Обмен холестерина в гепатоцитах при развитии алиментарной гиперхолестеринемии и механизмы действия пробукола и фибратов тема диссертации и автореферата по ВАК РФ 03.00.04, доктор биологических наук Косых, Владимир Алексеевич

• Косых, Владимир Алексеевич
• доктор биологических наук
• 2000

Оглавление диссертации доктор биологических наук Косых, Владимир Алексеевич

СПИСОК СОКРАЩЕНИЙ.

ВВЕДЕНИЕ.

ЛИТЕРАТУРНЫЙ ОБЗОР

ГЛАВА 1. РОЛЬ ПЕЧЕНИ В МЕТАБОЛИЗМЕ ХОЛЕСТЕРИНА В ОРГАНИЗМЕ.

1.1. Общие сведения о метаболизме липидов в организме.

1.2. Общие сведения о метаболизме холестерина в гепатоцитах и механизмах компенсации избыточного поступления пищевого холестерина в печень.

1.3. Обратный транспорт холестерина.

ГЛАВА 2. ВЛИЯНИЕ ЛИПИДОВ ПИЩИ НА РАЗВИТИЕ ГИПЕРЛИПИДЕМИИ.

2.1. Алиментарная ГХС у животных.

2.2. Алиментарная ГХС у человека.

2.3. Алиментарная ГТГ у человека.

ГЛАВА 3. РОЛЬ ЛИПИДОВ ПИЩИ В РЕГУЛЯЦИИ МЕТАБОЛИЗМА

ЛИПИДОВ ПЕЧЕНИ.

3.1.1 .Характеристика ЛП, продуцируемых печенью.

3.1.2.Продукция ЛОНП гепатоцитами.

3.1.3. Роль нейтральных липидов в регуляции продукции аполипопротеина В.

3.1.4.Механизм регуляции ano В продукции нейтральными липидами.

3.1.5. Продукция ЛВП гепатоцитами.

3.2. Регуляция активности холестерин-7а-гидроксилазы и синтеза желчных кислот.

ГЛАВА 4. МЕТАБОЛИЧЕСКИЕ РАЗЛИЧИЯ МЕЖДУ ГИПО- И ГИПЕРРЕАКТИВНЫМИ ИНДИВИДУУМАМИ.

4.1. Общая характеристика гипо- и гиперреактивности к пищевому холестерину.

4.2. Уровень общего холестерина и ЛП в плазме.

4.3. Всасывание пищевого холестерина в кишечнике.

4.4. Регуляция синтеза холестерина в печени и периферических тканях.

4.5. Экскреция стеролов с желчью.

4.6. Рецептор-опосредованное поглощение ЛНП печенью.

4.7. Продукции ЛОНП печенью.

Заключение диссертации по теме «Биохимия», Косых, Владимир Алексеевич

ВЫВОДЫ

1. Увеличение секреции гепатоцитами частиц липопротеидов очень низкой плотности ( ЛОНП ) в ответ на потребление кроликами обогащенного холестерином ( ХС ) корма является, наряду со снижением активности ЛНП-рецепторов, ведущей причиной развития алиментарной ГХС.

2. Наличие продуктов автоокисления холестерина в обогащенном ХС корме не приводит к дальнейшему увеличению количества секретируемых гепатоцитами кроликов частиц ЛОНП, по-сравнению с животными, получавшими неокисленный ХС. В то же время, потребление кроликами корма, содержащего ХС и продукты его автоокисления, вызывает усиленное накопление ХС и его эфиров в гепатоцитах, сопровождающееся увеличением секреции обогащенных эфирами холестерина ЛОНП, что может быть причиной быстрого развития алиментарной ГХС.

3. Избыточное поступление нейтральных липидов в составе обогащенных ТГ ремнантов хиломикрон (рХМ) и обогащенных ЭХС ЛП (Р-ЛОНП и ЛНП) в гепатоциты человека и кролика в условиях in vitro стимулирует секрециию частиц ЛОНП. Установлено, что регуляция продукции аполипопротеина В (ano В) ЛОНП осуществляется на посттранскрипционном уровне и в качестве стимуляторов его продукции выступают свободный и этерифицированный ХС.

