Metabolic-associated fatty liver disease (MAFLD)是全球最常見的慢性肝臟疾病，影響全球約 25% 的人口。低葉酸含量也被發現會增加肝臟損傷的風險，並且在許多患有慢性肝臟疾病的患者中發現葉酸含量降低，這意味著葉酸在肝臟疾病中扮演重要的角色。葉酸參與核苷酸，氨基酸和S-腺苷甲硫氨酸的生合成，對細胞增生和基因活性調節相當重要。然而，個體的葉酸含量如何影響肝臟生理和病理機制仍不清楚。在本篇研究中，我們使用可誘導葉酸缺乏的轉殖基因斑馬魚來研究葉酸缺乏是如何影響肝臟生理及病理變化。我們的研究結果顯示葉酸缺乏轉殖基因魚肝臟腫大，補充葉酸可以抑制肝臟腫大，證實了葉酸缺乏會導致肝臟腫大。抑制細胞增生和提供核苷酸並不能抑制葉酸缺乏誘導的肝腫大。在葉酸缺乏斑馬魚中觀察到 mixed lineage kinase domain-like (MLKL) 蛋白質磷酸化上升和yes-associated protein (YAP) 蛋白質磷酸化下降，抑制YAP表現和壞死性凋亡顯著避免葉酸缺乏誘導的肝臟腫大。利用流式細胞儀分析從葉酸缺乏轉殖基因魚肝臟分離出的肝臟細胞顯示肝臟細胞大小顯著增加。我們也發現抑制巨噬細胞、tumor necrosis factor α (TNFα)、MLKL及YAP可以顯著抑制葉酸缺乏誘導的肝臟腫大和肝臟細胞增大。此外，我們發現提高TNFα 蛋白質表現會抑制YAP蛋白質的磷酸化。同時，我們也發現葉酸缺乏還損害了自噬作用的過程，進而導致脂肪累積。我們在葉酸缺乏斑馬魚和Huh7中發現三酸甘油酯的表現量顯著上升。在葉酸缺乏細胞也觀察到 mTORs2448 蛋白質磷酸化下降和p62 蛋白質上升，表示自噬作用受到阻礙。葉酸缺乏也造成斑馬魚和Huh7 細胞中組織蛋白酶 L 的 mRNA 表現下降。在葉酸缺乏肝癌細胞中重新表現組織蛋白酶 L可以減弱葉酸缺乏所誘導的脂肪累積。簡而言之，葉酸缺乏增加肝細胞的大小和脂質累積，這可能會增加罹患肝臟疾病的風險。

Metabolic-associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide and affects approximately twenty-five percent of the global population. Low folate had been shown to increase the risks for liver damage and found in patients suffering from chronic liver diseases, implying a role for folate in hepatic pathogenesis. Folate participates in the biosynthesis of nucleotides, amino acids, and S-adenosylmethionine, and is crucial to cell proliferation and gene activity modulation. However, how individual’s folate status contribute to hepatic pathology remains unclear. In this study, we investigated how changing folate status affected liver physiology using a transgenic zebrafish line displaying inducible folate deficiency (FD). Our data show that FD larvae displayed liver enlargement, which was prevented by folate supplementation. Inhibiting cell proliferation and supplying with nucleotides did not rescue FD-induced hepatomegaly. Up-regulation of mixed lineage kinase domain-like (MLKL) phosphorylation and down-regulation of yes-associated protein (YAP) phosphorylation were observed in FD cells. Inhibition of MLKL and YAP expression significantly ameliorated FD-induced hepatomegaly. Flow cytometry analysis on the hepatocytes isolated from larval liver revealed significantly increased cell size. Inhibition of macrophage, tumor necrosis factor α (TNFα), MLKL, and YAP significantly rescued FD-induced hepatocyte enlargement. Moreover, the elevation of TNFα protein level has been closely associated with decreased YAP phosphorylation. FD also impaired the autophagy process resulting in lipid accumulation. The level of triglycerides significantly increased in FD fish and FD Huh7 cells. Down-regulation of mTORs2448 phosphorylation and up-regulation of p62 were observed in FD cells, indicating blockage of autophagy flux. FD significantly downregulated the expression of cathepsin L in vitro and in vivo. Reexpression of cathepsin L in FD Huh7 cells prevented FD-induced lipid accumulation. In conclusion, FD increased the size of hepatocytes and lipid accumulation in vitro and in vivo, which might increase the risk of developing liver disease.

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