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首页> 外文期刊>Nature >TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis
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TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis

机译：TTC39B缺乏症可稳定LXR，减少动脉粥样硬化和脂肪性肝炎

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摘要

Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available(1), are poorly understood. Despite the fact that its synthetic agonists induce fatty liver, the liver X receptor (LXR) transcription factor remains a target of interest because of its anti-atherogenic, cholesterol removal, and anti-inflammatory activities. Here we show that tetratricopeptide repeat domain protein 39B (Ttc39b, C9orf52) (T39), a high-density lipoprotein gene discovered in human genome-wide association studies(2), promotes the ubiquitination and degradation of LXR. Chow-fed mice lacking T39 (T39(-/-)) display increased high-density lipoprotein cholesterol levels associated with increased enterocyte ATP-binding cassette transporter A1 (Abca1) expression and increased LXR protein without change in LXR messenger RNA. When challenged with a high fat/high cholesterol/bile salt diet, T39(-/-) mice or mice with hepatocyte-specific T39 deficiency show increased hepatic LXR protein and target gene expression, and unexpectedly protection from steatohepatitis and death. Mice fed a Western-type diet and lacking low-density lipoprotein receptor (Ldlr(-/-)T39(-/-)) show decreased fatty liver, increased high-density lipoprotein, decreased low-density lipoprotein, and reduced atherosclerosis. In addition to increasing hepatic Abcg5/8 expression and limiting dietary cholesterol absorption, T39 deficiency inhibits hepatic sterol regulatory elementbinding protein 1 (SREBP-1, ADD1) processing. This is explained by an increase in microsomal phospholipids containing polyunsaturated fatty acids, linked to an LXRa-dependent increase in expression of enzymes mediating phosphatidylcholine biosynthesis and incorporation of polyunsaturated fatty acids into phospholipids. The preservation of endogenous LXR protein activates a beneficial profile of gene expression that promotes cholesterol removal and inhibits lipogenesis. T39 inhibition could be an effective strategy for reducing both steatohepatitis and atherosclerosis.
机译：介导脂肪性肝炎的细胞机制，在西方世界越来越普遍，没有可用的疗法（1），对此知之甚少。尽管其合成的激动剂诱导了脂肪肝，但由于其抗动脉粥样硬化，去除胆固醇和抗炎活性，肝X受体（LXR）转录因子仍然是人们关注的目标。在这里，我们显示在人全基因组关联研究中发现的高密度脂蛋白基因四糖肽重复域蛋白39B（Ttc39b，C9orf52）（T39）促进LXR的泛素化和降解。缺少T39（T39（-/-））的纯熟小鼠显示出高密度脂蛋白胆固醇水平升高，与肠细胞ATP结合盒转运蛋白A1（Abca1）表达增加相关，LXR蛋白增加而LXR信使RNA不变。当用高脂肪/高胆固醇/胆汁盐饮食挑战时，T39（-/-）小鼠或具有肝细胞特异性T39缺乏症的小鼠显示肝LXR蛋白和靶基因表达增加，并且出乎意料地防止脂肪性肝炎和死亡。喂食西式饮食且缺乏低密度脂蛋白受体（Ldlr（-/-）T39（-/-））的小鼠表现出脂肪肝减少，高密度脂蛋白增加，低密度脂蛋白减少以及动脉粥样硬化。除了增加肝脏Abcg5 / 8的表达并限制饮食中胆固醇的吸收外，T39缺乏还会抑制肝脏固醇调节元素结合蛋白1（SREBP-1，ADD1）的加工。这可以通过含有多不饱和脂肪酸的微粒体磷脂的增加来解释，这与介导磷脂酰胆碱生物合成的酶的表达的LXRa依赖性增加以及多不饱和脂肪酸掺入磷脂有关。内源性LXR蛋白的保存激活了基因表达的有益特征，从而促进了胆固醇的去除并抑制了脂肪形成。抑制T39可能是减少脂肪性肝炎和动脉粥样硬化的有效策略。

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  • 来源
    《Nature》 |2016年第7611期|303-307|共5页
  • 作者

    Hsieh Joanne; Koseki Masahiro; Molusky Matthew M.; Yakushiji Emi; Ichi Ikuyo; Westerterp Marit; Iqbal Jahangir; Chan Robin B.; Abramowicz Sandra; Tascau Liana; Takiguchi Shunichi; Yamashita Shizuya; Welch Carrie L.; Di Paolo Gilbert; Hussain M. Mahmood; Lefkowitch Jay H.; Rader Daniel J.; Tall Alan R.;

  • 作者单位

    Columbia Univ, Dept Med, Div Mol Med, New York, NY 10032 USA;

    Columbia Univ, Dept Med, Div Mol Med, New York, NY 10032 USA|Osaka Univ, Grad Sch Med, Cardiovasc Med, Suita, Osaka 5650871, Japan;

    Columbia Univ, Dept Med, Div Mol Med, New York, NY 10032 USA;

    Columbia Univ, Dept Med, Div Mol Med, New York, NY 10032 USA;

    Ochanomizu Univ, Fac Core Res, Bunkyo Ku, Tokyo 1128610, Japan;

    Columbia Univ, Dept Med, Div Mol Med, New York, NY 10032 USA;

    Suny Downstate Med Ctr, Hlth Sci Ctr, Dept Cell Biol, Brooklyn, NY 11203 USA;

    Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA;

    Columbia Univ, Dept Med, Div Mol Med, New York, NY 10032 USA;

    Columbia Univ, Dept Med, Div Mol Med, New York, NY 10032 USA;

    Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA|Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA;

    Osaka Univ, Grad Sch Med, Cardiovasc Med, Suita, Osaka 5650871, Japan;

    Columbia Univ, Dept Med, Div Mol Med, New York, NY 10032 USA;

    Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA;

    Suny Downstate Med Ctr, Hlth Sci Ctr, Dept Cell Biol, Brooklyn, NY 11203 USA;

    Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA;

    Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA|Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA;

    Columbia Univ, Dept Med, Div Mol Med, New York, NY 10032 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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