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研究生：	洪晧彰 Hung, Hao-Chang
論文名稱：	心肌營養蛋白-1在代謝性疾病所扮演之角色 The role of cardiotrophin-1 in metabolic disorders
指導教授：	張智仁 Chang, Chih-Jen
學位類別：	博士 Doctor
系所名稱：	醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	58
中文關鍵詞：	心肌營養蛋白-1
外文關鍵詞：	Cardiotropin-1
相關次數：	點閱：65 下載：1
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心肌營養蛋白-1是從肥厚老鼠的胚胎幹細胞中發現的，屬於IL-6細胞因子家族之一員，過去動物研究結果顯示心肌營養蛋白-1會引起心肌細胞的肥厚，進而造成左心室肥厚。而過去在人類的研究結果顯示高血壓患者的血中心肌營養蛋白-1濃度會隨著心臟衰竭的進展而越來越高。
動物實驗結果發現心肌營養蛋白-1是葡萄糖與脂肪代謝的主要調節因子，此外，心肌營養蛋白-1能改善肥胖小鼠的肝臟脂肪堆積，這些研究結果顯示心肌營養蛋白-1可能在代謝性疾病中扮演重要的角色，甚至心肌營養蛋白-1可能對於治療代謝性疾病是一個有潛力的藥物。然而，由於缺乏有關心肌營養蛋白-1與代謝性疾病之間的關係在人類的研究數據，所以目前要在臨床上使用心肌營養蛋白-1來治療代謝性疾病仍言之過早，因此，本研究係探討心肌營養蛋白-1在代謝性疾病所扮演的角色。
我們使用二個不同族群分別研究心肌營養蛋白-1與高血糖、肥胖及非酒精性脂肪肝之間的相關性，並使用肝臟星狀細胞及人類肝癌細胞來研究心肌營養蛋白-1與肝臟纖維化的關係。
第一部份結果顯示葡萄糖耐受不良與糖尿病患有較高的心肌營養蛋白-1，並與心肌營養蛋白-1呈現獨立正相關。第二部份結果顯示非酒精性脂肪肝者有較高的心肌營養蛋白-1，並與心肌營養蛋白-1呈現獨立正相關。第三部份結果顯示動脈硬度較高者有較高的心肌營養蛋白-1，且心肌營養蛋白-1與動脈硬度呈現獨立正相關。第四部份結果顯示過重與肥胖者有較低的心肌營養蛋白-1，並與心肌營養蛋白-1呈現獨立負相關。此外，細胞研究結果顯示棕櫚酸會造成人類肝癌細胞內脂肪堆積與增加心肌營養蛋白-1的表現，而心肌營養蛋白-1則會透過p38路徑增加肝臟星狀細胞的膠原I的表現。
因此，本研究計畫的研究結論為心肌營養蛋白-1與高血糖、非酒精性脂肪肝與動脈硬度呈現正相關，但與肥胖則呈現負相關，推測心肌營養蛋白-1未來可能可作為糖尿病、非酒精性脂肪肝與動脈硬度的生物指標，並有希望成為治療肥胖的方法。此外，細胞研究結果顯示心肌營養蛋白-1可能與肝臟纖維化的致病機轉相關。

Cardiotrophin-1, cloned from hypertrophied mouse embryonic stem cells, is one member of the interleukin 6 family of cytokines. Previous studies on cardiomyocyte suggested that cardiotrophin-1 chronically induce cardiomyocyte hypertrophy, thus subsequently lead to left ventricular hypertrophy. In human studies, cardiotrophin-1 increased progressively along with the progression of heart failure in subjects with hypertension.
Cardiotrophin-1 was found to be a master regulator of glucose and fat metabolism in vitro. Furthermore, cardiotrophin-1 was shown to eliminate hepatic steatosis in obese mice. Together, cardiotrophin-1 might play an important role in the metabolic disorders and represent a promising therapeutic agent for the treatment of metabolic disorders. However, the lack of human data of the relationship among cardiotrphin-1 and different metabolic disorders, such as diabetes, arterial stiffness, nonalcoholic fatty liver disease, and obesity, make it not clinically relevant before cardiotrphin-1 can be used in human. Therefore, the aim of this project was to investigate the role of cardiotrophin-1 in metabolic disorders.
We used two different populations to investigate the association between cardiotrophin-1 and different glycemia status, nonalcoholic fatty liver disease, arterial stiffness, and obesity. In vitro, hepatic stellate cells and HepG2 cells were used to study the relationship between cardiotrophin-1 and liver fibrosis.
The first part of work showed that subjects with IGT and NDD had significantly higher cardiotrophin-1 concentrations than those with NGT, and IGT and NDD were positively associated with cardiotrophin-1 concentrations. The second part of work showed that individuals with NAFLD had significantly higher serum cardiotrophin-1 levels than those without NAFLD, and the presence of NAFLD was independently associated with cardiotrophin-1. The third part of work showed that individuals with arterial stiffness had significantly higher serum cardiotrophin-1 levels, and cardiotrophin-1 was independently associated with arterial stiffness. The fourth part showed that obese and overweight individuals without diabetes had lower cardiotrophin-1 levels than normal weight ones, and both obesity and overweight were inversely associated with cardiotrophin-1. In addition, in vitro studies showed that palmitic acid treatment increased lipid accumulation and increased the expressions of cardiotrophin-1 dose-dependently in HepG2 cells. Cardiotrophin-1 increased the expression of collagen I in hepatic stellate cells (HSCs) through the p38 pathway.
According to the results, cardiotrophin-1 is positively associated with hyperglycemia, NAFLD, and arterial stiffness, but negatively associated with obesity in human. Cardiotrophin-1 may represent a surrogate marker of diabetes, NAFLD, and arterial stiffness, and maybe a promising therapy for obesity. In addition, cardiotrophin-1 may be involved in the pathogenesis of liver fibrosis.

