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Browsing by Subject "Glucose metabolism"
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Item Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer(SpringerNature, 2016-12-15) Li, J.; Gu, D.; Lee, SS-Y.; Song, B.; Bandyopadhyay, S.; Chen, S.; Konieczny, SF.; Ratliff, TL.; Liu, X.; Xie, J.; Cheng, J-X.; Department of Pediatrics, IU School of MedicineCancer cells are known to execute reprogramed metabolism of glucose, amino acids and lipids. Here, we report a significant role of cholesterol metabolism in cancer metastasis. By using label-free Raman spectromicroscopy, we found an aberrant accumulation of cholesteryl ester in human pancreatic cancer specimens and cell lines, mediated by acyl-CoA cholesterol acyltransferase-1 (ACAT-1) enzyme. Expression of ACAT-1 showed a correlation with poor patient survival. Abrogation of cholesterol esterification, either by an ACAT-1 inhibitor or by shRNA knockdown, significantly suppressed tumor growth and metastasis in an orthotopic mouse model of pancreatic cancer. Mechanically, ACAT-1 inhibition increased intracellular free cholesterol level, which was associated with elevated endoplasmic reticulum stress and caused apoptosis. Collectively, our results demonstrate a new strategy for treating metastatic pancreatic cancer by inhibiting cholesterol esterification.Item Long Non-coding RNA in Liver Metabolism and Disease: Current Status(Elsevier, 2017-09) Zhao, Yulan; Wu, Jianguo; Liangpunsakul, Suthat; Wang, Li; Medicine, School of MedicineLong non-coding RNAs (lncRNAs) are comprised of RNA transcripts exceeding 200 nucleotides in length but lacking identifiable open reading frames (with rare exceptions). Herein, we highlight emerging evidence demonstrating that lncRNAs are critical regulators of liver metabolic function and diseases. We summarize current knowledges about dysregulated lncRNAs and outline the underlying molecular mechanisms by which lncRNAs control hepatic lipid ad glucose metabolism, as well as cholestatic liver disease. lncLSTR, Lnc18q22.2, SRA, HULC, MALAT1, lncLGR, MEG3, and H19, lncHR1, lnc-HC, APOA1-AS, DYNLRB2-2, and LeXis are included in the discussion.Item Sirtuin 6 regulates glucose-stimulated insulin secretion in mouse pancreatic beta cells(Springer, 2016-01) Xiong, Xiwen; Wang, Gaihong; Tao, Rongya; Wu, Pengfei; Kono, Tatsuyoshi; Li, Kevin; Ding, Wen-Xing; Tong, Xin; Tersey, Sarah A.; Harris, Robert A.; Mirmira, Raghavendra G.; Evans-Molina, Carmella; Dong, X. Charlie; Department of Biochemistry & Molecular Biology, IU School of MedicineAIMS/HYPOTHESIS: Sirtuin 6 (SIRT6) has been implicated in ageing, DNA repair and metabolism; however, its function in pancreatic beta cells is unclear. The aim of this study is to elucidate the role of SIRT6 in pancreatic beta cells. METHODS: To investigate the function of SIRT6 in pancreatic beta cells, we performed Sirt6 gene knockdown in MIN6 cells and generated pancreatic- and beta cell-specific Sirt6 knockout mice. Islet morphology and glucose-stimulated insulin secretion (GSIS) were analysed. Glycolysis and oxygen consumption rates in SIRT6-deficient beta cells were measured. Cytosolic calcium was monitored using the Fura-2-AM fluorescent probe (Invitrogen, Grand Island, NY, USA). Mitochondria were analysed by immunoblots and electron microscopy. RESULTS: Sirt6 knockdown in MIN6 beta cells led to a significant decrease in GSIS. Pancreatic beta cell Sirt6 knockout mice showed a ~50% decrease in GSIS. The knockout mouse islets had lower ATP levels compared with the wild-type controls. Mitochondrial oxygen consumption rates were significantly decreased in the SIRT6-deficient beta cells. Cytosolic calcium dynamics in response to glucose or potassium chloride were attenuated in the Sirt6 knockout islets. Numbers of damaged mitochondria were increased and mitochondrial complex levels were decreased in the SIRT6-deficient islets. CONCLUSIONS/INTERPRETATION: These data suggest that SIRT6 is important for GSIS from pancreatic beta cells and activation of SIRT6 may be useful to improve insulin secretion in diabetes.