Exacerbated oxidative stress in the fasting liver according to fuel partitioning

Complete starvation may prove lethal due to excessive loss of body proteins. However, it is still not completely understood whether responses to food deprivation are time-dependently induced or triggered in relation with the successive phases of protein sparing and wasting that characterize prolonged fasting. As the liver has a wide range of vital functions, we examined the hepatic regulatory mechanisms elicited during prolonged fasting. We showed that fasting-induced transcriptome/proteome changes occur in close relation with fuel partitioning, independently of ATP levels. Omics data suggesting a worsening of oxidative stress during the proteolytic stage of fasting were further validated using biochemical assays. Low levels of antioxidant factors were indeed paralleled by their decreased activity that could be impaired by low NADPH levels. Oxidative damage to lipids and proteins was accordingly increased only during late fasting. At this stage, the gene/protein expression of several chaperones was also repressed. Together with the impairment of metabolic achievements, a vicious cycle involving protein misfolding and oxidative stress could jeopardize liver function when the proteolytic stage of fasting is reached. Thus, monitoring of liver impairments should help to better manage or treat catabolic and/or oxidative stress conditions, such as ageing and degeneration.