研究顯示內毒素血症相關蛋白質（脂多醣結合蛋白質，LBP）與許多代謝疾病有關，如：肥胖，糖尿病和非酒精性脂肪性肝病（NALFD），且減重手術後血清中LBP濃度會降低。然而，非手術的體重管理後肥胖病人血清LBP變化目前尚不清楚。此外，由於慢性C型肝炎病毒（HCV）感染與代謝疾病也相關，LBP和HCV感染之間的關係值得進一步研究。此論文旨在探討經過一年非手術體重管理後，肥胖病人血清LBP濃度的變化，並研究C型肝炎病人完成干擾素療法或非干擾素療法後，其血清LBP濃度的變化。
　　研究招募了120名非HCV感染者，42名使用長效型干擾素與雷巴威林治療的HCV感染者和17名口服直接作用型抗病毒藥物治療的HCV感染者進行病例對照研究。此外，還招募62名肥胖受試者，39名過重受試者和21名身體質量指數(BMI)正常的受試者參加為期一年的體重管理計劃。研究中收集這些病人的基本資料、身體組成分析、臨床數據、血清LBP濃度和腹部超音波檢查結果。所有受試者皆在進入研究前，提供國立臺灣大學醫學院附設醫院研究倫理委員會已核准之書面知情同意書。
　　HCV感染者在干擾素療法前分析其血清LBP濃度發現，其血清LBP顯著高於非HCV感染者（34.6 ± 7.3對20.0 ± 6.4 μg/ mL; p值 <0.001），尤其是肥胖的HCV感染者其血清LBP濃度最高（36.1 ± 7.8 μg/ mL）。HCV感染者不論是否使用干擾素療法或非干擾素療法，於持續病毒學抑制反應的這個時間點發現，其血清LBP濃度皆顯著下降（干擾素組: 27.4 ± 6.6對34.6 ± 7.3 μg/ mL，p值 <0.001; 非干擾素組: 15.9 ± 4.4對22.2 ± 5.7 μg/ mL，p值= 0.001）。經多變量分析後發現，治療前的血清LBP與BMI、糖化血色素、丙氨酸轉氨酶（ALT）和HCV感染皆具獨立相關性。再者，治療前血清LBP僅與ALT和脂肪肝有顯著相關。
另外，一年體重管理之前，肥胖和過重受試者的血清LBP濃度顯著高於正常組（其值分別為30.9 ± 7.4和29.6 ± 6.3對23.1 ± 5.6 μg/ mL，p值 <0.001）且經多變量分析發現，血清LBP與肥胖者的高敏感度C-反應蛋白（hs-CRP）和NAFLD纖維化數值（NFS）顯著相關。而經一年的體重管理後，肥胖者的血清LBP濃度顯著降低至26.5±7.1 μg/ mL（p值<0.001）。多元線性回歸分析後發現，肥胖者的血清LBP變化量與hs-CRP，白血球數目和NFS的變化量都具顯著相關。
　　在體外細胞研究中，此研究利用與牛血清白蛋白結合之棕櫚酸酯誘發肝癌細胞株形成脂肪肝後發現，肝細胞內LBP表現量隨著誘發時間而顯著增加。
　　總結以上研究發現，HCV感染者不論是否使用干擾素治療後，其血清LBP濃度皆顯著下降，此表示血清LBP的其一來源為病毒性發炎。而經一年非手術體重管理後，肥胖受試者血清LBP濃度顯著降低且加上血清LBP與BMI或NAFLD呈現正相關，這些結果顯示血清LBP的另一來源為代謝性發炎。因此，LBP可同時做為體內感染性源和非感染性源的發炎性生物標誌物。再者，血清LBP濃度變化與hs-CRP和NFS的變化也呈現正相關，這意味著LBP不僅是一種發炎症生物標誌物，也將有潛力作為評估NAFLD肝纖維化的非侵入性生物標誌物。

