Caffeine reduces hepatic lipid accumulation through regulation of lipogenesis and ER stress in zebrafish larvae

Caffeine, the main component of coffee, has showed its protective effect on non-alcoholic fatty liver disease (NAFLD) in many studies. However, the hepatoprotection of caffeine and its mechanisms in zebrafish were unexplored. Thus, this study's intentions are to establish a NAFLD model of zebrafish larvae and to examine the role of caffeine on fatty liver with the model.

We induced hepatoteatosis in zebrafish by overfeeding regimen and demonstrated caffeine have a role in suppression of hepatosteatosis by downregulation of genes associated with lipogenesis, ER stress, inflammatory response and enhancement of lipid oxidation, indicating zebrafish model may be used to identify putative pharmacological targets and to test novel drugs for human NAFLD treatment.

Growth and the incidence of fatty liver of zebrafish larvae increased with the increased amount of feeding in a dose-dependent manner. The degree of hepatic steatosis of larvae also gradually aggravated with the increased quantity and duration of feeding. Triglyceride contents of zebrafish fed for 20 days significantly increased in model group (180 mg/d) compared with control group (30 mg/d) (P < 0.001). Significant decreases in body weight and hepatic steatosis rate were observed in 2.5, 5, 8 % caffeine treatment group compared with model group (P < 0.05). Hepatic lipid accumulation was also significantly reduced in caffeine treatment larvae. Moreover, caffeine treatment was associated with upregulation of lipid β-oxidation gene ACO and downregulation of lipogenesis-associated genes (SREBP1, ACC1, CD36 and UCP2), ER stress-associated genes (PERK, IRE1, ATF6 and BIP), the inflammatory cytokine genes (IL-1beta and TNF-alpha) and autophagy associated genes (ATG12 and Beclin-1). Protein expression of CHOP, BIP and IL-1beta remarkably reduced in caffeine treatment group compared with model group. Conclusions: We induced hepatoteatosis in zebrafish by overfeeding regimen and demonstrated caffeine have a role in suppression of hepatosteatosis by downregulation of genes associated with lipogenesis, ER stress, inflammatory response and enhancement of lipid oxidation, indicating zebrafish model may be used to identify putative pharmacological targets and to test novel drugs for human NAFLD treatment.