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    Npc1l1 deficiency suppresses ileal fibroblast growth factor 15 expression and increases bile acid pool size in high-fat-diet-fed mice

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    Author
    Jia, Lin
    Ma, Yinyan
    Haywood, Jamie
    Jiang, Long
    Xue, Bingzhong
    Shi, Hang
    Dawson, Paul A.
    Yu, Liqing
    Date
    2021-12-09
    Journal
    Cells
    Publisher
    MDPI AG
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.3390/cells10123468
    Abstract
    Niemann–Pick C1-like 1 (NPC1L1) mediates intestinal uptake of dietary and biliary cholesterol and is the target of ezetimibe, a cholesterol absorption inhibitor used to treat hypercholes-terolemia. Genetic deletion of NPC1L1 or ezetimibe treatment protects mice from high-fat diet (HFD)-induced obesity; however, the molecular mechanisms responsible for this therapeutic benefit remain unknown. A major metabolic fate of cholesterol is its conversion to bile acids. We found that NPC1L1 knockout (L1-KO) mice fed an HFD had increased energy expenditure, bile acid pool size, and fecal bile acid excretion rates. The elevated bile acid pool in the HFD-fed L1-KO mice was en-riched with tauro-β-muricholic acid. These changes in the L1-KO mice were associated with reduced ileal mRNA expression of fibroblast growth factor 15 (FGF15) and increased hepatic mRNA expression of cholesterol 7α-hydroxylase (Cyp7A1) and mitochondrial sterol 27-hydroxylase (Cyp27A1). In addition, mRNA expression of the membrane bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and type 2 iodothyronine deiodinase (Dio2) were elevated in brown adipose tissue of L1-KO mice, which is known to promote energy expenditure. Thus, altered bile acid homeostasis and signaling may play a role in protecting L1-KO mice against HFD-induced obesity. © 2021 by the authors.
    Sponsors
    National Institutes of Health
    Keyword
    Cholesterol
    Energy expenditure
    NPC1L1
    Obesity
    TGR5
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17447
    ae974a485f413a2113503eed53cd6c53
    10.3390/cells10123468
    Scopus Count
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