T1622 Hepatic Steatosis and Increase Risk of Hepatocellular Carcinoma in Mice Heterozygous for Long Chain 3-Hydorxy Acyl-CoA Dehydrogenase (LCHAD)

Abstract

Objective: To improve hepatic ischemia-reperfusion (IR) injury of experimental fatty livers after treatment of steatosis with omega-3 fatty acids. Background: Major liver resections are associated with relatively high morbidity and mortality. One of the emerging risk factors for liver resections in theWesternworld is non-alcoholic fatty liver disease and chemotherapyassociated steatohepatitis. Fatty livers show a high susceptibility to IR injury and less regenerative capacity after major liver resection, leading to an increased risk of postoperative liver failure. Omega-3 lowers hepatic omega6:3 fatty-acids ratio resulting in decreased synthesis and increased hepatic fatty-acid degradation. Experimental studies have investigated prevention, but not reversal of steatosis by omega-3 fatty acids and the subsequent effect on hepatic IR injury. Methods: Steatosis was induced in male Wistar rats by feeding a methionine/ choline-deficient diet for 3 weeks. Rats were daily administered omega-3 (Omegaven), isocaloric control fatty acids (Lipofundin), or 0.9% NaCl (n=10/group) per gavage during 2 weeks. After treatment, rats were anesthetized and underwent partial (70%) hepatic ischemia for 40min. The non-ischemic lobes (30%) were resected prior to the reperfusion period. Blood was drawn at 20min, 6h, and 24h reperfusion, and at 6 and 24h rats (n=5/ group) were sacrificed for liver tissue extraction. Liver damage parameters (ALT) and bilirubin levels were determined from blood plasma. The histopathological steatosis degree was determined in the non-ischemic lobes, and total fatty acids content was assayed by gas chromatography. The extent of necrosis, cytokine levels, and total anti-oxidant capacity were determined at 6 and 24h reperfusion. Results: Omega-3 fatty acids significantly reduced the histopathological macrovesicular steatosis degree (mean%±SD): 30±15% omega-3 vs. 81±16% control fatty acids (p<0.01) and 79±16% NaCl (p<0.01). The total hepatic fatty acids and omega-6:3 ratios were significantly (p<0.01) lower in the omega-3 group. At 20min, 6h, and 24h reperfusion ALT release was significantly reduced (p<0.05), and at 6 and 24 h reperfusion bilirubin levels were significantly decreased (p<0.05) in omega-3treated livers. Furthermore, these livers revealed less necrosis and a decreased IL-6 and TNF-α content (p<0.05) at 24h reperfusion. Total antioxidant capacity was improved in omega-3-treated livers at 6 and 24h reperfusion. Conclusion: Omega-3 fatty acids treatment significantly decreases the hepatic steatosis degree in an experimental steatosis model, resulting in significantly decreased IR injury.