Pcsk9 .. هل سيمثّل فتحاً جديداً لمرضى ارتفاع الكوليسترول الورااثي في الدم

الكاتب : مروان الغفوري   المشاهدات : 553   الردود : 3    ‏2005-04-03
      مشاركة رقم : 1    ‏2005-04-03
  1. مروان الغفوري

    مروان الغفوري شاعر وكاتب

    التسجيل :
    ‏2004-01-13
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    Deleting Pcsk9 gene results in increased LDL-receptor expression and lower LDL-cholesterol levels

    Mar 31, 2005 Michael O'Riordan


    Dallas, TX - In the livers of mice lacking Pcsk9, a gene that encodes proprotein covertase subtilisin kexin 9a (Pcsk9), implicated as a possible participant in lipid metabolism, there is an increased expression of LDL-receptor protein compared with normal mice, according to the results of a new study.[1] The increased number of hepatic LDL receptors results in decreased plasma cholesterol levels and an increased clearance of circulating lipoproteins, report investigators.

    "We are starting to gain some insight into how this Pcsk9 protein causes low cholesterol," senior researcher Dr Jay Horton (University of Texas Southwestern, Dallas) told heartwire. "What we found was that when we delete the gene that encodes the protein, the expression of the LDL receptor is increased, as much as 2.8 times in the knockout mice compared with mice with the Pcsk9 protein."

    The results of the study are published online before print March 29, 2005 in the Proceedings of the National Academy of Sciences.



    Increase in LDL receptors, no change in mRNA
    In an interview with heartwire, Horton said that recent studies have suggested that the Pcsk9 protein might transcriptionally regulate hepatic LDL receptors. One study showed that overexpression of Pcsk9 decreased the number of LDL receptors on the liver cells of wild-type mice, resulting in an increase in total and LDL cholesterol. Another study showed that mutations in Pcsk9 are associated with an autosomal dominant form of hypercholesterolemia, which is caused by defective receptor-mediated clearance of LDL cholesterol. These studies led researchers to hypothesize that the Pcsk9 protein might function to reduce LDL-receptor expression levels in the liver.

    Targeting this protein, investigators knocked out Pcsk9 in mice, which resulted in, on average, hepatic LDL-receptor levels that were 2.8 times higher than in the wild-type mice. This resulted in plasma cholesterol levels that were 48% lower, despite similar levels of plasma triglycerides. In the Pcsk9-knockout mice, plasma cholesterol levels were reduced to 46 mg/dL, whereas the cholesterol levels of the normal mice were 96 mg/dL.

    Importantly, Horton and colleagues found no changes in the mRNA encoding the LDL-receptor protein or in other proteins involved in cholesterol and fatty-acid synthesis. This study, he said, is the first clear documentation that there is also posttranscriptional regulation of the LDL receptor.

    Horton added that this study largely confirms and provides mechanistic insight into work published last month by Drs Jonathan Cohen and Helen Hobbs (University of Texas Southwestern, Dallas).[2] In a study published in the February 2005 issue of Nature Genetics, Cohen and Hobbs showed that humans with mutations in Pcsk9 had LDL-cholesterol levels 40% lower than those without the mutation.



    Dual role of statins
    After determining that mice lacking the Pcsk9 protein had more LDL receptors, the researchers then treated the Psck9-knockout mice with a statin. Horton explained that statins work by reducing cellular cholesterol levels, which, in turn, activates sterol regulatory element-binding protein-2 (SREBP-2). While the activation of SREBP-2 leads to the transcriptional activation of more LDL receptors, it also activates Pcsk9, the protein investigators now know leads to reduced LDL-receptor proteins.

    "It's a bit of a biologic conundrum that we don't quite understand yet," said Horton. "The cell is simultaneously activating one pathway, which leads to more LDL-receptor protein expression, and Pcsk9, which leads to a reduction. We hypothesized that by removing this Pcsk9 part of the pathway, the negative regulator, we could get a greater benefit with a statinthat is, a further induction of the LDL receptor."

