Ossabaw miniature swine develop metabolic syndrome along with severe liver injury and progressive fibrosis that resembles human non-alcoholic steatohepatitis (NASH) when fed high-fat, high-fructose atherogenic (NASH) diet. Aim: To test the effect of FGF21 therapy on liver histology and metabolic indices in Ossabaw Swine with metabolic syndrome and NASH. Methods: Eight Ossabaw swine were fed an average of 5000 kcal per
day of NASH diet and developed metabolic syndrome find more and NASH after 30 weeks of feeding. The pigs were then treated with FGF21 at 1mg/kg subcutaneously once daily for 16 weeks while continuing on NASH diet. Pre- and post-treatment liver biopsies were evaluated according to predefined histological scoring system. Staging of fibrosis accounted for
bridging fibrous septa normally present in swine livers. Improvement in histological features after FGF21 therapy was defined as a reduction of > 1 point, whereas worsening was defined as an increase of > 1 point compared to pre-therapy biopsy. Insulin sensitivity was assessed with an oral glucose tolerance test. Results: Mean body weight was 53.5, 88, and 90 kg at study weeks 0, 30, and 46, respectively. Sixteen weeks of FGF21 therapy significantly reduced fasting total cholesterol (265 vs 173 mg/dL, p<0.05) and the peak post-prandial triglycerides (142 vs 92.5 mg/dL, p <0.05). Although fasting glucose did not significantly change, fasting insulin was significantly lower following FGF21 therapy (25 vs 14 μU/ml, p< 0.05). All liver biopsies prior to initiating MAPK inhibitor FGF21 therapy showed significant fibrosis and extensive hepatocyte ballooning. Following FGF21 therapy, improvement in fibrosis, ballooning, portal and lobular inflammation was noted in 62.5%, 87.5%, 50%, and 25%, respectively.
Electron microscopy showed markedly decreased number of secondary lysosomes within hepatocytes and an increased number of lipid-laden Kupffer cells after FGF21 therapy. Except for itching at the injection site, FGF21 was well tolerated. MCE Conclusions: FGF21 therapy results in improvements in liver necroinflammation and fibrosis, insulin sensitivity, and post-prandial lipidemia in Ossabaw miniature swine with diet-induced NASH. These observations suggest that FGF21 should be further investigated as a potential treatment for NASH. Disclosures: Naga P. Chalasani – Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aege-rion; Grant/Research Support: Intercept, Lilly, Gilead, Cumberland, Galectin The following people have nothing to disclose: Samer Gawrieh, Mouhamad Alloosh, Rachel M. Sheridan, Tiebing Liang, Howard C. Masuoka, Michael Sturek Hepatic fibrosis in NASH is the common pathophysiologic process resulting from chronic liver inflammation associated with rise in proinflammatory cytokines and oxidative stress.
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