PDF(Pubmed)
Abstract：
Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is a growing epidemic with an estimated prevalence of 20%-30% in Europe and the most common cause of chronic liver disease worldwide. The onset and progression of MASLD are orchestrated by an interplay of the metabolic environment with genetic and epigenetic factors. Emerging evidence suggests altered DNA methylation pattern as a major determinant of MASLD pathogenesis coinciding with progressive DNA hypermethylation and gene silencing of the liver-specific nuclear receptor PPARα, a key regulator of lipid metabolism. To investigate how PPARα loss of function contributes to epigenetic dysregulation in MASLD pathology, we studied DNA methylation changes in liver biopsies of WT and hepatocyte-specific PPARα KO mice, following a 6-week CDAHFD (choline-deficient, L-amino acid-defined, high-fat diet) or chow diet. Interestingly, genetic loss of PPARα function in hepatocyte-specific KO mice could be phenocopied by a 6-week CDAHFD diet in WT mice which promotes epigenetic silencing of PPARα function via DNA hypermethylation, similar to MASLD pathology. Remarkably, genetic and lipid diet-induced loss of PPARα function triggers compensatory activation of multiple lipid sensing transcription factors and epigenetic writer-eraser-reader proteins, which promotes the epigenetic transition from lipid metabolic stress towards ferroptosis and pyroptosis lipid hepatoxicity pathways associated with advanced MASLD. In conclusion, we show that PPARα function is essential to support lipid homeostasis and to suppress the epigenetic progression of ferroptosis-pyroptosis lipid damage associated pathways towards MASLD fibrosis.
摘要：
代谢功能障碍相关的脂肪变性肝病（MASLD）是一种日益增长的流行病，在欧洲估计患病率为20％-30％，是全球慢性肝病的最常见原因。MASLD的发生和发展是通过代谢环境与遗传和表观遗传因素的相互作用来协调的。新的证据表明，改变DNA甲基化模式是MASLD发病机制的主要决定因素，与肝脏特异性核受体PPARα的进行性DNA超甲基化和基因沉默相吻合。脂质代谢的关键调节剂。为了研究PPARα功能丧失如何导致MASLD病理学中的表观遗传失调，我们研究了WT和肝细胞特异性PPARαKO小鼠肝活检中的DNA甲基化变化，在6周的CDAHFD(胆碱缺乏，L-氨基酸定义，高脂肪饮食）或饮食。有趣的是,肝细胞特异性KO小鼠中PPARα功能的遗传丧失可以通过WT小鼠中6周的CDAHFD饮食来表现，该饮食通过DNA超甲基化促进PPARα功能的表观遗传沉默，类似于MASLD病理学。值得注意的是,遗传和脂质饮食诱导的PPARα功能丧失触发多种脂质传感转录因子和表观遗传书写者-擦除者-阅读蛋白的代偿激活，它促进了从脂质代谢应激向铁凋亡和焦凋亡的表观遗传转变与晚期MASLD相关的脂质肝毒性途径。总之,我们表明PPARα功能对于支持脂质稳态和抑制铁凋亡-焦凋亡脂质损伤相关途径向MASLD纤维化的表观遗传进展至关重要。
