Possible role for human leukocyte antigen haplotype in rofecoxib-associated acute pancreatitis and cholestatic hepatitis.
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Aged↗
Biomedical subjects
Yutaka Uehara
Publications and source records attributed to Yutaka Uehara.
Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles.
We have identified an unusual potential dual Akt/protein kinase B consensus phosphorylation motif in the protein Synip (RxKxRS(97)xS(99)). Surprisingly, serine 97 is not appreciably phosphorylated, whereas serine 99 is only a specific substrate for Akt2 but not Akt1 or Akt3. Although wild-type Synip (WT-Synip) undergoes an insulin-stimulated dissociation from Syntaxin4, the Synip serine 99 to phenylalanine mutant (S99F-Synip) is resistant to Akt2 phosphorylation and fails to display insulin-stimulated Syntaxin4 dissociation. Furthermore, overexpression of WT-Synip in 3T3L1 adipocytes had no effect on insulin-stimulated recruitment of glucose transporter 4 (GLUT4) to the plasma membrane, whereas overexpression of S99F-Synip functioned in a dominant-interfering manner by preventing insulin-stimulated GLUT4 recruitment and plasma membrane fusion. These data demonstrate that insulin activation of Akt2 specifically regulates the docking/fusion step of GLUT4-containing vesicles at the plasma membrane through the regulation of Synip phosphorylation and Synip-Syntaxin4 interaction.
3T3 Cells↗
Molecular mechanisms associated with leptin resistance: n-3 polyunsaturated fatty acids induce alterations in the tight junction of the brain.
High-fat diets cause peripheral leptin resistance, and dietary lipid composition affects sensitivity to leptin. We examined the role of n-3 polyunsaturated fatty acid (PUFA) in peripheral leptin resistance. Dietary PUFAs (0.4% wt/wt) caused insensitivity to peripherally but not intracerebroventricularly administered leptin. n-3 PUFA increased body weight, associated with a significant reduction of leptin concentration in the cerebrospinal fluid. Dietary n-3 PUFA reduced transport of endogenous or exogenously administered leptin into the brain, associated with increased expression of hypothalamic occludin, but caused no change in expression of leptin receptors, proteins associated with leptin signaling or other tight junction proteins. Continuous intracerebroventricular infusion of an antisense morpholino oligonucleotide targeted to occludin mRNA reversed n-3 PUFA-induced insensitivity to peripherally administered leptin. We conclude that n-3 PUFA induces peripheral leptin resistance via an increase in the expression of hypothalamic occludin, reducing paracellular transport of leptin into the brain.
Animals↗
Differential activation of epidermal growth factor (EGF) receptor downstream signaling pathways by betacellulin and EGF.
To determine the downstream signaling pathways regulated by betacellulin (BTC) in comparison with epidermal growth factor (EGF), we used Chinese hamster ovary cells overexpressing the human EGF receptor (ErbB1/EGFR). The overall time-dependent activation of EGFR autophosphorylation was identical in cells treated with 1 nm BTC or 1.5 nm EGF. Analysis of site-specific EGFR phosphorylation demonstrated that the BTC and EGF tyrosine phosphorylation of Y1086 was not significantly different. In contrast, the autophosphorylation of Y1173 was markedly reduced in BTC-stimulated cells, compared with EGF stimulation that directly correlated with a reduced BTC stimulation of Shc tyrosine phosphorylation, Ras, and Raf-1 activation. On the other hand, Y1068 phosphorylation was significantly increased after BTC stimulation, compared with EGF in parallel with a greater extent of Erk phosphorylation. Expression of a dominant interfering MEK kinase 1 (MEKK1) and Y1068F EGFR more efficiently blocked the enhanced Erk activation by BTC, compared with EGF. Interestingly BTC had a greater inhibitory effect on apoptosis, compared with EGF, and expression of Y1068F EGFR abolished this enhanced inhibitory effect. Together, these data indicated that although BTC and EGF share overlapping signaling properties, the ability of BTC to enhance Erk activation occurs independent of Ras. The increased BTC activation results from a greater extent of Y1068 EGFR tyrosine phosphorylation and subsequent increased recruitment of the Grb2-MEKK1 complex to the plasma membrane, compared with EGF stimulation. The increased Erk activation by BTC associated with antiapoptotic function.
