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Arazyme, a metalloprotease from the spider <i>Nephila clavata</i>, exerts hepatoprotective activity in CCL₄-induced acute hepatic injury. This study investigated the hepatoprotective effects in high-fat diet (HFD)-induced non-alcoholic fatty liver disease-like C57BL/6J mice. The mice were randomly divided into four groups (<i>n</i> = 10/group): the normal diet group, the HFD group, the arazyme group (HFD with 0.025% arazyme), and the milk thistle (MT) group (HFD with 0.1% MT). Dietary supplementation of arazyme for 13 weeks significantly lowered plasma triglyceride (TG) and non-esterified fatty acid levels. Suppression of HFD-induced hepatic steatosis in the arazyme group was caused by the reduced hepatic TG and total cholesterol (TC) contents. Arazyme supplementation decreased hepatic lipogenesis-related gene expression, sterol regulatory element-binding transcription protein 1 (<i>Srebf1)</i>, fatty acid synthase (<i>Fas</i>), acetyl-CoA carboxylase 1 (<i>Acc1</i>), stearoyl-CoA desaturase-1 (<i>Scd1</i>), <i>Scd2</i>, glycerol-3-phosphate acyltransferase (<i>Gpam</i>), diacylglycerol <i>O</i>-acyltransferase 1 (<i>Dgat1</i>), and <i>Dgat2</i>. Arazyme directly reduced palmitic acid (PA)-induced TG accumulation in HepG2 cells. Arazyme suppressed macrophage infiltration and tumor necrosis factor &#945; (<i>Tnfa</i>), interleukin-1&#946; (<i>Il1b</i>), and chemokine-ligand-2 (<i>Ccl2</i>) expression in the liver, and inhibited secretion of TNF&#945; and expression of inflammatory mediators, <i>Tnfa</i>, <i>Il1b</i>, <i>Ccl2</i>, <i>Ccl3</i>, <i>Ccl4</i>, and <i>Ccl5</i>, in PA-induced RAW264.7 cells. Arazyme effectively protected hepatic steatosis and steatohepatitis by inhibiting SREBP-1-mediated lipid accumulation and macrophage-mediated inflammation.