中文摘要	I
ABSTRACT	II
致謝	IV
INTRODUCTION	1
Tissue distribution of cardiotrophin-1	1
Cardiotrophin-1 receptor	1
Receptor signaling mechanisms of the IL-6 family of cytokines (3) (Figure 3)	2
Signaling pathway of cardiotrophin-1	2
Regulatory factors of cardiotrophin-1 (Table 1)	3
The cardiotrophin-1 null mice	4
Actions of cardiotrophin-1	5
MATERIALS AND METHODS	8
Human study	8
Cardiotrophin-1 and different glycemia status, nonalcoholic fatty liver disease, and arterial stiffness	8
Cardiotrophin-1 and obesity	10
Cell study	12
RESULTS	14
Human study	14
Cardiotrophin-1 and different glycemia status	14
Cardiotrophin-1 and nonalcoholic fatty liver disease (NAFLD)	14
Cardiotrophin-1 and arterial stiffness	15
Cardiotrophin-1 and obesity	15
Cell study	16
DISCUSSION	17
CONCLUSION	23
TABLES	24
Table 1. Regulatory factors of cardiotrophin-1.	25
Table 2. Comparisons of clinical characteristics among subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and newly diagnosed diabetes (NDD).	26
Table 3. Multivariate linear regression analyses of clinical variables and cardiotrophin-1 among subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and newly diagnosed diabetes (NDD).	27
Table 4. Comparisons of clinical characteristics between subjects with and without NAFLD.	28
Table 5. Multivariate linear regression analyses of cardiotrophin-1 and clinical variables in individuals with and without NAFLD.	29
Table 6. Comparisons of clinical characteristics between subjects with baPWV ≤ 1400 and > 1400 cm/sec.	30
Table 7. Multivariate logistic regression analyses of clinical variables and baPWV > 1400 cm/sec.	31
Table 8. Comparisons of clinical characteristics among subjects who were normal weight, overweight, and obese.	32
Table 9. Multivariate linear regression analyses of cardiotrophin-1 and clinical variables among subjects who were normal weight, overweight, and obese.	33
FIGURES	34
Figure 1. Chromosomal location of cardiotrophin-1.	35
Figure 2. Cytokine receptor of the IL-6 family (3).	35
Figure 3. Receptor signaling mechanisms of the IL-6 family of cytokines (3).	36
Figure 4. Schematic representation of cardiotrophin-1 signaling pathways and their different effects on the cardiac cell (13).	37
Figure 5. Plasma cardiotrophin-1 levels increased progressively along with the progression of heart failure in subjects with hypertensive heart disease (14).	38
Figure 6. Schematic representation of the metabolic actions of cardiotrophin-1 (35).	39
Figure 7. Comparisons of cardiotrophin-1 levels between subjects with and without hypertension.	40
Figure 8. Comparisons of cardiotrophin-1 levels among subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and newly diagnosed diabetes (NDD).	41
Figure 9. Cardiotrophin-1 levels in normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and newly diagnosed diabetic (NDD) subjects with and without obesity.	42
Figure 10. Comparisons of cardiotrophin-1 levels between individuals with and without NAFLD.	43
Figure 11. Comparisons of cardiotrophin-1 levels between individuals with baPWV≤1400 cm/sec and baPWV>1400 cm/sec.	44
Figure 12. Comparisons of cardiotrophin-1 levels among subjects who were normal weight, overweight, and obese.	45
Figure 13. Effects of different doses of palmitic acid on lipid accumulation in HepG2 cells. All groups were stained with oil red O.	46
Figure 14. Palmitic acid treatment resulted in the increased the expression of cardiotrophin-1 dose-dependently in HepG2 cells.	47
Figure 15. Palmitic acid treatment increased the expression of SOCS3 in HepG2 cells.	48
Figure 16. Cardiotrophin-1 upregulated the phosphorylation of p38 in hepatic stellate cells.	49
Figure 17. Treatment of cardiotrphin-1 increased the expression of collagen I in hepatic stellate cells.	50
Figure 18. Increased expression of collagen I by cardiotrophin-1 was abolished by p38 inhibitor, SB203580, in hepatic stellate cells.	51
Figure 19. Summary of the results of the human and cell study in this project.	52
Figure 20. Hypothesis of the role of cardiotrophin-1 in the process from obesity to NAFLD, and to diabetes.	53
References	54
                                    

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