BACKGROUNDHepatic steatosis is one of the histopathologic features of chronic hepatitis C. It was reported recently that the expression of hepatitis C virus (HCV) core protein in transgenic mice induced hepatocellular carcinoma (HCC) in association with steatosis. The objective of this study was to determine the relation between hepatic steatosis and hepatocarcinogenesis in patients with chronic HCV infection.METHODSThe authors studied 161 patients with chronic HCV infection who were diagnosed at Nagasaki University Hospital, Nagasaki, Japan, between January 1980 and December 1999. Age, gender, body mass index (BMI), habitual drinking, diabetes mellitus, serum alanine aminotransferase (ALT) level, HCV serotype, serum level of HCV core protein, interferon (IFN) treatment, hepatic fibrosis inflammation, and hepatic steatosis were studied with regard to their significance in the development of HCC using univariate and multivariate analyses.RESULTSThe cumulative incidence rates of HCC were 24%, 51%, and 63% at 5 years, 10 years, and 15 years, respectively. Multivariate analysis identified hepatic steatosis, together with aging, cirrhosis, and no IFN treatment, as independent and significant risk factors for HCC (P = 0.0135, P = 0.0390, P = 0.0068, and P = 0.0142, respectively). In addition, hepatic steatosis was correlated with BMI, serum ALT levels, and triglyceride levels.CONCLUSIONSThe findings of the current study indicate that hepatic steatosis is a risk factor for HCC in patients with chronic HCV infection. Patients with chronic HCV and hepatic steatosis should be monitored carefully for HCC. Cancer 2003;97:3036–43. © 2003 American Cancer Society.DOI 10.1002/cncr.11427

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RNA interference (RNAi) is the process by which double-stranded RNA directs sequence-speci¢c degradation of mRNA. In mammalian cells, RNAi can be triggered by 21-nucleotide duplexes of short interfering RNA (siRNA). We examined e¡ects of siRNA on hepatitis B virus (HBV) replication. Human hepatoma cells were transfected with HBV DNA and siRNA against HBV-pregenome RNA. Transfection experiments demonstrated that the siRNA reduced the amount of HBV-pregenome RNA and resulted in reduction of the levels of replicative intermediates and viral protein. Our results indicate that siRNA-mediated gene silencing inhibits HBV replication through suppression of viral RNA, which may be useful as a potential therapeutic modality. ß

Cidea (cell death-inducing DNA fragmentation factor ␣-like effector A), a member of a novel family of proapoptotic proteins, is expressed abundantly in the brown adipose tissue of the mouse. Although Cidea mRNA is not detectable in the mouse liver, we now show that peroxisome proliferator-activated receptor (PPAR) ␣ ligands Wy-14,643 and ciprofibrate increase the Cidea mRNA level in a PPAR␣-dependent manner, whereas Cidea induction in liver by PPAR␥ overexpression is PPAR␣ independent. Increase in Cidea mRNA content in liver did not alter the expression of uncoupling protein 1 (Ucp1) gene, which regulates thermogenesis, lipolysis, and conservation of energy. Although Cidea is considered to be a proapoptotic factor, Cidea induction in liver did not result in increased apoptosis. To elucidate the mechanism by which PPAR␣ and PPAR␥ regulate Cidea gene expression in the liver, we analyzed the promoter region of the Cidea gene. Three putative peroxisome proliferator response elements (PPREs) are found in the Cidea gene promoter. Transactivation, gel-shift, and chromatin immunoprecipitation assays indicated that the proximal PPRE in Cidea gene (Cidea-PPRE1 at ؊680/؊668) is functional for both PPAR␣ and -␥. We conclude that Cidea is a novel target gene for both PPAR␣ and -␥ in the liver where these two transcription factors utilize the same PPRE region for dual regulation. The induction of Cidea in liver with these PPAR␣ and -␥ agonists suggests a possible role for Cidea in energy metabolism and a less likely role in hepatocyte apoptosis.

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Disruption of the gene encoding for the transcription coactivator peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP/TRAP220/DRIP205/Med1) in the mouse results in embryonic lethality. Here, we have reported that targeted disruption of the Pbp/Pparbp gene in hepatocytes (Pbp ⌬Liv ) impairs liver regeneration with low survival after partial hepatectomy. Analysis of cell cycle progression suggests a defective exit from quiescence, reduced BrdUrd incorporation, and diminished entry into G 2 /M phase in Pbp ⌬Liv hepatocytes after partial hepatectomy. Pbp ⌬Liv hepatocytes failed to respond to hepatocyte growth factor/scatter factor, implying that hepatic PBP deficiency affects c-met signaling. Pbp gene disruption also abolishes primary mitogen-induced liver cell proliferative response. Striking abrogation of CCl 4 -induced hepatocellular proliferation and hepatotoxicity occurred in Pbp ⌬Liv mice pretreated with phenobarbital due to lack of expression of xenobiotic metabolizing enzymes necessary for CCl 4 activation. Pbp ⌬Liv mice, chronically exposed to Wy-14,643, a PPAR␣ ligand, revealed a striking proliferative response and clonal expansion of a few Pbp fl/fl hepatocytes that escaped Cre-mediated gene deletion in Pbp ⌬Liv livers, but no proliferative expansion of PBP null hepatocytes was observed. In these Pbp ⌬Liv mice, none of the Wy-14,643-induced hepatic adenomas and hepatocellular carcinomas was derived from PBP ⌬Liv hepatocytes; all liver tumors developing in Pbp ⌬Liv mice maintained non-recombinant Pbp alleles and retained PBP expression. These studies provide direct evidence in support of a critical role of PBP/TRAP220 in liver regeneration, induction of hepatotoxicity, and hepatocarcinogenesis.Transcription cofactors/coregulators consist of corepressors, coactivators, and coactivator-or corepressor-associated proteins, which participate in nuclear receptor-directed transcription (1-3). The functional significance for the existence of Ͼ200 nuclear receptor cofactors is not readily evident, but there is an increasing recognition of the general importance of some of these molecules in gene expression, embryogenesis, cell growth, and oncogenesis, as well as energy and xenobiotic metabolism (1, 3). Emerging gene knock-out mouse models show that some of the coactivators that directly bind to transcription factors to enhance gene expression are essential for embryonic growth and survival (see Ref. 3 for review). For example, the disruption of a coactivator gene such as peroxisome proliferated-activated receptor (PPAR) 2 -binding protein (PBP; also known as TRAP (thyroid hormone receptor-associated protein) 220/DRIP (vitamin D 3 receptor-interacting protein) 205)/Med1 (Mediator 1)) is embryonically lethal between gestational days 11.5 and 12.5, implying that this coactivator is widely involved in the transcriptional activity of many transcription factors (4, 5-7). To define the in vivo role of this coactivator, we used conditional mutagenesis in mice and found that deletion of the Pbp/Pparbp gen...

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