    Treating the Pcsk9-knockout mice with lovastatin did result in a reduction of plasma cholesterol levels above and beyond what was seen in the normal mice and knockout mice not treated with a statin, the researchers found. In addition to plasma cholesterol levels decreasing to 41 mg/dL, the expression of LDL-receptor proteins in the livers of the statin-treated, Pcsk9-knockout mice was 4.6 times higher than the chow-fed wild-type mice.

    "You could hypothesize that based on these mice studies, an inhibitor of this protease would likely work alone as an agent to reduce LDL cholesterol but would also work synergistically with a statin to reduce LDL-cholesterol levels even further," said Horton.

    Next steps for the researchers will be to determine exactly how the Pcsk9 protein acts on the LDL receptor. It is not known whether it acts directly on the receptor or works indirectly by destroying other proteins, said Horton.
     
  2.   مشاركة رقم : 2    ‏2005-04-04
  3. عبد المطلب

    عبد المطلب عضو

    التسجيل :
    ‏2005-03-20
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    الأخ مروان يالله نفك العربي تقوم تعطينا إنجليزي هداك الله ..
    ممكن تترجم ما كتبته فضلا لا أمراً
     
  4.   مشاركة رقم : 3    ‏2005-04-05
  5. عاشق الابتسامات

    عاشق الابتسامات مشرف سابق

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    ‏2003-03-28
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    الاديب و الطبيب مروان الغفوري ,,
    كم انا سعيد بمشاركاتك هذه في مجلسنا هذا و كم هي امنية ان تشاركنا فيه دوما لننهض به
    بالفعل هناك مقالات طبية كثيرة باللغة الانجليزية يسر طلابالطب و الاطباء قرائتها و التي قد لا يستطيع فهمها العامة و قد خطرت لي فكرة بانشاء فرع في هذا المجلس للاطباء وطلبة الطب فما رأيك اخي مروان في هذا
    هل توافقني في ذلك ؟؟ وماهو رأي الاخوة الاعزاء في المجلس و ذلك حتى نكون دوما على علم بأحدث ما يتوصل اليه الطب وحتى نستطيع ان نتناقش فيما بيننا بشكل اكثر افادة ..

    العزيز مروان كم افرحني رؤية اسمك بين كتاب مجلس الطب والصحة
    واتمنى دوما وجودك كما هو امل الرواد للمجلس و لك ان تمر على هذا الرابط
    http://www.ye1.org/vb/showthread.php?t=114027


    الاخ العزيز عبد المطلب ربما لان هذه المقالة طبية اراد بها الدكتور مروان شريحة الاطباء والطلاب لم تترجم و اختصار المقالة هي دراسة اشارت عن تقدم الابحاث و اكتشاف عوامل لخفض الكلسترول الضار في الجسم الذي هو من العوامل المهمة في ازدياد الخطر بالاصابة بالضغط وامراض القلب المنتشرة عالميا اما ترجمة المقالة حرفيا فسيكون من الصعب فهمه مالم يكن القارىء درس الطب و كم هو شيء مشرف ومبهج ان نجد من هم حريصين على العلم والاستفادة بارك الله لك وفيك ايها الطيب
     
  6.   مشاركة رقم : 4    ‏2005-04-05
  7. عبدالله

    عبدالله مشرف سابق

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    آآآخيراً مروان هنا ..

    في محادثة قصيرة وخجولة مع الاديب مروان الغفوري على برنامج المحادثة الشهير (( مسانجر )) , تحدثنا سريعاً عن مجلس الطب والصحة , وابدى لي رايه الخاص في هذا القسم , ودعوته لزيارتنا وها هو قد حط رحاله.

    د.مروان الغفوري .. لما لا نجتمع حتى نرتقي بهذا القسم , ونجعلة يقدم "طبً ".


    احترامي.
     

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