Glycogenic hepatopathy in a primitive teleost fish model: the inductive effect of high carbohydrate diet and the alleviating role of betaine

Carbohydrate-induced glycogenic hepatopathy is underdiagnosed and difficult to discriminate from hepatic steatosis in humans. The present study used liver biopsy and other diagnostic tools, and adopted metabolomic technology to identify glycogenic hepatopathy rather than hepatic steatosis in largemouth bass induced by high carbohydrate diet (HC). HC induced obvious liver injury in largemouth bass with disarranged hepatocytes, partial cell membrane damage, and irregular distribution of nuclei, accompanied by increased serum ALT and AST activities. PAS staining and glycogen content analysis detected significant increases in liver glycogen content, whereas intrahepatic triglyceride content and programmed cell death were not affected. Metabolomic analysis indicated that up-regulated metabolites were mainly enriched in glycogen synthesis precursors, whereas betaine and unsaturated fatty acids were down-regulated, confirming that HC induced glycogenic hepatopathy rather than hepatic steatosis in largemouth bass. The significantly decreased betaine in both serum and liver of largemouth bass served as a potential key regulator in such disease, whose supplementation could alleviate HC-induced liver injury and serum ALT activity. Betaine supplementation increased betaine and carnitine contents in liver and serum, resulting in decreased hepatic glycogen deposition and cortisol content in largemouth bass. Further study showed that dietary betaine significantly improved the capacity of largemouth bass to resist against ammonia stress. Therefore, our study established a glycogenic hepatopathy-inducing and evaluation model in a primitive teleost and also identified the betaine as the key metabolic marker and prevent strategy, which help advance the understanding of human liver diseases.