硫辛酸提高三酸甘油脂水解酶之表現並減少肝臟三酸甘油脂之堆積

Adipose triglyceride lipase(ATGL)為近年發現的水解三酸甘油脂之關鍵酵素。過去的研究中顯示經由活化AMPK，可以增加ATGL的表現，進而促進脂肪的水解；而α-lipoic acid則可以活化AMPK途徑。由於目前脂肪肝在臨床上並無有效的藥物可以治療脂肪肝或是減緩脂肪肝的發展，α-lipoic acid可嘗試用為脂肪肝的治療藥物。曾有研究顯示α-lipoic acid可以有效抑制肝臟脂肪合成途徑，但是目前對於α-lipoic acid造成脂肪分解的機制並不明瞭。本研究先證實在給予HepG2細胞高糖(30 mM glucose)高脂(0.1 mM palmitate)的情況下， HepG2細胞會產生脂肪堆積的現象，並由此建立細胞脂肪肝模式。而實驗中發現以AMPK活化劑AICAR或metformin處理細胞後，皆可以促進ATGL蛋白的表現，並且有效使細胞內的脂肪堆積情形下降。以α-lipoic acid處理細胞之後的確可活化AMPK並促進ATGL的蛋白表現；FoxO1為ATGL的轉錄因子，α-lipoic acid可以使FoxO1去磷酸化並移至細胞核內，使得ATGL蛋白表現量增加。本實驗證明 α-lipoic acid 會經由AMPK或p38/FoxO1/ATGL途徑有效減緩脂肪堆積。經由本研究以了解α-lipoic acid對於脂肪水解的訊息途徑，並證明促進ATGL表現可減低肝細胞內已堆積之脂肪。

關鍵字

ATGL ； α-lipoic acid ；脂肪肝

並列摘要

Recent discovered adipose triglyceride lipase (ATGL) is responsible for triacylglycerol hydrolase activity in cells. Activation of AMP-activated protein kinase (AMPK) signaling pathway induces ATGL protein expression and improve lipid hydrolysis. Alpha-lipoic acid has been shown to activate the AMPK signaling pathway, and effectively inhibits the lipogenesis pathway in liver. However, the mechanisms by which α-lipoic acid stimulate lipolysis remain unclear. In the present study, we established a liver steatosis cell model by incubating HepG2 cells with high fat (0.1mM palmitate) and high glucose (30mM glucose) medium. Treatment of cells with the AMPK activators, AICAR or metformin, induced ATGL protein expression, and ameliorated intracellular lipid accumulation. α-lipoic acid-induced ATGL expression and reduction of intracellular lipid accumulation were associated with increases of AMPK and p38 phosphorylation. Forkhead box O1 (FoxO1) is a transcription factor that regulates ATGL expression. α-lipoic dephosphorylated FoxO1, and stimulated FoxO1 translocation into the nucleus. In conclusion, we demonstrated that α-lipoic acid could induced ATGL expression, which effectively ameliorate intracellular lipid accumulation through FoxO1/ATGL pathway in liver cells. Our data suggest that α-lipoic acid may be a potential therapeutic agent for fatty liver disease.

並列關鍵字

ATGL, α-lipoic acid, liver steatosis

參考文獻

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硫辛酸提高三酸甘油脂水解酶之表現並減少肝臟三酸甘油脂之堆積

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