Истинная форма рецептора

Рецептор ЛНП представляет собой гликопротеин, частично погруженный в плазматическую мембрану. Рецепторы ЛНП есть на большинстве клеток организма. Они были выделены из надпочечников В. Шнейдером. Д. Рассел и Т. Ямамото клонировали комплементарную ДНК, синтезированную на мРНК рецепторов, секвенировали ее, и по этим данным была определена аминокислотная последовательность молекулы рецептора (в нем 839 аминокислот). Установлены места присоединения углеводных цепочек и участок, находящийся в мембране. Истинная форма рецептора не известна, и здесь представлена лишь его схема.

Каким образом аномалия рецепторов ЛНП приводит к перепроизводству самих ЛНП? Ответ на этот вопрос был получен при изучении одной любопытной линии кроликов с генетическим дефектом, сходным с тем, что имеет место при семейной гиперхолестеролемии человека.

Эта линия кроликов была обнаружена в 1978 г. И. Ватанабе из Медицинской школы Университета в Кобе и получила название WHHL (от английского Watanabe heritable hiperlipidemia — наследуемая гиперлипидемия Ватанабе). Кролики WHHL гомозиготны по мутантному гену, кодирующему рецептор ЛНП, и у них синтезируется менее 5% нормального количества активных рецепторов ЛНП. У таких животных от рождения повышено содержание циркулирующих ЛНП, и они подвержены атеросклерозу, причем признаки поражения сердца появляются уже к двухлетнему возрасту. Результаты исследований, проведенных нами (совместно с Т. Кита и Д. Билхеймером), а также Стейнбергом и его сотрудниками, показали, что в организме кроликов WHHL, как и в организме больных людей, гомозиготных по признаку семейной гиперхолестеролемии, образуется слишком много ЛНП и слишком много времени требуется для их деградации.

Для того чтобы выяснить причины избыточного производства ЛНП, Кита вводил нормальным кроликам и кроликам WHHL меченные радиоактивным изотопом ЛОНП, являющиеся предшественником ЛНП, и прослеживал судьбу радиоактивной метки на всем пути транспорта липидов. Он обнаружил, что скорость экстракции триглицеридов из ЛОНП и образования ЛПП у нормальных животных и у особей WHHL одинаковы. Но у нормальных кроликов подавляющая часть новообразованных частиц ЛПП быстро удаляется из циркуляции вследствие связывания с рецепторами ЛНП на клетках печени. А у животных WHHL печеночные клетки лишены рецепторов ЛНП, в результате чего большая часть ЛПП остается в кровяном русле и впоследствии превращается в ЛНП, создавая тем самым избыток последних. То есть у кроликов уменьшение количества рецепторов ЛНП приводит сразу к двум последствиям: образуется больше ЛНП и снижается скорость их удаления из кровяного русла. Эти два процесса синергически влияют на уровень ЛНП, и он становится непропорционально высоким.

 

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