PI3K/AKT/mTOR通路
粒体自噬
生物
内分泌学
癌症研究
内科学
化学
自噬
生物化学
医学
信号转导
细胞凋亡
作者
Thomas Winans,Zachary Oaks,G. Choudhary,Akshay Patel,Nick Huang,T. Faludi,Dániel Krakkó,James P. Nolan,Jacqueline S. Lewis,Sarah L. Blair,Zhi-Wei Lai,Steve K. Landas,Frank A. Middleton,John M. Asara,Sookja K. Chung,Brenda Wyman,Parastoo Azadi,Katalin Bánki,András Perl
标识
DOI:10.1016/j.jaut.2023.103112
摘要
Transaldolase deficiency predisposes to chronic liver disease progressing from cirrhosis to hepatocellular carcinoma (HCC). Transition from cirrhosis to hepatocarcinogenesis depends on mitochondrial oxidative stress, as controlled by cytosolic aldose metabolism through the pentose phosphate pathway (PPP). Progression to HCC is critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Although AR inactivation blocked susceptibility to hepatocarcinogenesis, it enhanced growth restriction, carbon trapping in the non-oxidative branch of the PPP and failed to reverse the depletion of glucose 6-phosphate (G6P) and liver cirrhosis. Here, we show that inactivation of the TAL-AR axis results in metabolic stress characterized by reduced mitophagy, enhanced overall autophagy, activation of the mechanistic target of rapamycin (mTOR), diminished glycosylation and secretion of paraoxonase 1 (PON1), production of antiphospholipid autoantibodies (aPL), loss of CD161+ NK cells, and expansion of CD38+ Ito cells, which are responsive to treatment with rapamycin in vivo. The present study thus identifies glycosylation and secretion of PON1 and aPL production as mTOR-dependent regulatory checkpoints of autoimmunity underlying liver cirrhosis in TAL deficiency.
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