Lack of adiponectin promotes formation of cholesterol gallstones in mice.

Plasma adiponectin levels are reduced in obese people, and hypoadiponectinemia is recently reported to associate with cholesterol gallstone formation in human. The aim of this study was to examine the role of adiponectin in gallstone formation using adiponectin knockout mice. We analyzed male knockout and C57BL6J mice fed normal or lithogenic diet for 6 weeks. On lithogenic diet, the prevalence rate of gallstone was significantly greater in knockout mice than C57BL6J mice. The molar percentages of beta and omega-muricholic acid were significantly higher and hepatic sterol 12 alpha-hydroxylase expression (cyp8b1) was significantly lower in knockout mice than C57BL6J mice fed normal diet. The bile apolipoprotein A-I protein levels were decreased in knockout mice. Histological examination showed gallbladder wall thickening and accumulation of glycoprotein in the gallbladder of knockout mice. Gallbladder phospholipase A2-IVA expression was significantly higher in knockout mice than in C57BL6J mice fed lithogenic diet. Our results indicate that lack of adiponectin promotes gallstone formation in mice.

Adiponectin deficiency enhanced the severity of cerulein-induced chronic pancreatitis in mice.

BACKGROUND: Adiponectin is recognized as an antiinflammatory and antifibrotic protein derived from adipocytes, and low serum adiponectin levels are present in obesity. Recent studies have highlighted the relationship between obesity and pancreatic diseases. However, the role of adiponectin in chronic pancreatitis remains uncertain. The aim of this study was to determine the effects of adiponectin in chronic pancreatitis. METHODS: We investigated the effects of adiponectin in experimental chronic pancreatitis by using adiponectin-knockout (APN-KO) mice. Chronic pancreatitis was induced by repeated hourly (6 times) intraperitoneal injections of 50 microg/kg cerulein three times per week for 4 weeks in wild-type (WT) and APN-KO mice. We evaluated the severity of chronic pancreatitis biochemically and morphologically. RESULTS: In cerulein-treated mice, macroscopically and histologically, severe pancreatic damage was observed in APN-KO mice compared with findings in WT mice. The histological scores for chronic pancreatitis, including glandular atrophy, pseudotubular complex, fibrosis, and total scores, were significantly higher in APN-KO mice than in WT mice. Activated pancreatic stellate cells and F4/80-positive pancreatic macrophages accumulated in the pancreas of APN-KO mice but not in WT mice. Overexpression of the mRNAs of transforming growth factor-beta1, CD68, and monocyte chemoattractant protein-1 was noted in APN-KO mice but not in WT mice. The gene expression level of collagen1 (alpha1) tended to be higher in APN-KO mice than in WT mice, albeit insignificantly. CONCLUSIONS: Adiponectin deficiency enhanced the severity of cerulein-induced chronic pancreatitis in mice. Hypoadiponectinemia could enhance the severity of chronic pancreatitis.

A case of pancreatic acinar cell carcinoma metastatic to skin.

We report a rare case of pancreatic acinar cell carcinoma with widespread metastases in a 68-year-old woman who presented with subcutaneous nodules as the initial symptom. Computed tomography showed a pancreatic mass with hepatic tumors and enlarged lymph nodes besides ring-enhanced subcutaneous nodules. Magnetic resonance diffusionweighted imaging detected the presence of lesions in other organs. Histological analysis of a colonic polypoid lesion revealed carcinoma with endocrine and acinar differentiation compatible with pancreatic origin. Regrettably, she died of a cerebral infarction without any treatment, and autopsy findings confirmed our diagnosis.

[A case of eosinophilic gastroenteritis with ascites and protein-losing gastroenteropathy].

A 24-year-old man presented with abdominal distension, diarrhea, and nausea. Blood tests showed eosinophilia (WBC 14400/microl, Eos 36%) and slight hypoproteinemia (TP 6.4 mg/dl, Alb 3.7 mg/dl). Ultrasonography and computed tomography revealed massive ascites (WBC 11500/microl, Eos 95%, protein 4.7 g/dl) and wall thickening of the small intestine. Endoscopic and histological examinations showed mucosal redness and edema with eosinophilic infiltration throughout the digestive tracts. Fecal alpha1- antitrypsin clearance was increased (44.6 ml/day). A diagnosis of eosinophilic gastroenteritis with ascites and protein-losing gastroenteropathy was made, and was classified as mixed type of both predominant subserosal and mucosal disease. Prednisolone therapy improved all the symptoms and findings. Measurements of serum levels of several cytokines and chemokines showed that interleukin-5 and soluble interleukin-2 receptor, but not eotaxin, were possible indicators of the disease activity. It should be kept in mind that eosinophilic gastroenteritis is one of the causes of ascites.

[A case of iron deficiency anemia in which iron absorption increased after Helicobacter pylori eradication].

