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    Home > Biochemistry News > Biotechnology News > "Nature" heavy: Chinese scientists crack the mechanism of action of metformin

    "Nature" heavy: Chinese scientists crack the mechanism of action of metformin

    • Last Update: 2022-05-23
    • Source: Internet
    • Author: User
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    In 1957, when metformin was first marketed in France as an alternative to insulin for lowering blood sugar, no one could have imagined that this inconspicuous drug at the time has become a "star" drug more than half a century later
    .

    As a derivative of the natural product goatine, metformin is not only widely used in clinical treatment as a first-line drug for the treatment of type 2 diabetes, but also can reduce the body weight of diabetic patients, reduce liver fat content, and reduce the risk of diabetes-induced cancer
    .
    In Drosophila and mouse experiments, metformin even delayed aging and extended the lifespan of individuals

    .

    Countless people have benefited from this ancient drug, but for scientists, a key question has remained unanswered: What is the target of metformin? In other words, we know metformin works, but exactly how it works is not clear
    .

    Previous studies have proposed several candidate theories for the mechanism of action of metformin
    .
    Among them, AMPK (that is, adenosine monophosphate-activated protein kinase) involved in the regulation of metabolic homeostasis has attracted much attention

    .
    Previous studies have found that AMPK phosphorylation of acetyl-CoA carboxylase is essential for the decline of fatty liver and atherosclerotic symptoms in diabetic mice treated with metformin

    .

    Evidence suggests that metformin works by inhibiting a class of mitochondrial electron transport chain complexes that activate AMPK
    .
    However, the exact target through which metformin activates the AMPK protein is still unknown

    .

    Now, this "mystery of the century" has finally ushered in the answer
    .
    In a study published in "Nature", Professor Lin Shengcai, Professor Zhang Chensong and Professor Deng Xianming of Xiamen University collaborated to reveal the target of metformin, laying a foundation for further expanding its application range

    .

    In the journal "Cell Metabolism" 6 years ago, a study led by Professor Lin Shengcai's team proposed that metformin may activate AMPK protein through the lysosomal pathway
    .
    Based on this discovery, the next goal of the research team is to find specific targets based on this pathway

    .

    To this end, the authors synthesized photosensitive metformin chemical probes—when metformin molecules bind to a protein molecule, they can be detected by tags on the probe
    .
    In this way, the research team screened 113 proteins that could bind to metformin from more than 2,000 candidate proteins

    .

    Subsequently, the research team sequentially inhibited the expression of these 113 proteins through gene silencing, and finally found a distinctive protein-only when the expression of presenilin enhancer 2 (PEN2, a subunit of γ-secretase) was inhibited , cells become insensitive to metformin treatment, and metformin cannot activate AMPK
    .
    This result suggests that it is PEN2 that is targeted by metformin when it works

    .

    ▲Metformin binds to PEN2 to activate AMPK (Image source: Reference [1])

    Next, the research team revealed the pathway by which metformin works based on this newly discovered target
    .
    As shown in the figure below, when metformin binds to PEN2, the latter can form a complex with a subunit of the lysosomal proton pump v-ATPase (ATP6AP1), and such a structure results in the inhibition of v-ATPase and the activation of AMPK.

    .

    ▲ Molecular pathway of metformin’s effect (Image source: Reference [1])

    In subsequent animal experiments, the research team further verified the above mechanism
    .
    AMPK activation decreased when the Pen2 gene was knocked out, or when a mutation was introduced to prevent PEN2 from binding to ATP6AP1

    .

    Normally, metformin mediates a decrease in liver fat content
    .
    But in mouse experiments, the lipid-lowering function was lost after specifically knocking out the Pen2 gene in the liver

    .
    A specific knockout of the Pen2 gene in the gut of mice resulted in an impaired ability to lower blood sugar

    .
    In addition, as mentioned earlier, metformin can prolong the lifespan of nematodes

    .
    However, after knocking out pen2 in nematodes, the effect of prolonging life is also lost

    .

    Through this series of experimental designs, this study is the first to clearly demonstrate the mechanism of action of metformin at the molecular level
    .
    At present, while metformin plays an important role in its efficacy, it can also cause side effects such as stomach discomfort

    .
    Based on the drug's mechanism of action, future researchers may be able to develop new, safer alternatives

    .
    At the same time, whether there are other targets and action pathways for this miraculous drug remains to be further studied

    .
    Through these studies, this time-honored drug is expected to burst into more vigorous vitality in the 21st century

    .

    References:

    [1] Ma, T.
    , Tian, ​​X.
    , Zhang, B.
    et al.
    Low-dose metformin targets the lysosomal AMPK pathway through PEN2.
    Nature (2022).
    https://doi.
    org/10.
    1038/s41586-022 -04431-8

    [2] Chen-Song Zhang et al.
    Metformin Activates AMPK through the Lysosomal Pathway.
    Cell Metabolism (2016).
    DOI: https://doi.
    org/10.
    1016/j.
    cmet.
    2016.
    09.
    003

    [3] Breakthrough! Lin Shengcai and Deng Xianming's team collaborated to decipher metformin targets.
    Retrieved Feb 24th, 2022 from https://life.
    xmu.
    edu.
    cn/info/1045/5230.
    htm

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