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김종숙
김종숙 (Jongsook Kim Kemper) 저자 이메일 보기
University of Illinois at Urbana-Champaign
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MicroRNA‐210 promotes bile acid‐induced cholestatic liver injury by targeting mixed‐lineage leukemia‐4 methyltransferase in mice
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Abstract

Bile acids (BAs) are important regulators of metabolism and energy balance, but excess BAs cause cholestatic liver injury. The histone methyltransferase, Mixed‐lineage leukemia‐4 (MLL4), is a transcriptional coactivator of the BA‐sensing nuclear receptor, Farnesoid‐X‐Receptor (FXR), and epigenetically upregulates FXR targets important for the regulation of BA levels, Small Heterodimer Partner (SHP) and Bile Salt Export Pump (BSEP). MLL4 expression is aberrantly downregulated and BA homeostasis is disrupted in cholestatic mice, but the underlying mechanisms are unclear. Here, we examined whether elevated microRNA‐210 (miR‐210) in cholestatic liver promotes BA‐induced pathology by inhibiting MLL4 expression. MiR‐210 was the most highly elevated miR in hepatic SHP‐downregulated mice with elevated hepatic BA levels. MLL4 was identified as a direct target of miR‐210 and overexpression of miR‐210 inhibited MLL4, and subsequently, BSEP and SHP expression, resulting in defective BA metabolism and hepatotoxicity with inflammation. MiR‐210 levels were elevated in cholestatic mouse models, and in vivo silencing of miR‐210 ameliorated BA‐induced liver pathology and decreased hydrophobic BA levels in a MLL4‐dependent manner. In gene expression studies, SHP inhibited miR‐210 expression by repressing a transcriptional activator, Kruppel‐like factor‐4 (KLF4). In primary biliary cholangitis/cirrhosis (PBC) patients, hepatic levels of miR‐210 and KLF4 were highly elevated, whereas nuclear levels of SHP and MLL4 were reduced. In conclusion, hepatic miR‐210 is physiologically regulated by SHP, but is elevated in cholestatic mice and PBC patients, promoting BA‐induced liver injury in part by targeting MLL4. The miR‐210/MLL4 axis is a potential target for the treatment of BA‐associated hepatobiliary disease.
 
Keywords : FXR, SHP, BSEP, FGF19, PBC patients
 

논문정보
- 형식: Research article
- 게재일: 2019년 09월 (BRIC 등록일 2019-10-02)
- 연구진: 국외연구진
- 분야: Medicine
Dot/Icm 제 4 유형 커플링 단백질 복합체의 선택적 이펙터 단백질 인식[Nat. Commun.]
김현민
발표: 김현민 (KAIST)
일자: 2020년 9월 29일 (화) 오후 02시 (한국시간)
언어: 한국어
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