Several previous studies show that the endotoxemia-related biomarker, lipopolysaccharide-binding protein (LBP), is associated with metabolic diseases, such as obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD). The level of LBP is reduced after surgical weight loss. However, the change of serum LBP in obese patients after non-surgical weight management is still unclear at present. Moreover, since chronic hepatitis C virus (HCV) infection is associated with metabolic derangements, the relationship between LBP and HCV infection deserves additional studies. Our study aims to investigate the change of serum LBP levels in obese subjects after one-year medical weight management and investigate the change of LBP level in HCV-infected subjects after interferon-based or interferon-free therapy.
We recruited 120 non-HCV subjects, 42 and 17 HCV-infected subjects respectively treated with peginterferon α-2a/ribavirin and direct-acting antiviral drugs for a case-control study. In the second study, a total of 62 subjects with obesity, 39 subjects with overweight, and 21 subjects with normal body mass index (BMI) were enrolled for a one-year weight management program. Basic information, body composition analysis, clinical data, serum LBP level, and abdominal ultrasonography findings were collected. All the subjects provided written informed consent before being enrolled. These studies were approved by the Research Ethics Committee of the National Taiwan University Hospital.
Serum LBP level was significantly higher in HCV-infected subjects before interferon-based therapy than non-HCV subjects (34.6 ± 7.3 versus 20.0 ± 6.4 μg/mL; p-value < 0.001), especially in HCV-infected subjects with obesity (36.1 ± 7.8 μg/mL). In HCV-infected subjects, the LBP level significantly decreased at sustained virologic response (27.4 ± 6.6 versus 34.6 ± 7.3 μg/mL, p-value < 0.001; 15.9 ± 4.4 versus 22.2 ± 5.7 μg/mL, p-value = 0.001), regardless of interferon-based or interferon-free therapy. The levels of serum LBP at baseline was independently associated with BMI, hemoglobin A1c, alanine aminotransferase (ALT) and HCV infection in non-HCV and HCV-infected subjects by multivariate linear regression analyses. Moreover, serum LBP was only associated with ALT and fatty liver in HCV-infected subjects before interferon-based therapy.
Before one-year weight management, the serum LBP levels of the obese and overweight subjects were significantly higher than that of the normal group (30.9±7.4 and 29.6±6.3 versus 23.1±5.6 μg/mL, respectively, p<0.001). In the multivariate analyses, LBP was associated with high sensitive C-reactive protein (hs-CRP) and NAFLD fibrosis score (NFS) before weight management in the obese group. After one-year weight management, serum LBP in the subjects with obesity was significantly reduced to 26.5±7.1 μg/mL (p-value < 0.001). The change of LBP in response to weight management was significantly related to the changes of hs-CRP, leukocyte count and NFS by multivariate linear regression analyses also in the obese group.
In vitro study, the increased expression of LBP in fatty liver induced by bovine serum albumin conjugated palmitate was observed in human immortalize hepatoma cell line (HuH-7).
In summary, the serum level of the endotoxemia-related biomarker, LBP, decreased either after interferon-based or interferon-free therapy in HCV-infected subjects, suggesting a hepatic origin of LBP in viral inflammation. After one-year of non-surgical weight management, the serum level of LBP significantly lowered in the obese subjects. The association of LBP with BMI or NAFLD in these results suggests the other origin of LBP in metabolic inflammation. All together, LBP may serve as an inflammatory biomarker of both infectious and non-infectious origins. In addition, a positive correlation was found between the change of serum LBP levels and the change in hs-CRP and NFS, implying that LBP is not only an inflammatory biomarker, but may also be a potential biomarker like NFS as a non-invasive test for the evaluation of liver fibrosis in NAFLD.

口試委員會審定書 i
誌謝 ii
中文摘要 iii
Abstract vi
Introduction 1
1. Endotoxemia 1
2. LPS and LBP 2
3. LBP and acute or chronic inflammatory diseases in human studies 4
4. HCV and metabolic diseases 6
5. HCV infection and LBP 7
6. Obesity and inflammation 8
7. The pathophysiology of NAFLD and NASH 9
8. NAFLD fibrosis score (NFS) and fibrosis-4 (FIB-4) index 11
9. Obesity and LBP 12
10. NAFLD and LBP in human study 13
11. LBP studies in animal and cell line models of liver diseases 14
12. NAFLD and palmitate 14
13. The managements of obesity and NAFLD 15
14. The treatments of HCV 15
15. Hypothesis 16
16. Study goal and specific aims 17
Subjects and Methods 19
1. HCV-infected patients’ enrollment and treatments 19
2. Obese subjects’ enrollment and treatments 20
3. Biochemical analysis of human blood samples 21
4. LBP assay 22
5. Abdominal ultrasound examination and evaluative scores 23
6. Cell biology investigation 25
7. Statistical Analysis 28
Results 30
Part I. LBP and viral inflammation 30
1-1. High LBP concentrations in HCV-infected patients before anti-HCV therapy 30
1-2. Serum LBP decreased after interferon-based therapy 31
1-3. Serum LBP decreased after interferon-free therapy 33
Part II. LBP and metabolic inflammation 34
2-1. The obese/overweight subjects had higher serum LBP 34
2-2. The characteristics of groups with different BMI after one-year weight 34
2-3. Weight reduction led to decreased levels of LBP 35
2-4. The relationship between LBP and NFS in the obese group 36
Part III. LBP and metabolic inflammation in cell biology investigation 38
Discussion 40
Part I. LBP and viral inflammation 40
Part II. LBP and metabolic inflammation 44
Part III. LBP and metabolic inflammation in cell biology investigation 50
Perspectives 51
References 58
Tables 82
Figures 100
附錄 114

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