AP 2017 Award

AP-1

THE LINK BETWEEN NON-ALCOHOLIC FATTY LIVER DISEASE AND INSULIN RESISTANCE BY HEPATOCYTE-DERIVED FIBRINOGENRELATED PROTEIN 1

1,2H-T WU, 3 H-Y OU, 3H-C HUNG, 2F-H LU, 2J-S WU, 2Y-C YANG, 2C-J CHANG

1Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Taiwan, R.O.C. 2Department of Family Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Taiwan, R.O.C. 3Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Taiwan, R.O.C.

OBJECTIVE Non-alcoholic fatty liver disease (NAFLD) is highly correlated with insulin resistance (IR); however, the link between these two diseases was still obscure. It was known that in hepatogenesis in embryonic stage, whereas the role of this protein in NAFLD and IR was unknown. Thus, the aim of this study was to clarify the role of HFREP-1in these two diseases.

MATERIAL AND METHODS A total of 200 healthy and diabetic patients with or without NAFLD was enrolled for the determination of plasma HFREP-1 concentrations by commercial assay kits. Lentiviral vectors containing HFREP-1 or short hairpin RNA targeted to HFREP-1 were injected through portal vein in mice to overexpress or knockdown HFREP-1. Glucose and insulin tolerance tests, as well as hyperinsulinemic-euglycemic clamp were used to evaluate insulin sensitivity. HepG2 hepatocellular carcinoma cell line was used for the investigation of mechanisms in detail.

RESULT In this study, we found that plasma HFREP-1 concentrations were significantly increased in subjects with prediabetes, including impaired fasting glucose and impaired glucose tolerance, and gradually increased in diabetic patients. In addition, plasma HFREP-1 concentrations HFREP-1 induced lipid accumulation in liver and systemic IR through an ERK1/2-dependent pathway. On the other hand, knockdown of hepatic HFREP-1 improved high fat diet-induced NAFLD and IR.

CONCLUSION HFREP-1 is a novel therapeutic candidate to combat NAFLD and IR.

AP-2

LIRAGLUTIDE PREVENTS AND REVERSES MONOCROTALINE- INDUCED PULMONARY ARTERIAL HYPERTENSION BY SUPPRESSING ET-1 AND ENHANCING ENOS/SGC/PKG PATHWAYS

M-Y LEE1,2,3, K-B TSAI4, J-H HSU5,6, S-J SHIN2, J-R WU5,6, J-L YEH1,7

1Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 2Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. 3Department of Internal Medicine, Kaohsiung Municipal Hsiaokang Hospital, Kaohsiung, Taiwan. 4Department of Pathology, Kaohsiung Municipal Hsiaokang Hospital, Kaohsiung, Taiwan. 5Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. 6Department of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 7Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung, Taiwan.

OBJECTIVE Liraglutide, a glucagon-like peptide-1 receptor agonist, is widely used to treat diabetes. However, its effect on pulmonary arterial hypertension is unknown. In this study, we investigated its effects on rats with monocrotaline-induced PAH and mechanisms on rat pulmonary artery smooth muscle cells.

METHOD Liraglutide was investigated for both prevention and treatment of MCTinduced PAH. The hemodynamic and body weight changes, right heart hypertrophy, lung morphology, immunereactivity of endothelial nitric oxide synthase, endothelin-1 and cyclic guanosine monophosphate levels, protein expressions of eNOS, soluble guanylyl cyclase, protein kinase G and Rho kinase II pathway were measured in both in vivo and in vitro. Cell migration and cell cycle were also determined.

RESULT Liraglutide both prevented and reversed MCT-induced PAH, right ventricle hypertrophy and pulmonary vascular wall remodeling. Protein expression of ROCK II was increased while eNOS, sGC and PKG were decreased. Pretreatment with liraglutide inhibited platelet-derived growth factorBB stimulated PASMCs migration, which were associated with cell-cycle arrest at G0/G1 phase. CONCLUSION Liraglutide may have both preventive and therapeutic effects on MCTinduced PAH, through the eNOS/sGC/PKG and Rho kinase pathways. Thus, liraglutide may have a therapeutic role in pulmonary vascular remodelling.

