Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease
Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease
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DOI：
10.1016/j.celrep.2018.12.094
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发表时间：
2019-01-22
期刊：
影响因子：
8.8
通讯作者：
Pineda-Torra, Ines
中科院分区：
文献类型：
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作者：
Becares, Natalia;Gage, Matthew C.;Pineda-Torra, Ines
非酒精性脂肪性肝病（NAFLD）是肝移植的一种非常常见的适应症。富含脂肪的饮食如何促进脂肪肝进展到更具破坏性的炎症和纤维化阶段，目前还知之甚少。在这里，我们表明，破坏肝脏X受体α（LXR α，NR 1H 3）中Ser 196（S196 A）的磷酸化可以延缓高脂高胆固醇饮食小鼠的NAFLD进展。从机制上讲，这是由关键的组蛋白乙酰化（H3 K27）和促纤维化和促炎基因的转录变化解释的。此外，S196 A-LXR α表达揭示了新的饮食特异性LXR α反应基因的调节，包括诱导Ces 1f，涉及肝脏脂质的分解。这涉及S196 A脂肪肝中诱导的H3 K27乙酰化和改变的LXR和TBLR 1辅因子在Ces 1f基因上的占有率。总的来说，受损的Ser 196-LXR α磷酸化作为一种新型的营养分子传感器，在NAFLD进展期间深刻地改变了肝脏H3 K27乙酰组和转录组，将LXR α磷酸化作为替代的抗炎或抗纤维化治疗靶点。
Non-alcoholic fatty liver disease (NAFLD) is a very common indication for liver transplantation. How fat-rich diets promote progression from fatty liver to more damaging inflammatory and fibrotic stages is poorly understood. Here, we show that disrupting phosphorylation at Ser196 (S196A) in the liver X receptor alpha (LXR alpha, NR1H3) retards NAFLD progression in mice on a high-fat-high-cholesterol diet. Mechanistically, this is explained by key histone acetylation (H3K27) and transcriptional changes in profibrotic and pro-inflammatory genes. Furthermore, S196A-LXR alpha expression reveals the regulation of novel diet-specific LXR alpha-responsive genes, including the induction of Ces1f, implicated in the breakdown of hepatic lipids. This involves induced H3K27 acetylation and altered LXR and TBLR1 cofactor occupancy at the Ces1f gene in S196A fatty livers. Overall, impaired Ser196-LXR alpha phosphorylation acts as a novel nutritional molecular sensor that profoundly alters the hepatic H3K27 acetylome and transcriptome during NAFLD progression placing LXR alpha phosphorylation as an alternative anti-inflammatory or anti-fibrotic therapeutic target.