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
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Nature. 2016 Jul 14;535(7611):303-7. doi: 10.1038/nature18628. Epub 2016 Jul 6.
Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available, 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, 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 element-binding protein 1 (SREBP-1, ADD1) processing. This is explained by an increase in microsomal phospholipids containing polyunsaturated fatty acids, linked to an LXRα-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.
细胞机制介导的脂肪性肝炎在西方世界日益普遍且尚无有效治疗方法，人们对其了解甚少。尽管其合成激动剂可诱导脂肪肝，但肝脏X受体（LXR）转录因子因其抗动脉粥样硬化、胆固醇清除和抗炎活性，仍是一个备受关注的靶点。我们在此表明，四肽重复结构域蛋白39B（Ttc39b，C9orf52）（T39）是在全基因组关联研究中发现的一种高密度脂蛋白基因，可促进LXR的泛素化和降解。以普通饲料喂养的缺乏T39（T39(-/-)）的小鼠，其高密度脂蛋白胆固醇水平升高，这与肠上皮细胞ATP结合盒转运蛋白A1（Abca1）表达增加以及LXR蛋白增加有关，而LXR信使核糖核酸无变化。当用高脂肪/高胆固醇/胆盐饮食进行挑战时，T39(-/-)小鼠或肝细胞特异性缺乏T39的小鼠显示肝脏LXR蛋白和靶基因表达增加，且意外地对脂肪性肝炎和死亡具有保护作用。喂食西式饮食且缺乏低密度脂蛋白受体的小鼠（Ldlr(-/-)T39(-/-)）显示脂肪肝减轻、高密度脂蛋白增加、低密度脂蛋白降低以及动脉粥样硬化减轻。除了增加肝脏Abcg5/8表达并限制膳食胆固醇吸收外，T39缺乏还抑制肝脏固醇调节元件结合蛋白1（SREBP-1，ADD1）的加工。这是由于含有多不饱和脂肪酸的微粒体磷脂增加所致，这与LXRα依赖性增加介导磷脂酰胆碱生物合成以及将多不饱和脂肪酸掺入磷脂的酶的表达有关。内源性LXR蛋白的保留激活了有益的基因表达谱，促进胆固醇清除并抑制脂肪生成。抑制T39可能是减轻脂肪性肝炎和动脉粥样硬化的有效策略。