AP-3

IRAK1, A TARGET OF MIR-146B, REDUCES CELL AGGRESSIVENESS OF HUMAN PAPILLARY THYROID CARCINOMA

1,2CHEN-KAI CHOU, 3SHUN-YU CHI, 1CAI-HUA HUANG, 3FONG-FU CHOU, 4CHAOCHENG HUANG, 1RUE-TSUAN LIU, , 2HONG-YO KANG

1Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan, 2Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taiwan, Departments of 3Surgery, 4Pathology Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan,

Objective: MicroRNA (miR)-146b is overexpressed in papillary thyroid carcinoma (PTC) and is associated with extrathyroidal invasion, advanced tumor stage, and poor prognosis. However, the underlying mechanism of miR-146b in relation to its oncogenic behavior in PTC and its putative targets remain unknown. The purpose of this study was to investigate interleukin-1 receptor-associated kinase 1 (IRAK1) as the potential miR-146b target gene and its involvement in PTC.

Design: assays to identify IRAK1 as a miR-146b target gene. In vitro gain/loss-of-function experiments were further performed to determine the effects of IRAK1 on proliferation, colony formation, and woundhealing in PTC cancer cell lines. Expression levels of miR-146b and IRAK1 of 50 cases of PTC and its adjacent normal thyroid specimens were assessed via quantitative real-time polymerase chain reaction.

Results: Microarray expression profile revealed that the mRNA level of IRAK1 gene was downregulated by miR-146b. IRAK1 mRNA was found to be a molecular target of miR146b posttranscriptional repression in BCPAP cells by reporter gene assays. MiR-146b promoted the migration and proliferation of PTC cells by downregulating IRAK1 expression, whereas restoration of IRAK1 expression reversed this effect. In addition, the expression of IRAK1 mRNA lower in PTC clinical tissue samples than normal adjacent thyroid specimens and showed a strong inverse correlation with the expression of miR-146b in PTC specimens.

Conclusion: Our results demonstrated that IRAK1 is a direct target of miR-146b and has functional roles to inhibit various aggressive PTC cell activities. In conjunction with current therapeutic regimens, targeting the miR-146b-IRAK1 axis may provide a potential approach for PTC management.

AP-4

CARDIOTROPHIN-1 IS INVERSELY ASSOCIATED WITH OBESITY IN NON-DIABETIC INDIVIDUALS.

1,2,3HUNG HC, 3,4LU FH, 4WU HT, 1,3OU HY, 3,4YANG YC, 3,4WU JS, 3,4CHANG CJ

1Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan. 2The Institute of Basic Medical Sciences of National Cheng Kung University, Tainan, Taiwan. 3College of Medicine, National Cheng Kung University, Tainan, Taiwan. 4Department of Family Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.

OBJECTIVE Cardiotrophin-1 is known to be a key regulator of energy homeostasis, as well as glucose and lipid metabolism in vivo. However, there are inconsistent results of the association between cardiotrophin-1 and obesity in humans, possibly confounded by hyperglycemia. Therefore, the aim of this study was to investigate the relationships among cardiotrophin-1 levels, overweight and obese individuals without diabetes in a Chinese population.

METHODS The subjects were recruited for the population-based study for chronic diseases conducted in Tainan. Informed consent was obtained from all participants, and the study was approved by the IRB of the National Cheng Kung University Hospital.

RESULTS The median serum cardiotrophin-1 levels were 447.9, 350.6, and 288.1 pg/ml in non-diabetic subjects who were of normal weight (n = 522), overweight (n = 203), and obese (n = 93), cardiotrophin-1 levels than those with normal weight. The multivariate linear regression analyses showed that overweight (p < 0.01), obese (p < 0.01), and smoking (p < 0.01) were negatively related to cardiotrophin-1 after adjusting for age, gender, HOMA-IR, hypertension, total cholesterol, HDL, triglyceride, eGFR, ALT, and alcohol drinking.

CONCLUSION The results of this study provided epidemiological evidence that non-diabetic those with normal weight, and both obesity and being overweight were inversely associated with cardiotrophin-1 levels.