕВЫЕ СЛОВА: холестерин, 25‑гидроксихолестерин, LX‑рецепторы, NMDA‑рецепторы, синаптическая передача, нейровоспаление, микроглия.

Аннотация

Холестерин – важный компонент плазматических мембран и предшественник ряда биологически активных соединений, в том числе гидроксихолестеринов (ГХ). Последние контролируют ключевые звенья клеточного гомеостаза холестерина. ГХ, проникая через мембранные и сосудистые барьеры, могут оказывать дистанционное действие, выступая в роли пара- и эндокринных агентов. 25‑ГХ в небольших количествах образуется в эндоплазматической сети многих клеток и является мощным локальным регулятором синтеза холестерина, его внутриклеточного транспорта и депонирования. При запуске воспалительных реакций продукция 25‑ГХ значительно возрастает в макрофагах, дендритных клетках и микроглии. Также синтез 25‑ГХ может повышаться при ряде неврологических заболеваний, таких как болезнь Альцгеймера, боковой амиотрофический склероз, спастическая параплегия 5‑го типа и Х‑сцепленная адренолейкодистрофия. При этом пока не известно, в каких случаях 25‑ГХ может усиливать патологию, а когда – обладать протекторными свойствами. Молекулярными мишенями для действия 25‑ГХ являются некоторые транскрипционные факторы (LX-рецепторы, SREBP2, ROR), сопряженный с G‑белком рецептор (GPR183), ионные каналы (NMDA-рецепторы, SLO1), молекулы адгезии (α5β1- и αvβ3-интегрины), а также оксистерин-связывающие белки. Такое изобилие белков, взаимодействующих с 25‑ГХ, предполагает наличие у данного ГХ способности принимать участие во многих физиологических и патологических процессах. В представленном обзоре мы сфокусировались на регуляции продукции 25‑ГХ и его универсальной роли в контроле клеточного гомеостаза холестерина, а также на эффектах 25‑ГХ как сигнальной молекулы, опосредующей влияние воспаления на процессы в нервно-мышечной системе и мозге. Исходя из накопившихся данных следует заключить, что 25‑ГХ препятствует накоплению клеточного холестерина и выступает в качестве мощного модулятора нейровоспаления, синаптической передачи и миелинизации. Его усиленная продукция в ответ на широкий спектр «нарушений» может выполнять протективную роль, ограничивая гибель нейронов. Тем не менее сверхвысокие концентрации 25‑ГХ оказывают нейротоксическое действие.

Сноски

* Адресат для корреспонденции.

# Авторы внесли равный вклад в работу.

Финансирование

Работа выполнена при финансовой поддержке гранта РФФИ № 20‑04‑00077 (части 3.1–3.7), а также частично грантов РНФ № 22‑25‑00396 (части 1 и 2) и № 21‑14‑00044 (часть 3.8).

Благодарности

Авторы выражают благодарность Закирьяновой Г.Ф. и проф. Бухараевой Э.А. за обсуждение данного обзора. Работа частично поддержана государственным заданием для ФИЦ Казанского научного центра РАН.

Конфликт интересов

Авторы заявляют об отсутствии конфликта интересов.

Соблюдение этических норм

Настоящая статья не содержит описания выполненных авторами исследований с участием людей или использованием животных в качестве объектов.

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