Development of nonalcoholic steatohepatitis model through combination of high-fat diet and tetracycline with morbid obesity in mice

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease closely associated with obesity, type 2 diabetes and hyperlipidemia. For further understanding of NASH, development and characterization of appropriate animal models with metabolic abnormalities is important. Based on the “two hit theory”, we tried to develop a new murine model of NASH with metabolic abnormalities. For the first hit to achieve metabolic abnormalities, a high-fat diet (HFD: 60 cal% fat) was fed to C57BL/6 mice for 10 weeks. For the second hit, 30 mg/kg tetracycline was injected intraperitoneally once daily for 10 days. The HFD-fed mice treated with tetracycline showed robust increases in triglyceride content and expression levels of proinflammatory cytokine mRNAs in the liver. In addition, plasma ALT levels were significantly elevated by this combinational treatment. Furthermore, histological examination demonstrated that combinational treatment induced multifocal inflammatory cellular infiltration in the livers of all mice, and thus caused mild steatohepatitis. The HFD-tetracycline model could be useful for further understanding NASH.