Lack of UCP2 reduces fas-mediated liver injury in ob/ob mice and reveals importance of cell-specific UCP2 expression

✍ Scribed by Péter Fülöp; Zoltán Derdák; Anthony Sheets; Edmond Sabo; Eric P. Berthiaume; Murray B. Resnick; Jack R. Wands; György Paragh; György Baffy

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 901 KB
• Volume: 44
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.21310

✦ Synopsis

Fatty liver is vulnerable to conditions that challenge hepatocellular energy homeostasis. Lipidladen hepatocytes highly express uncoupling protein-2 (UCP2), a mitochondrial carrier that competes with adenosine triphosphate (ATP) synthesis by mediating proton leak. However, evidence for a link between UCP2 expression and susceptibility of liver to acute injury is lacking. We asked whether absence of UCP2 protects ob/ob mice from Fas-mediated acute liver damage. UCP2-deficient ob/ob mice (ob/ob:ucp2 ؊/؊ ) and UCP2-competent littermates (ob/ob:ucp2 ؉/؉ ) received a single dose of agonistic anti-Fas antibody (Jo2). Low-dose Jo2 (0.15 mg/kg intraperitoneally) caused less serum alanine aminotransferase (ALT) elevation and lower apoptosis rates in ob/ob:ucp2 ؊/؊ mice. High-dose Jo2 (0.40 mg/kg intraperitoneally) proved uniformly fatal; however, ob/ob:ucp2 ؊/؊ mice survived longer with less depletion of liver ATP stores, indicating that fatty hepatocytes may benefit from lack of UCP2 during Jo2 challenge. Although UCP2 reportedly controls mitochondrial oxidant production, its absence had no apparent effect on fatty liver tissue malondialdehyde levels augmented by Jo2. This finding prompted us to determine UCP2 expression in Kupffer cells, a major source of intrahepatic oxidative stress. UCP2 expression was found diminished in Kupffer cells of untreated ob/ob:ucp2 ؉/؉ mice, conceivably contributing to increased oxidative stress in fatty liver and limiting the impact of UCP2 ablation. In conclusion, whereas UCP2 abundance in fatty hepatocytes exacerbates Fas-mediated injury by compromising ATP stores, downregulation of UCP2 in Kupffer cells may account for persistent oxidative stress in fatty liver. Our data support a cell-specific approach when considering the therapeutic effects of mitochondrial uncoupling in fatty liver disease. (HEPATOLOGY 2006;44:592-601.) O besity has become exceedingly prevalent in the United States, and nonalcoholic fatty liver disease (NAFLD) associated with this trend is now present in over 20% of the population. 1 Although con-sidered mostly benign, NAFLD may result in significant morbidity when featuring histological signs of inflammation and fibrosis described as nonalcoholic steatohepatitis with a potential to progress into cirrhosis and hepatocellular carcinoma. Fatty liver is also more susceptible to acute injury such as ischemia-reperfusion and endotoxinemia. In a pilot study on patients with biopsy-proven nonalcoholic steatohepatitis, recovery from hepatic adenosine triphosphate (ATP) depletion induced by intravenously given fructose was less efficient than in healthy controls, suggesting impaired hepatic energy homeostasis in fatty liver disease. Although a follow-up study on healthy volunteers could not confirm a similar connection, baseline hepatic ATP stores in these individuals inversely correlated with higher body mass index. These observations indicate that diminished ATP reserves in fatty liver may account for its increased vulnerability.

Uncoupling protein 2 (UCP2) is an inner mitochondrial membrane carrier with debated evolutionary role and biological function. UCP2 has wide tissue expression, but its overall abundance is typically very low. 10 UCP2 has been shown to mediate proton leak in various