Autophagy and mitochondrial biogenesis impairment contribute to age-dependent liver injury in experimental sepsis: dysregulation of AMP-activated protein kinase pathway

作者：Inata Yu; Kikuchi Satoshi; Samraj Ravi S; Hake Paul W; O'Connor Michael; Ledford John R; O'Connor James; Lahni Patrick; Wolfe Vivian; Piraino Giovanna; Zingarelli Basilia

来源：The FASEB Journal, 2018, 32(2): 728-741.

DOI：10.1096/fj.201700576R

• AICAR
• cecal ligation and puncture
• MODS
• PGC-1 alpha

Age is an independent risk factor of multiple organ failure in patients with sepsis. However, the age-related mechanisms of injury are not known. AMPK is a crucial regulator of energy homeostasis, which controls mitochondrial biogenesis by activation of peroxisome proliferator-activated receptor-gamma coactivator-alpha (PGC-1 alpha) and disposal of defective organelles by autophagy. We investigated whether AMPK dysregulation might contribute to age-dependent liver injury in young (2-3 mo) and mature male mice (11-13 mo) subjected to sepsis. Liver damage was higher in mature mice than in young mice and was associated with impairment of hepatocyte mitochondrial function, structure, and biogenesis and reduced autophagy. At molecular analysis, there was a time-dependent nuclear translocation of the active phosphorylated catalytic subunits AMPK alpha 1/alpha 2 and PGC-1 alpha in young, but not in mature, mice after sepsis. Treatment with the AMPK activator 5-amino-4-imidazolecarboxamide riboside-1-beta-D-ribofuranoside (AICAR) improved liver mitochondrial structure in both age groups compared with vehicle. In loss-of-function studies, young knockout mice with systemic deficiency of AMPK alpha 1 exhibited greater liver injury than did wild-type mice after sepsis. Our study suggests that AMPK is important for liver metabolic recovery during sepsis. Although its function may diminish with age, pharmacological activation of AMPK may be of therapeutic benefit.

• 出版日期2018-2