The effect of significant weight loss on nonalcoholic fatty liver disease remains unclear. In this case series of 36 selected obese patients, we examined the effect of weight loss on nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis (NASH) and hepatic fibrosis. These 36 patients (11 males, 25 females) had paired liver biopsies, the first at the time of laparoscopic adjustable gastric band placement and the second after weight loss. Second biopsies were obtained from two groups: those requiring a subsequent laparoscopic procedure (n ‫؍‬ 19) and those with index biopsy score of 2 or greater for zone 3-centric hepatic fibrosis (n ‫؍‬ 17). All biopsies were scored, blinded to the patient's identity and clinical condition, for individual histological features and for NASH stage and grade. Initial biopsies demonstrated NASH in 23 patients and steatosis in 12 patients. Repeat biopsies were taken at 25.6 ؎ 10 months (range, 9 -51 months) after band placement. Mean weight loss was 34.0 ؎ 17 kg, and percentage of excess weight loss was 52 ؎ 17%. There were major improvements in lobular steatosis, necroinflammatory changes, and fibrosis at the second biopsy (P < .001 for all). Portal abnormalities remained unchanged. Only four of the repeat biopsies fulfilled the criteria for NASH. There were 18 patients with an initial fibrosis score of 2 or more compared with 3 patients at follow-up (P < .001). Those with the metabolic syndrome (n ‫؍‬ 23) had more extensive changes before surgery and greater improvement with weight loss. In conclusion, weight loss after surgery provides major improvement or resolution of obesity and metabolic syndrome-associated abnormal liver histological features in severely obese subjects.

Deregulated activation of STAT3 is frequently associated with many human hematological and epithelial malignancies, including gastric cancer. While exaggerated STAT3 signaling facilitates an antiapoptotic, proangiogenic, and proproliferative environment for neoplastic cells, the molecular mechanisms leading to STAT3 hyperactivation remain poorly understood. Using the gp130 Y757F/Y757F mouse model of gastric cancer, which carries a mutated gp130 cytokine receptor signaling subunit that cannot bind the negative regulator of cytokine signaling SOCS3 and is characterized by hyperactivation of the signaling molecules STAT1 and STAT3, we have provided genetic evidence that IL-11 promotes chronic gastric inflammation and associated tumorigenesis. Expression of IL-11 was increased in gastric tumors in gp130 Y757F/Y757F mice, when compared with unaffected gastric tissue in wild-type mice, while gp130 Y757F/Y757F mice lacking the IL-11 ligand-binding receptor subunit (IL-11Rα) showed normal gastric STAT3 activation and IL-11 expression and failed to develop gastric tumors. Furthermore, reducing STAT3 activity in gp130 Y757F/Y757F mice, either genetically or by therapeutic administration of STAT3 antisense oligonucleotides, normalized gastric IL-11 expression and alleviated gastric tumor burden. Surprisingly, the genetic reduction of STAT1 expression also reduced gastric tumorigenesis in gp130 Y757F/Y757F mice and coincided with reduced gastric inflammation and IL-11 expression. Collectively, our data have identified IL-11 as a crucial cytokine promoting chronic gastric inflammation and associated tumorigenesis mediated by excessive activation of STAT3 and STAT1.

Gastric cancer (GC) is associated with chronic inflammation; however, the molecular mechanisms promoting tumorigenesis remain ill defined. Using a GC mouse model driven by hyperactivation of the signal transducer and activator of transcription (STAT)3 oncogene, we show that STAT3 directly upregulates the epithelial expression of the inflammatory mediator Toll-like receptor (TLR)2 in gastric tumors. Genetic and therapeutic targeting of TLR2 inhibited gastric tumorigenesis, but not inflammation, characterized by reduced proliferation and increased apoptosis of the gastric epithelium. Increased STAT3 pathway activation and TLR2 expression were also associated with poor GC patient survival. Collectively, our data reveal an unexpected role for TLR2 in the oncogenic function of STAT3 that may represent a therapeutic target in GC.

The cell phenotype of so-called bile duct adenoma (BDA) was investigated immunohistochemically using monoclonal antibodies to two recently identified antigens (designated D10 and 1F6) extracted from human liver and cultured biliary epithelium. The acini and tubules of BDA consisted of serous and mucous cells that expressed D10 and 1F6. The intrahepatic peribiliary glands of normal liver, comprising intramural mucous glands and extramural tubuloalveolar seromucinous glands, similarly expressed D10 and 1F6 antigens. Antigen 1F6 was present in the cells forming the canals of Hering and normal bile ductules but not in interlobular and larger bile ducts. Proliferating bile ductules associated with large bile duct obstruction and alcoholic cirrhosis or the epithelia of the von Meyenberg complex and polycystic liver did not exhibit this combined profile of D10 and 1F6 expression and mucous cells. These findings suggest an origin of BDA from peribiliary glands rather than from bile ductules or ducts. Consistent with this view was our finding that 18 of the 30 BDA were spatially related to a large-calibre bile duct. Therefore, BDA, well known for its benign behavior is a small mass of disorganized but mature peribiliary gland acini and tubules within a variable amount of stroma and should properly be called a peribiliary gland hamartoma.