hemp3quilt posted an update 1 week, 1 day ago
05) ( Fig. 3D). After confirming a preventive effect on steatohepatitis, we further examined whether CXCL10 neutralization could treat steatohepatitis after it has been established. After induction of steatohepatitis in mice fed the MCD diet for 3 weeks, anti-CXCL10 mAb or control mAb was supplemented for 10 days under MCD diet. Histological analysis of livers by H&E and Oil red O staining showed significantly reduced lipid accumulation and inflammatory cell infiltration in MCD-fed mice treated with anti-CXCL10 mAb (Fig. 3E). Anti-CXCL10 http://www.selleckchem.com mAb treatment in MCD-fed mice also significantly decreased hepatic triglyceride and lipid peroxide levels compared to MCD-fed mice administrated with control mAb (Fig. 3F). Moreover, CXCL10 neutralization suppressed hepatic TNF-α (p <0.05) and ICAM-1 (p <0.05) mRNA expression ( Fig. 3G). These data added further weight to the effects of CXCL10 in mediating inflammation, oxidative stress and steatosis in the evolution of steatohepatitis. Since the MCD model reflects pathologically severe steatohepatitis with choline and amino acid nutritional deficiency and a context of “lipid trapping” in the liver with severe oxidative stress, it remains important to establish whether human NASH related to over-nutrition is also associated with increased liver expression and circulating levels of CXCL10. To this end, we assayed CXCL10 mRNA in liver biopsy from 15 control subjects and 22 NAFLD patients (11 simple steatosis patients and 11 human NASH patients). The results showed that hepatic CXCL10 mRNA levels were significantly higher in primary NASH tissue compared to simple steatosis (p <0.05) and normal controls (p <0.001) ( Fig. 4A), inferring that hepatic CXCL10 production is prominent in patients with NASH. We next ascertained the clinical impact of CXCL10 in NASH patients. We enrolled a well-established prospective cohort of 73 control subjects without fatty liver measured by proton-magnetic resonance spectroscopy and 147 age and gender matched biopsy-proven NAFLD patients, 69 of whom were diagnosed as NASH  and . We found that serum CXCL10 was significantly increased in a stepwise fashion from control subjects (111 [IQR: 98–146] pg/ml), patients with simple steatosis (170 [133–225] pg/ml) to patients with NASH (248 [154–310] pg/ml) (Fig. 4B, all p <0.0001). In NAFLD patients (simple steatosis and NASH), CXCL10 was significantly and positively correlated with lobular inflammation (rho: 0.26, p = 0.002) and hepatocyte ballooning degeneration (rho: 0.24, p = 0.004), which are two major histological features of NASH ( Table 3). Multivariable linear regression analysis also demonstrated that the serum CXCL10 level was positively associated with lobular inflammation (Beta: 47.9; 95% CI: 15.0–80.8; p = 0.005) and ballooning (Beta: 51.1; 95% CI: 20.0–82.1; p = 0.001) independent of metabolic syndrome, body mass index (BMI), ALT, triglyceride, fasting glucose and cholesterol.