• Biologists find new protective factor ag

    From ScienceDaily@1:317/3 to All on Tue Apr 19 22:30:42 2022
    Biologists find new protective factor against excessive lipid
    accumulation in liver of obese mouse

    Date:
    April 19, 2022
    Source:
    The University of Hong Kong
    Summary:
    Non-alcoholic fatty liver disease (NAFLD), commonly known as fatty
    liver disease, is a prevalent disease frequently seen in obese
    people. Having high fat content in the liver is detrimental as it
    is strongly associated with severe health problems like diabetes,
    high blood pressure, and liver cancer. A research team uncovers
    a new protective mechanism against this disorder.



    FULL STORY ========================================================================== Non-alcoholic fatty liver disease (NAFLD), commonly known as fatty liver disease, is a prevalent disease frequently seen in obese people. Having
    high fat content in the liver is detrimental as it is strongly associated
    with severe health problems like diabetes, high blood pressure, and liver cancer. A research team led by Dr Chi Bun CHAN, Assistant Professor from
    the School of Biological Sciences, Faculty of Science, the University
    of Hong Kong (HKU), uncovers a new protective mechanism against this
    disorder. The research findings have recently been published in the
    scientific journal Hepatology.


    ==========================================================================
    The liver is the vital organ that orchestrates the overall glucose and
    fat metabolisms in the human body. Disruption of the fat metabolism in
    the liver will eventually result in hyperglycemia and hyperlipidemia,
    which are strong risk factors for developing diabetes, hyperlipidemia,
    and liver cancer. It is predicted that the number of NAFLD patient
    will increase from 80 million in 2015 to 100 million in 2030. While the outcomes of fat accumulation in the liver have been well established,
    it remains unclear if the liver possesses any defensive mechanism to
    work against the damage.

    To answer this question, Dr Chan's team examined the expression of genes
    in the liver of high fat diet-induced obese mouse and found a protein,
    SH3 domain binding kinase (SBK1), was exclusively elevated in the
    obese mouse liver. SBK1 is a protein kinase first discovered in 2001,
    but no follow-up study has been performed to determine its functions in mammals. Hence, the functions of this novel protein remain unknown.

    For the first time, Dr Chan's team found that fatty acid accumulation is
    an inducer of SBK1 in the mouse liver. They also observed that the mice
    without the SBK1 gene in their liver, called 'LSKO (liver-specific SBK1 knockout)' mice, have higher lipid accumulation and fibrosis in this
    tissue. Moreover, the LSKO mice displayed uncontrolled hepatic glucose
    output and higher blood glucose level, and are less sensitive to insulin stimulation than their control cohort, which are strong indicators of
    diabetes development.

    In addition to the animal studies, Dr Chan's team also utilised cultured
    cell models to answer how SBK1 gene controlled the lipid metabolism in
    the liver.

    They found that SBK1 phosphorylated and enhanced the activity of Nur77,
    a well- established transcriptional factor, in liver cells to control
    fatty acid uptake and lipid synthesis. When the SBK1 protein activity
    was abolished in the liver cells, they took up more fatty acids and
    developed excessive lipid accumulation that interfered the insulin
    signaling. Surprisingly, another metabolic hormone in the liver cells, fibroblast growth factor 21 (FGF21), was also reduced when the SBK1
    protein was abolished in the cultured liver cells and the LSKO mice.

    Since FGF21 is an important hormone from the liver to communicate with
    other peripheral organs like white adipose tissues, the reduced FGF21
    hormone production in the LSKO liver thus impairs the communication
    between the liver and other organs, leading to the development of insulin resistance in other tissues.

    To extend their findings to therapeutic application, the research team
    further tested if manipulating the SBK1 protein activity in the liver
    could rescue the damaging effect of obesity. Using adenovirus-mediated
    gene delivery, they transiently increased the amount of SBK1 protein
    in the mouse's liver with fructose diet-induced fatty liver disease
    and found pathological symptoms like liver steatosis, inflammation,
    etc. hyperlipidemia, and hyperglycemia were all alleviated.



    ==========================================================================
    'Our findings clearly show that SBK1 protein is an important regulator of
    the lipid metabolism that was neglected before,' said Dr Chan. 'We are
    very excited to see that increasing its activity effectively alleviates
    the health problems caused by fatty liver. But we still need more
    studies to fully depict its functional activity so that we can develop
    SBK1 activator as a new treatment agent for this common liver disease,'
    Dr Chan further added.

    This work was supported by the Hong Kong Research Grant Council, the
    Health and Medical Research Fund, and HKU Seed Fund for Basic Research.

    Key findings on the liver protective factor SBK1:
    * Fatty acid accumulation will induce SBK1 protein in the mouse liver,
    which serves to control lipid accumulation and fibrosis in the
    liver.

    * SBK1 protein phosphorylates and enhances the activity of Nur77,
    a well-
    established transcriptional factor, in liver cells to control the
    expression of genes for lipid synthesis. If the activity of SBK1 is
    inhibited, the Nur77-controlled gene expression will be interfered,
    leading to more fatty acid uptake and lipid accumulation.

    * Insufficient SBK1 protein decreases the production of a metabolic
    hormone
    fibroblast growth factor 21 (FGF21) in the liver cell, which
    impairs the communication between the liver and other organs,
    leading to the development of insulin resistance in other tissues.

    Note: SBK1 protein -- serves to control lipid accumulation in the liver.

    Nur77 -- a well-established transcriptional factor in liver cells to
    control the expression of genes for lipid synthesis.

    FGF21 -- a metabolic hormone fibroblast growth factor 21 in the liver
    cell, which impairs the communication between the liver and other organs.


    ========================================================================== Story Source: Materials provided by The_University_of_Hong_Kong. Note:
    Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Palak Ahuja, Xinyi Bi, Chun Fai Ng, Margaret Chui Ling Tse,
    Miaojia Hang,
    Brian Pak Shing Pang, Elsie Chit Yu Iu, Wing Suen Chan, Xin Ci
    Ooi, Anqi Sun, Oana Herlea‐Pana, Zhixue Liu, Xiuying Yang,
    Baowei Jiao, Xin Ma, Kelvin Ka Lok Wu, Leo Tsz On Lee, Kenneth
    King Yip Cheng, Chi Wai Lee, Chi Bun Chan. Src homology 3 domain
    binding kinase 1 protects against hepatic steatosis and insulin
    resistance through the Nur77‐ fibroblast growth factor 21
    pathway. Hepatology, 2022; DOI: 10.1002/ hep.32501 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/04/220419103243.htm

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