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

Abstract

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.)

Upregulation of UCP2 by Adiponectin: The Involvement of Mitochondrial Superoxide and hnRNP K

“…On the contrary, there lacks sufficient information on whether replacement with UCP2 could alleviate NAFLD [30]. In fatty liver tissues, the lipid-laden hepatocytes express high levels of UCP2, whereas the expression of UCP2 in Kupffer cells decreases [40]. The present study demonstrates that UCP2 expression is significantly reduced in NPCs, but not PCs fractions of AKO livers.…”

Effects of TCDD on the expression of nuclear encoded mitochondrial genes

“…TCDD elicited temporal and dose-dependent differential expression of UCP2 and UCP5. UCP2 is highly expressed in Kupffer cells, but not in healthy hepatocytes (Fulop et al, 2006). However, UCP2 is highly expressed in fatty liver hepatocytes (Fulop et al, 2006; Grav et al, 2003).…”

“…UCP2 is highly expressed in Kupffer cells, but not in healthy hepatocytes (Fulop et al, 2006). However, UCP2 is highly expressed in fatty liver hepatocytes (Fulop et al, 2006; Grav et al, 2003). TCDD (30 μg/kg) induces fatty accumulation in C57BL/6 mouse liver (Boverhof et al, 2005).…”

“…Although no effect on hepatic UCP2 protein levels were reported following 5 μg/kg TCDD treatment in C57BL/6J mice (Shertzer et al, 2006), our results suggest UCP2 mRNA expression increases over time and is dose-responsive. It is possible that in TCDD-induced fatty liver, UCP2 is activated to reduce the hyperpolarization of the inner mitochondrial membrane to modulate hydrogen peroxide generation (Fulop et al, 2006; Negre-Salvayre et al, 1997). In fact, TCDD depolarizes the inner mitochondrial membrane in primary rat hepatocytes, treated with 15nM TCDD for 72 hrs (Aly and Domenech, 2009).…”

Studies of UCP2 transgenic and knockout mice reveal that liver UCP2 is not essential for the antiobesity effects of fish oil

“…Subsequent studies showed that, under conditions associated with increased hepatic UCP2 expression (e.g., fatty liver and endotoxin-mediated liver injury), cellspecific expression would change with UCP2 being expressed primarily in hepatocytes. UCP2 mRNA and protein levels were increased in hepatocytes from ob/ob mice (8,10). Bacterial lipopolysaccharide-injected rats showed increased expression of UCP2 mRNA in hepatocytes, whereas UCP2 mRNA levels were decreased in macrophages (9).…”