Adaptor Proteins, Signal Transducing↗
A patient with classic severe primary hyperparathyroidism in whom both Tc-99m MIBI scintigraphy and FDG-PET failed to detect the parathyroid tumor.
A 24-year-old woman was admitted to our department for further examination of hypercalcemia, a high level of intact parathyroid hormone (PTH) and a right parathyroid tumor. She complained of bone pain throughout her body and was unable to walk due to systemic cystic osteofibrosis, including a brown tumor of the left lower extremities. Neck ultrasonography (US) and magnetic resonance imaging (MRI) revealed a tumor 2 cm in diameter in the upper side of the right thyroid lobe. 99mTc sestamibi (99mTc-MIBI) imaging and F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) were performed to diagnose primary hyperparathyroidism and examination of other parathyroid glands. However, neither imaging modality detected the parathyroid tumor. To confirm the diagnosis, we performed selective venous sampling around the parathyroid and the patient was diagnosed with primary hyperparathyroidism due to a right parathyroid tumor. Resection of the right parathyroid tumor was performed and the pathological diagnosis was parathyroid adenoma. To date, both 99mTc-MIBI and FDG-PET are useful to localize parathyroid tumors. In this case, however, neither modality detected the tumor. Although recent studies state that expression of P-glycoprotein (P-gp) in parathyroid tumors plays an important role in the false-negative results of both 99mTc-MIBI scans and FDG-PET, immunohistological study detected no P-gp expression in the parathyroid tumor in the current case.
Adenoma↗
[Fitz-Hugh-Curtis syndrome presenting spontaneous regression of ascites].
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Adult↗
Circulating concentrations of soluble leptin receptor: influence of menstrual cycle and diet therapy.
Concentrations of the soluble leptin receptor (sOB-R) may be related to leptin resistance in obesity. We measured sOB-R concentrations in serum in 103 non-diabetic Japanese men and women. All subjects were grouped according to body mass index (BMI; in kg/m(2)). Serum sOB-R concentrations did not differ significantly between normal-weight (18.5 < or = BMI < 25.0) men and women, but were significantly higher in underweight subjects (BMI < 18.5) than in normal-weight subjects. In contrast, overweight (25 < or = BMI < 30) and obese (30 < or = BMI < 35.0, 35.0 < or = BMI < 40, and BMI > or = 40) subjects had significantly lower sOB-R concentrations than did normal-weight subjects. Serum sOB-R concentrations were inversely correlated with BMI and serum immunoreactive leptin concentrations. Very low-energy diet therapy for 4 wk significantly lowered serum immunoreactive leptin concentrations but did not significantly affect serum sOB-R concentrations. Serum sOB-R concentrations did not change significantly during the menstrual cycle. Our results showed that serum sOB-R concentrations decrease with increasing BMI and that sex hormones likely do not affect serum sOB-R concentrations in non-pregnant women. The reduction in serum sOB-R concentrations in overweight and obese persons may reflect downregulation of hypothalamic leptin receptor production as a result of an increase in circulating leptin and might be an important factor in leptin resistance.
Adult↗
Is leptin a key factor which develops obesity by ovariectomy?
Withdrawal of estrogen by ovariectomy increases adiposity, but decreases the circulating levels of the ob gene product, leptin, which inhibits food intake. The reduction of circulating leptin levels may thus play an important role in the induction of obesity by ovariectomy. To examine this hypothesis, body weight change by ovariectomy was investigated in leptin-deficient genetically obese (ob/ob) mice with leptin supplement. Prior to the operation, obese (ob/ob) female mice were treated with intraperitoneal administration of recombinant mouse leptin (1.0 microg/g body weight/day) for 8 days. Then, half of the leptin-treated mice and their lean littermates were bilaterally ovariectomized and their body weight changes were observed for 56 days. From 16 days after the operation, a significant increase in body weight by ovariectomy was observed only in lean mice without leptin treatment. From 44 days, a significant body weight gain by ovariectomy was observed in leptin-treated obese mice. Ovariectomy significantly increased retroperitoneal white adipose tissue weight in their lean littermates, but not in leptin-treated obese mice. It was suggested that the reduction of circulating leptin levels may play an important role in the increases of acute phase body weight gain by ovariectomy, but during static phase, the direct effects of estrogen withdrawal may appear independent of leptin-mediated effects.
Adipose Tissue↗