BACTERIAL LIPOPOLYSACCHARIDE INDUCES UNCOUPLING PROTEIN-2 EXPRESSION IN HEPATOCYTES BY A TUMOR NECROSIS FACTOR-ALPHA-DEPENDENT MECHANISM

The liver is a target for bacterial lipopolysaccharide (LPS) and parti cipates in the metabolic response to endotoxemia. Recently published e vidence indicates that LPS increases the expression of mitochondrial u ncoupling protein-2 (UCP-2) mRNAs in several tissues, including the li ver. Because hepatocytes in the healthy liver do not express UCP-2, LP S was thought to induce UCP-2 in liver macrophages, which express UCP- 2 constitutively. However, the present studies of cultured peritoneal macrophages indicate that LPS reduces steady state levels of UCP-2 mRN As in these cells. In contrast, UCP-2 mRNAs are induced in hepatocytes isolated from LPS treated rats and transfection of these hepatocytes with UCP-2 promoter-reporter constructs demonstrates substantial incre ases in UCP-2 promoter activity. LPS induction of hepatocyte UCP-2 exp ression is virtually abolished by prior treatment of rats with neutral izing antibodies to tumor necrosis factor alpha (TNF). Futhermore, TNF alpha treatment induces UCP-2 mRNA accumulation in primary cultures o f hepatocytes from healthy rats. Thus, hepatocytes are likely to be im portant contributors to endotoxin-related increases in liver UCP-2 via a mechanism that involves the LPS-inducible cytokine, TNF alpha. (C) 1998 Academic Press.