家族性高コレステロール血症のための新しい細胞現象型は,LDL受容体の偏向的ターゲティングの欠陥によるものです
U M Koivisto1, A L Hubbard, I Mellman
1Department of Cell Biology, Ludwig Institute for Cancer Research, Yale University School of Medicine, 333 Cedar Street, PO Box 208002, New Haven, CT 06520, USA.
Cell
|June 8, 2001
まとめ
LDL受容体の突然変異は,受容体を細胞表面に誤って標的にし,コレステロールのクリアランスを損なうことで,家族性高コレステロール血症を引き起こす. これは,ヒトの病気におけるタンパク質ターゲティング信号の重要な役割を強調しています.
科学分野:
- 細胞生物学 細胞生物学
- 分子遺伝学 分子遺伝学
- 皮質細胞の極性について
背景:
- 偏極化された上皮細胞における膜タンパク質の基礎側標的化は,細胞プラズマ領域の分類信号に依存する.
- 家族性高コレステロール血症 (FH) - トルコのLDL受容体アレルには,基礎側向標的化に影響を与える変異が含まれています.
研究 の 目的:
- 特定のLDL受容体の変異がタンパク質標的化に与える影響と,家族性高コレステロール血症との関連を調査する.
- エピテリア細胞の極性および疾患の病原性を維持する基礎側向標的信号の役割を確認する.
主な方法:
- Madin-Darby犬の腎臓 (MDCK) と肝臓の上皮細胞を使用して,受容体の局所化を研究しました.
- コレステロールのクリアランスを評価するために,LDL受容体が欠乏したマウスのウイルスにコードされた変異性受容体を使用した.
主要な成果:
- 変異したLDL受容体は,両方の細胞タイプでアピカル表面に誤って標的にされた.
- ベースラテラル/シヌソイド表面からのLDLのエンドサイトーシスの減少が観察されました.
- 変異した受容体は,体内でコレステロールのクリアランスを媒介できず,偏光表現の欠陥を示しています.
結論:
- LDL受容体のベース・ラテラル・ターゲティング・シグナルの欠陥は,家族性高コレステロール血症を引き起こす可能性があります.
- この研究は,上皮細胞の極性および疾患におけるこれらの信号の重要性を遺伝的に確認します.
- 肝細胞内のLDL受容体の局所化が変化すると,高コレステロール血症の病原化に寄与する.
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