A 48-year-old woman with iron deficiency anemia (Hb 8.1 g/dl) and Helicobacter pylori (H. pylori)-associated enlarged fold gastritis underwent successful H. pylori eradication. Hemoglobin, serum iron concentrations, and other indices of iron deficiency anemia reached almost normal levels 10 to 16 months after the first eradication treatment. Iron absorption tests and measurements of basal acid output were performed before and after eradication therapy. Iron absorption almost doubled within 3.5 months, whereas basal acid output was nothing but it increased after 15 months. Therefore, it was suggested that the increase in iron absorption was possibly involved in improvement of iron deficiency anemia after H. pylori eradication therapy. Furthermore, it was also suggested that mechanisms other than increase in acid secretion might be involved in increase in iron absorption.

Adiponectin deficiency enhances colorectal carcinogenesis and liver tumor formation induced by azoxymethane in mice.

AIM: To investigate the causal relationship between hypoadiponectinemia and colorectal carcinogenesis in in vivo experimental model, and to determine the contribution of adiponectin deficiency to colorectal cancer development and proliferation. METHODS: We examined the influence of adiponectin deficiency on colorectal carcinogenesis induced by the administration of azoxymethane (AOM) (7.5 mg/kg, intraperitoneal injection once a week for 8 wk), by using adiponectin-knockout (KO) mice. RESULTS: At 53 wk after the first AOM treatment, KO mice developed larger and histologically more progressive colorectal tumors with greater frequency compared with wild-type (WT) mice, although the tumor incidence was not different between WT and KO mice. KO mice showed increased cell proliferation of colorectal tumor cells, which correlated with the expression levels of cyclooxygenase-2 (COX-2) in the colorectal tumors. In addition, KO mice showed higher incidence and frequency of liver tumors after AOM treatment. Thirteen percent of WT mice developed liver tumors, and these WT mice had only a single tumor. In contrast, 50% of KO mice developed liver tumors, and 58% of these KO mice had multiple tumors. CONCLUSION: Adiponectin deficiency enhances colorectal carcinogenesis and liver tumor formation induced by AOM in mice. This study strongly suggests that hypoadiponectinemia could be involved in the pathogenesis for colorectal cancer and liver tumor in human subjects.

Effect of adiponectin on murine colitis induced by dextran sulfate sodium.

BACKGROUND & AIMS: Adiponectin, an adipose tissue-derived hormone, exhibits anti-inflammatory properties and has various biological functions, such as increasing insulin sensitivity, reducing hypertension, and suppressing atherosclerosis, liver fibrosis, and tumor growth. The aim of the present study was to determine the effect of adiponectin on intestinal inflammation. METHODS: We investigated the effect of adiponectin on dextran sulfate sodium (DSS)-induced colitis by using adiponectin-knockout (APN-KO) mice and an adenovirus-mediated adiponectin expression system. We also examined the contribution of adiponectin deficiency to trinitrobenzene sulfonic acid (TNBS)-induced colitis. In vitro, we examined the effect of adiponectin on intestinal epithelial cells. RESULTS: After administration of 0.5% DSS for 15 days, APN-KO mice developed much more severe colitis compared with wild-type mice. The messenger RNA expression levels of chemokines were significantly higher in the colonic tissues of DSS-treated APN-KO mice compared with wild-type mice, accompanied by increased cellular infiltration, including macrophages. Adenovirus-mediated supplementation of adiponectin significantly attenuated the severity of colitis, but there were no differences in the severity of TNBS-induced colitis between the 2 groups. Adiponectin receptors were expressed in intestinal epithelial cells, and adiponectin inhibited lipopolysaccharide-induced interleukin-8 production in intestinal epithelial cells. CONCLUSIONS: Adiponectin is protective against DSS-induced murine colitis, probably due to the inhibition of chemokine production in intestinal epithelial cells and the following inflammatory responses, including infiltration of macrophages and release of proinflammatory cytokines.

Intectin, a novel small intestine-specific glycosylphosphatidylinositol-anchored protein, accelerates apoptosis of intestinal epithelial cells.

Intestinal epithelial cells undergo rapid turnover and exfoliation especially at the villus tips. This process is modulated by various nutrients especially fat. Apoptosis is one of the important regulatory mechanisms of this turnover. Therefore, identification of the factors that control epithelial cell apoptosis should help us understand the mechanism of intestinal mucosal turnover. Here, we report the identification of a novel small intestine-specific member of the Ly-6 family, intectin, by signal sequence trap method. Intectin mRNA expression was exclusively identified in the intestine and localized at the villus tips of intestinal mucosa, which is known to undergo apoptosis. Intectin mRNA expression was modulated by nutrition. Intestinal epithelial cells expressing intectin were more sensitive to palmitate-induced apoptosis, compared with control intestinal epithelial cells, and such effect was accompanied by increased activity of caspase-3. Intectin expression also reduced cell-cell adhesion of intestinal epithelial cells.