Caspase-1 Cleavage of Aldolase B Impairs Hepatic Fructose Metabolism and Aggravates Chronic Viral Hepatitis

Abstract Of dietary monosaccharides, fructose is primarily metabolized by aldolase B (ALDOB) in the liver, whilst glucose is metabolized elsewhere in the body. It has been documented that overconsumption of dietary fructose, especially industrial fructose, associates significantly with advanced inflammation in chronic hepatitis C (CHC) patients. However, little is known about whether impaired fructolysis might attribute to CHC hepatopathogenesis. Herein we found that the level of ALDOB protein was significantly reduced in CHC patients and mice that were persistently infected by HCV. In vitro, HCV infection activated caspase-1, and caspase-3 to a lesser extent, which proteolyzed ALDOB and blocked fructose metabolism in hepatocytes. Downregulation of ALDOB attenuated HCV replication, indicating an intrinsic anti-HCV role for homeostatic fructolysis. On the other hand, reduced ALDOB caused intracellular fructose 1-phospate accumulation that provoked severe cellular toxicity through intracellular ATP depletion and heightened glycation, which was aggravated by HCV infection. Taken together, these results have unveiled that inflammatory activation of caspase-1 impairs homeostatic fructolysis and exacerbates liver damage.