Transcription factor CCAAT/enhancer binding protein beta (C/EBP\#946;) is essential in cell proliferation, apoptosis, inflammation, and carcinogenesis. Recent studies in C/EBP\#946;-null mice strongly indicate an essential pathogenic role of C/EBP\#946; in multiple liver diseases. Moreover, C/EBP\#946; is induced in liver cancer in humans. Inflammation is a major risk factor for cancer. The resistance of C/EBP\#946;-null mice to endotoxic shock induced by lipopolysaccharide (LPS) (due to defects in macrophage activation) precludes the use of C/EBP\#946;-null mice to elucidate the role of C/EBP\#946; in hepatocytes in regulating hepatic gene expression, inflammatory response, and metabolic homeostasis during LPS-induced inflammation. Thus, we have, for the first time, generated mice with adult-hepatocyte-specific knockout (HKO) of C/EBP\#946; by crossing C/EBP\#946; floxed mice with Alb-cre mice. The successful generation of mice with hepatocyte-specific knockout of C/EBP\#946; was confirmed by: 1) selective loss of basal expression and markedly-attenuated induction of C/EBP\#946; mRNA in liver but not in kidney 16 h after LPS (5 mg/kg ip) administration, and 2) the loss of C/EBP\#946; protein in hepatocytes, in contrast to an induction of C/EBP\#946; protein in non-hepatocytes in LPS-treated C/EBP\#946; HKO mice. Sixteen hours after LPS treatment, C/EBP\#946; HKO mice had near-normal body temperature, in contrast to marked hypothermia in wild-type (WT) mice. Hepatic induction of certain inflammatory cytokines by LPS was attenuated in C/EBP\#946; HKO mice. In LPS-treated C/EBP\#946; HKO mice, hepatic mRNA expression of a PPAR\#945; target gene, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2, was strongly induced and correlated highly with decreased blood levels of non-esterified fatty acids. Hepatic mRNA expression of \#947;-glutamylcysteine synthetase catalytic subunit (Gclc), a key enzyme in glutathione synthesis, was decreased in LPS-treated WT mice but not C/EBP\#946; HKO mice, although nuclear localization of Nrf2, a master regulator of antioxidative response and a transactivator of Gclc, remained unchanged. C/EBP\#946; strongly inhibited activation of an antioxidant response element by Nrf2, indicating that C/EBP\#946; directly inhibits the transcriptional activity of Nrf2 in liver. Hepatic mRNA expression of small heterodimer partner (SHP), a tumor suppressor of hepatocellular carcinoma, was markedly down-regulated by LPS in WT mice but not in C/EBP\#946; HKO mice. Taken together, C/EBP\#946; in hepatocytes plays a key role in promoting inflammation and disrupting metabolic homeostasis during endotoxemia. Knockout of C/EBP\#946; specifically in hepatocytes during inflammation results in increased expression/activity of transcription factors essential in energy metabolism, antioxidative response, and tumor suppression, namely PPAR\#945;, Nrf2, and SHP. Activation of C/EBP\#946; in hepatocytes may be a key risk factor for inflammation-related liver diseases and liver carcinogenesis.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3804.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO