Although various function of chemerin have been suggested, its physiological role remains to be elucidated. Here we show that chemerin-deficient mice are glucose intolerant irrespective of exhibiting reduced macrophage accumulation in adipose tissue. The glucose intolerance was mainly due to increased hepatic glucose production and impaired insulin secretion. Chemerin and its receptor ChemR23 were expressed in β-cell. Studies using isolated islets and perfused pancreas revealed impaired glucose-dependent insulin secretion (GSIS) in chemerin-deficient mice. Conversely, chemerin transgenic mice revealed enhanced GSIS and improved glucose tolerance. Expression of MafA, a pivotal transcriptional factor for β-cell function, was downregulated in chemerin-deficient islets and a chemerin-ablated β-cell line and rescue of MafA expression restored GSIS, indicating that chemerin regulates β-cell function via maintaining MafA expression. These results indicate that chemerin regulates β-cell function and plays an important role in glucose homeostasis in a tissue-dependent manner.

Background: Liver dysfunction in adult hypopituitary patients with GH deficiency (GHD) has been reported and an increased prevalence of nonalcoholic fatty liver disease (NAFLD) has been suggested. Objective: The objective of the present study was to elucidate the pathophysiology of the liver in adult hypopituitary patients with GHD. Patients and methods: We recruited 69 consecutive Japanese adult hypopituitary patients with GHD and examined the prevalence of NAFLD by ultrasonography and nonalcoholic steatohepatitis (NASH) by liver biopsy. Patients had been given routine replacement therapy except for GH. We compared these patients with healthy age-, gender-, and BMI-matched controls. We further analyzed the effect of GH replacement therapy on liver function, inflammation and fibrotic markers, and histological changes. Results: The prevalence of NAFLD in hypopituitary patients with GHD was significantly higher than in controls (77 vs 12%, P!0.001). Of 16 patients assessed by liver biopsy, 14 (21%) patients were diagnosed with NASH. GH replacement therapy significantly reduced serum liver enzyme concentrations in the patients and improved the histological changes in the liver concomitant with reduction in fibrotic marker concentrations in patients with NASH. Conclusions: Adult hypopituitary patients with GHD demonstrated a high NAFLD prevalence. The effect of GH replacement therapy suggests that the NAFLD is predominantly attributable to GHD.

Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) and cirrhosis determines patient prognosis; however, effective treatment for fibrosis has not been established. Oxidative stress and inflammation activate hepatic stellate cells (HSCs) and promote fibrosis. In contrast, cellular senescence inhibits HSCs’ activity and limits fibrosis. The aim of this study was to explore the effect of IGF-I on NASH and cirrhotic models and to clarify the underlying mechanisms. We demonstrate that IGF-I significantly ameliorated steatosis, inflammation, and fibrosis in a NASH model, methionine-choline-deficient diet-fed db/db mice and ameliorated fibrosis in cirrhotic model, dimethylnitrosamine-treated mice. As the underlying mechanisms, IGF-I improved oxidative stress and mitochondrial function in the liver. In addition, IGF-I receptor was strongly expressed in HSCs and IGF-I induced cellular senescence in HSCs in vitro and in vivo. Furthermore, in mice lacking the key senescence regulator p53, IGF-I did not induce cellular senescence in HSCs or show any effects on fibrosis. Taken together, these results indicate that IGF-I induces senescence of HSCs, inactivates these cells and limits fibrosis in a p53-dependent manner and that IGF-I may be applied to treat NASH and cirrhosis.

Objective: The prevalence and clinical characteristics of IgG4-related hypophysitis remain unclear due to the limited number of case reports. Therefore, in this study, we screened consecutive outpatients with hypopituitarism and/or diabetes insipidus (DI) to estimate its prevalence. Methods: A total of 170 consecutive outpatients with hypopituitarism and/or central DI were screened at Kobe University Hospital for detecting IgG4-related hypophysitis by pituitary magnetic resonance imaging, measuring serum IgG4 concentrations, assessing the involvement of other organs, and carrying out an immunohistochemical analysis to detect IgG4-positive cell infiltration. Results: Among the screened cases, 116 cases were excluded due to diagnosis of other causes such as tumors and congenital abnormalities. Additionally, 22 cases with isolated ACTH deficiency were analyzed and were found not to meet the criteria of IgG4-related hypophysitis. The remaining 32 cases were screened and seven were diagnosed with IgG4-related hypophysitis, of which three cases were diagnosed by analyzing pituitary specimens. IgG4-related hypophysitis was detected in 30% (seven of 23 patients) of hypophysitis cases and 4% of all hypopituitarism/DI cases. The mean age at the onset of IgG4-related hypophysitis was 61.8G8.8 years, and the serum IgG4 concentration was 191.1G78.3 mg/dl (normal values 5-105 mg/dl and values in IgG4-related disease (RD) R135 mg/dl). Pituitary gland and/or stalk swelling was observed in six patients, and an empty sella was observed in one patient. Multiple co-existing organ involvement was observed in four of the seven patients prior to the onset of IgG4-related hypophysitis. Conclusion: These data suggest that the prevalence of IgG4-related hypophysitis has been underestimated. We should also consider the possibility of the development of hypopituitarism/DI caused by IgG4-related hypophysitis during the clinical course of other IgG4-RDs.

Adaptation under fasting conditions is critical for survival in animals. Sirtuin 1 (SIRT1), a protein deacetylase, plays an essential role in adaptive metabolic and endocrine responses under fasting conditions by modifying the acetylation status of various proteins. Fasting induces growth hormone (GH) resistance in the liver, leading to decreased serum insulin-like growth factor-I (IGF-I) levels as an endocrine adaptation for malnutrition; however, the underlying mechanisms of this action remain to be fully elucidated. Here we report that in vivo knockdown of SIRT1 in the liver restored the fasting-induced decrease in serum IGF-I levels and enhanced the GH-dependent increase in IGF-I levels, indicating that SIRT1 negatively regulates GH-dependent IGF-I production in the liver. In vitro analysis using hepatocytes demonstrated that SIRT1 suppresses GH-dependent IGF-I expression, accompanied by decreased tyrosine phosphorylation on signal transducer and activator of transcription (STAT) 5. GST pull-down assays revealed that SIRT1 interacts directly with STAT5. When the lysine residues adjacent to the SH2 domain of STAT5 were mutated, STAT5 acetylation decreased concomitant with a decrease in its transcriptional activity. Knockdown of SIRT1 enhanced the acetylation and GH-induced tyrosine phosphorylation of STAT5, as well as the GH-induced interaction of the GH receptor with STAT5. These data indicate that SIRT1 negatively regulates GH-induced STAT5 phosphorylation and IGF-I production via deacetylation of STAT5 in the liver. In addition, our findings explain the underlying mechanisms of GH resistance under fasting conditions, which is a known element of endocrine adaptation during fasting.

C luster of differentiation 98/4F2 is a heterodimeric protein with a relative molecular mass of 125 000 (GP125), comprising a 90-kDa hc and 35-kDa lc.(1-3) CD98 was originally identified as a cell-surface antigen associated with the activation of lymphocytes (2) and is expressed on the basal layer of the squamous epithelium and a wide variety of tumors,suggesting its functional involvement in lymphocyte activation, cell proliferation, and malignant transformation. In fact, mAb against rat and human CD98 hc inhibits the activation of lymphocytes and proliferation of tumor cells. (5,6) In addition, NIH3T3 and Balb3T3 cells transfected with cDNA of human and rat CD98 hc have shown various malignant phenotypes.(7-9) CD98 lc have been revealed to be amino acid transporters, (3,10) and multiple functions of CD98 hc, such as cell fusion, (11) regulation of β 1 integrin activation, (12) and induction of apoptosis, (13) have been demonstrated. Transporters corresponding to the amino acid transport system L, y + L, , and Asc have been shown to be CD98 lc, which require CD98 hc for their membrane-based expression. (3,9,14) Six amino acid transporters (LAT1, LAT2, y + LAT1, y + LAT2, Asc-1, and xCT) that belong to the SLC7 family, have been identified to be CD98 lc, and all CD98 lc are believed to be sorted to the plasma membrane via association with CD98 hc. (15 -21) l-type amino-acid transporter 1 is a 12-membrane pass non-glycosylated protein that was first identified as CD98 lc associated with CD98 hc glycoprotein, and mediates Na + -independent large amino acid transport (system L). (3,22) It is reported that mRNA of LAT1 is expressed widely on tumor cells in addition to in the testis, ovary, and brain. (3,(23)(24)(25) However, because specific mAb recognizing the extracellular domain of native human LAT1 protein have not been obtained until now, the precise expression profile of LAT1 protein in normal and cancer cells remains unsolved. In the present paper, we report the successful production of specific mAb against human LAT1 protein, and discuss the specificity and usefulness of anti-LAT1 mAb in cancer therapy. Materials and MethodsCell culture. Human leukemia cells (Molt-4, Jurkat, Daudi, Raji, CCRF-SB, K562, and U937), mouse myeloma cells (P3 × 63Ag8.653), and peripheral blood leukocytes from healthy volunteers were cultured in RPMI-1640 medium (Sigma-Aldrich, St Louis, MO, USA). Human tumor cell lines from the tongue (HEp2), larynx (HSC-3), lung (A549), esophagus (TE-3), breast , liver (HepG2, Hep3B, and HLF), pancreas (PK-1 and PaCa-1), stomach , colon (SW1116, HT29, DU145, and LS-174T), cervix (HeLa and ME180), prostate (PC-3), kidney (ACHN and TOS-1), and bladder (T24, J82, KU-1, KK47, and MGH-U1), glioblastoma cells (KNS-42), melanoma cells (SK-MEL-37), neuroblastoma cells (Tagawa), HEK293F human embryonic kidney cells (Invitrogen, Carlsbad, CA, USA), Int407 embryonic intestine cells, RH7777 rat hepatoma cells (kindly donated by Mitsubishi Tanabe Pharma, Yokohama, Japan), and RenCa mouse renal carcinoma ce...

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