4. Повышенная чувствительность кроликов к развитию алиментарной ГХС сопряжена с низкой базальной скростью синтеза желчных кислот, значительным ее снижением при пищевой нагрузке ХС и увеличением секреции ЭХС-ЛОНП. К характерным особенностям метаболизма ХС у кроликов, устойчивых к развитию алиментарной ГХС, относятся: а) высокая и устойчивая к пищевой нагрузке ХС базальная скорость синтеза желчных кислот в гепатоцитах; б) высокий уровень секреции ano Е гепатоцитами и увеличение содержания в плазме ano Е-содержащих ЛВП, осуществляющих обратный транспорт ХС.

5. Ремнанты хиломикрон подавляют синтез желчных кислот в культивируемых гепатоцитах кролика и человека, что согласуется с эффектом обогащенного ХС корма на синтез желчных кислот у кроликов. В качестве ингибиторов синтеза желчных кислот могут выступать основные компоненты рХМ - олеиновая и пальмитиновая кислоты. В отличие от рХМ, ЛВП2, осуществляющие обратный транспорт ХС в печень, стимулируют синтез желчных кислот, и тем самым обеспечивают поддержание нормального уровня ХС в плазме при пищевой нагрузке.

6. Ответ гепатоцитов кролика и человека на избыточную доставку в них пищевого ХС не сопровождается увеличением синтеза желчных кислот как в крысиных гепатоцитах. Процесс синтеза желчных кислот у кролика и человека, в отличие от крысы, следовательно, не играет определяющей роли в компенсаторной реакции, направленной на снижение внутрипеченочного уровня ХС и его выведения из организма, что является одной из причин большей подверженности кролика и человека к развитию алиментарной ГХС.

7. Пробукол и а-токоферол в концентрациях сравнимых с терапевтическими дозами стимулируют синтез желчных кислот в культивируемых гепатоцитах кролика. Этот эффект опосредован увеличением внутриклеточного содержания ХС -субстрата для ХС-7а-гидроксилазы - ключевого фермента биосинтеза желчных кислот. В отличие от а-токоферола, обеспечивающего приток ХС в клетку за счет стимуляции синтеза ХС, действие пробукола связано со стимуляцией синтеза и секреции апо Е, ассоциация которого с ЛВПг приводит к увеличению рецептор-зависимого захвата этих частиц гепатоцитами.

8. Безафибрат в концентрациях сравнимых с терапевтическими дозами подавляет секрецию частиц ЛОНП культивируемыми гепатоцитами человека, снижая продукцию апо В на посттранскрипционном уровне. Этот эффект опосредован ингибированием безафибратом синтеза ТГ и ЭХС, являющихся незаменимыми компонентами для формирования частиц ЛОНП.

9. Фибраты в терапевтической концентрации снижают уровень экспрессии гена апо С-111 в печени крыс и культивируемых гепатоцитах крысы и человека. В отличие от гепатоцитов крысы, в клетках человека этот эффект не сопровождается побочным воздействием на метаболизм липидов в печени, проявляющимся в

191 увеличении уровня экспрессии генов пероксисомальных ферментов. Полученные результаты означают, что гипотриглицеридемическое действие фибратов может быть связано с уменьшением уровня экспрессии гена ano C-III, снижением содержания ano C-III в частицах ЛОНП и сопряженным с этим увеличением клиренса этих липопротеидов печенью.

10. Увеличение фибратами содержания ano A-I и ano A-II в плазме человека обусловлено увеличением скорости транскрипции генов ano A-I и ano A-II в гепатоцитах человека. Стимуляция фибратами экспрессии гена ano A-I в печени может рассматриваться в качестве положительного терапевтического воздействия этих препаратов при лечении дислипопротеидемии и атеросклероза.

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