[Abstract unavailable

Our results indicate that although HCV infection can be self-limited or associated with ESLD, the majority of adults have persistent viremia without clinically demonstrable liver disease. Further research is needed to explain the less frequent clearance of HCV infection among black persons and to improve utilization of treatment for those infected in the context of injection drug use. JAMA. 2000;284:450-456

Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning problem in hepatology, and is associated with insulin resistance. Exendin-4 is a peptide agonist of the glucagon-like peptide (GLP) receptor that promotes insulin secretion. The aim of this study was to determine whether administration of Exendin-4 would reverse hepatic steatosis in ob/ob mice. N onalcoholic fatty liver disease (NAFLD) is reported in some Western countries to be the most common liver disease, surpassing the prevalence of chronic hepatitis C virus or alcoholic liver disease. 1 NAFLD represents a disease spectrum ranging from simple steatosis to steatohepatitis and fibrosis. Approximately 3% of patients afflicted with NAFLD will develop cirrhosis. 2,3 At present, the central pathophysiological problem in patients afflicted with NAFLD is insulin resistance. Thus, there is a clear association between NAFLD and the metabolic syndrome that includes type 2 diabetes mellitus, obesity, hypertension, and hyperlipidemia. Improvement of insulin resistance, or insulin sensitivity, has therapeutic potential in preventing the progression of NAFLD because the accumulation of triglycerides in hepatocytes is believed to be the first step in the current two-hit hypothesis of the pathophysiological development of NAFLD. 4 Hence, it is hypothesized that improving insulin sensitivity would reduce hepatocyte triglyceride accumulation, thereby preventing the second step of hepatocyte vulnerability to oxidative stress. 4 Exendin-4 is a 39 amino acid agonist of the glucagonlike peptide 1 (GLP-1) receptor. Exendin-4 is present in the saliva of the Gila monster, Heloderma suspectum. 5 GLP-1, a gastrointestinal hormone secreted by the L cells of the intestine, regulates blood glucose primarily via stimulation of glucose-dependent insulin release. However, the major drawback of its clinical use is its short biological half-life, necessitating continuous administra-

The present study examined the roles of peroxisome proliferator-activated receptors (PPAR) in activation of hepatic stellate cells (HSC), a pivotal event in liver fibrogenesis. RNase protection assay detected mRNA for PPAR␥1 but not that for the adipocyte-specific ␥2 isoform in HSC isolated from sham-operated rats, whereas the transcripts for neither isoforms were detectable in HSC from cholestatic liver fibrosis induced by bile duct ligation (BDL). Semi-quantitative reverse transcriptasepolymerase chain reaction confirmed a 70% reduction in PPAR␥ mRNA level in HSC from BDL. Nuclear extracts from BDL cells showed an expected diminution of binding to PPAR-responsive element, whereas NF-B and AP-1 binding were increased. Treatment of culturedactivated HSC with ligands for PPAR␥ (10 M 15-deoxy-⌬ 12,14 -PGJ 2 (15dPGJ 2 ); 0.1ϳ10 M BRL49653) inhibited DNA and collagen synthesis without affecting the cell viability. Suppression of HSC collagen by 15dPGJ 2 was abrogated 70% by the concomitant treatment with a PPAR␥ antagonist (GW9662). HSC DNA and collagen synthesis were inhibited by WY14643 at the concentrations known to activate both PPAR␣ and ␥ (>100 M) but not at those that only activate PPAR␣ (<10 M) or by a synthetic PPAR␣-selective agonist (GW9578). 15dPGJ 2 reduced ␣1(I) procollagen, smooth muscle ␣-actin, and monocyte chemotactic protein-1 mRNA levels while inducing matrix metalloproteinase-3 and CD36. 15dPGJ 2 and BRL49653 inhibited ␣1(I) procollagen promoter activity. Tumor necrosis factor ␣ (10 ng/ml) reduced PPAR␥ mRNA, and this effect was prevented by the treatment with 15dPGJ 2 . These results demonstrate that HSC activation is associated with the reductions in PPAR␥ expression and PPAR-responsive element binding in vivo and is reversed by the treatment with PPAR␥ ligands in vitro. These findings implicate diminished PPAR␥ signaling in molecular mechanisms underlying activation of HSC in liver fibrogenesis and the potential therapeutic value of PPAR␥ ligands for liver fibrosis.