背景:代谢相关脂肪性肝病(MAFLD),影响全球三分之一人口的普遍肝脏疾病,包括从脂肪肝到严重肝性脂肪变性的范围。遗传和生活方式因素,特别是饮食和营养,有助于其病因。叶酸缺乏,经常遇到的营养不良类型,与MAFLD的发病机制有关,并显示影响脂质沉积。然而,这种关系的潜在机制仍未完全理解。我们研究了叶酸介导的单碳代谢(OCM)在体外使用人肝癌细胞和体内使用转基因荧光斑马鱼显示范围对肝脏脂质代谢的影响,stage-,和诱导后持续时间可控的叶酸缺乏。
结果:叶酸介导的单碳代谢紊乱,通过诱导叶酸缺乏或添加抗叶酸药物,损害自噬并导致肝细胞中的脂质积累。受干扰的叶酸状态下调组织蛋白酶L,参与自噬的关键酶,通过抑制mTOR信号。干扰的线粒体生物学,包括线粒体重新定位和增加的融合裂变动力学,也发生在缺乏叶酸的肝细胞。叶酸补充可有效减轻组织蛋白酶L活性抑制引起的自噬和脂质积累,即使抑制与叶酸缺乏没有直接关系。
结论:叶酸介导的OCM的破坏减少了组织蛋白酶L的表达,并通过mTOR信号传导阻碍了自噬,导致肝细胞内脂质积累。这些发现强调了叶酸在调节肝脏自噬过程和调节脂质代谢中的关键作用。
BACKGROUND: Metabolic associated fatty liver disease (MAFLD), a prevalent liver disorder affecting one-third of the global population, encompasses a spectrum ranging from fatty liver to severe hepatic steatosis. Both genetic and lifestyle factors, particularly diet and nutrition, contribute to its etiology. Folate deficiency, a frequently encountered type of malnutrition, has been associated with the pathogenesis of MAFLD and shown to impact lipid deposition. However, the underlying mechanisms of this relationship remain incompletely understood. We investigated the impact of disturbed folate-mediated one-carbon metabolism (OCM) on hepatic lipid metabolism both in vitro using human hepatoma cells and in vivo using transgenic fluorescent zebrafish displaying extent-, stage-, and duration-controllable folate deficiency upon induction.
RESULTS: Disturbed folate-mediated one-carbon metabolism, either by inducing folate deficiency or adding anti-folate drug, compromises autophagy and causes lipid accumulation in liver cells. Disturbed folate status down-regulates cathepsin L, a key enzyme involved in autophagy, through inhibiting mTOR signaling. Interfered mitochondrial biology, including mitochondria relocation and increased fusion-fission dynamics, also occurs in folate-deficient hepatocytes. Folate supplementation effectively mitigated the impaired autophagy and lipid accumulation caused by the inhibition of cathepsin L activity, even when the inhibition was not directly related to folate deficiency.
CONCLUSIONS: Disruption of folate-mediated OCM diminishes cathepsin L expression and impedes autophagy via mTOR signaling, leading to lipid accumulation within hepatocytes. These findings underscore the crucial role of folate in modulating autophagic processes and regulating lipid metabolism in the liver.