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研究生:邱冠霆
研究生(外文):Kuan-Ting Chiu
論文名稱:高遷移率族蛋白負向調節脂肪細胞之脂質水解作用:第一型小窩蛋白的角色
論文名稱(外文):High Mobility Group Box 1 Negatively Regulates Lipolysis in Adipocytes : Role of Caveolin-1
指導教授:李宗玄
指導教授(外文):Tzong-Shyuan Lee
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:109
中文關鍵詞:高遷移率族蛋白脂質水解作用第一型小窩蛋白激素敏感脂肪酵素
外文關鍵詞:high mobility group box 1lipolysiscaveolin-1hormone sensitive lipase
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肥胖的原因在於白色脂肪組織累積過量的脂質,此特徵增加了許多疾病的危險性。脂肪細胞調節脂質的平衡主要藉由釋放多種脂肪素 (adipokine) 來作用,例如: 脂聯素 (adiponectin) 等。高遷移率族蛋白 (high mobility group box1, HMGB1) 不僅是當作一個重要的細胞核內蛋白去穩定染色體以及調控轉錄反應,並且會藉由胞吐作用 (exocytosis) 釋放至細胞外空間進一步調節發炎反應。然而,高遷移率族蛋白於脂質生成中所扮演的確切角色和詳細機制仍然未知。第一型小窩蛋白 (caveolin-1, Cav-1) 是膜穴樣內陷 (caveolae) 的主要結構蛋白,它可藉由和其他細胞內蛋白的連結來調節脂質代謝、蛋白質的分泌、內在化 (internalization) 和小泡運送 (vesicle trafficking)。因此在本篇研究,我們藉由活體內和細胞培養的實驗來探討是否高遷移率族蛋白會和第一型小窩蛋白連結而調節脂質代謝。藉由西方式墨點雜交的結果得知高遷移率族蛋白、第一型小窩蛋白和磷酸化的第一型小窩蛋白在脂肪分化的過程中的表現會增加。在3T3-L1前脂肪細胞株的實驗中,加入高遷移率族蛋白不會影響前脂肪細胞的增生和分化;但加入高遷移率族蛋白會顯著性的減弱藉由飢餓或加入β3腎上腺素能受體 (CL316,243) 所誘發的脂質水解 (lipolysis) 和激素敏感脂肪酵素 (hormone sensitive lipase, HSL) 磷酸化程度,其機制主要是透過抑制蛋白質激酶A (protein kinase A, PKA) 和細胞外信號調節激酶 (extracellular signal-regulated kinase, ERK) 的活化。另一方面,我們也發現到在脂肪細胞分化後,高遷移率族蛋白和第一型小窩蛋白的結合量增加,並藉由使用Src激酶抑制劑的實驗中,發現抑制第一型小窩蛋白的磷酸化會促使高遷移率族蛋白釋放增加。除此之外,在禁食或挨餓狀況下,不論藉由使用老鼠或老鼠胚胎纖維芽母細胞 (mouse embryonic fibroblasts, MEFs) 的模式,第一型小窩蛋白剔除 (caveolin-1 knockout, Cav-1 KO) 後,高遷移率族蛋白釋放較正常多。總歸上述內容,我們發現高遷移率族蛋白透過第一型小窩蛋白來調控脂肪水解作用。
Obesity is characterized by excess fat accumulation in white adipose tissue, which increases the risk of various diseases. Adipocytes release various adipokines such as adiponectin to regulate lipid homeostasis. High mobility group box 1 (HMGB1) is not only a key protein for stabilization of chromosome and regulation of transcription in nucleus, but also released into the extracellular space via exocytosis to modulate inflammatory response. However, the exact role and underlying mechanisms of HMGB1 in adipogenesis are largely unknown. Caveolin-1 (Cav-1) is major structure protein of caveolae, which plays a crucial role in lipid metabolism and mediates secretion, internalization and vesicle trafficking of proteins by interacting with intracellular proteins. In the present study, we performed in vitro and in vivo experiments to explore whether Cav-1 interacts with HMGB1 to regulate adipogenesis. Western blotting showed that the levels of HMGB1, Cav-1 and phosphorylated Cav-1 were significantly increased during differentiation of 3T3-L1 adipocytes in a time-dependent manner. HMGB1 treatment did not affect preadipocyte proliferation and differentiation. By contrast, starvation- or 刍3-adrenoreceptor agonist CL-induced lipolysis and phosphorylation of hormone sensitive lipase were significantly attenuated upon HMGB1 treatment via inhibition on activation of protein kinase A and extracellular signal-regulated kinase phosphorylation in 3T3-L1 adipocytes. We also found that the increases in release of HMGB1, Cav-1 phosphorylation and interaction between HMGB1 and Cav-1 were Src kinase-dependent, as revealed by its abolition after inhibition using pharmacologic inhibitors. After starvation or fasting, secretion of HMGB1 was increased in Cav-1 deficient mouse embryonic fibroblast and mice compared to wildtypes. Collectively, the findings suggest that HMGB1 plays a critical role in adipocyte lipolysis via interaction with Cav-1.
致謝 IV
Abbreviations V
Abstract VI
摘要 VIII
Introduction 1
Obesity 1
Adipogenesis 1
Preadipocytes 2
Differentiation 3
1. CCAAT/enhancer binding protein (C/EBP) family 4
2. Peroxisome proliferator-activated receptors 讪 (PPAR讪) 5
3. Sterol regulatory element binding protein-1 (SREBP-1) 5
4. Adipocyte fatty acid binding protein (AFABP, aP-2) 6
Lipolysis 6
Adipose triacylglyceride lipase (ATGL) 7
Hormone sensitive lipase (HSL) 8
Perilipin, adipophilin, and TIP47 family (PAT family) 11
Adipocyte fatty acid binding protein (aP-2) 12
Caveolin-1 (Cav-1) 12
Other regulators of lipid homeostasis 13
HMG family 14
High mobility group box 1 (HMGB1) 15
The effect of HMGB1 on nucleus 15
The secretary mechanism of HMGB1 16
The effect of soluble-HMGB1 (sHMGB1) on immune system 17
The other functions of HMGB1 18
The effect of HMGB1 on adipocyte metabolism 18
Objectives 19
Materials and methods 20
Reagents and antibodies 20
Mice 20
Cell culture 21
Differentiation condition for 3T3-L1 preadipocytes 21
Isolation of mouse embryonic fibroblasts (MEFs) 21
Isolation of RNA 22
RT-PCR 23
Preparation of whole cell lysates 24
MTT assay 25
Western blot 25
Immunoprecipitation 26
Determination of glycerol release and cellular triacylglyceride (TG) 27
Determination of cyclic adenosine monophosphate (cAMP) level 27
Statistical analysis 27
Results 29
Induction of HMGB1 and Cav-1 during 3T3-L1 differentiation 29
Cav-1 interacts with HMGB1 in adipocytes 30
Cav-1 negatively regulates HMGB1 secretion in adipocytes 30
HMGB1 attenuates starvation-induced lipolysis in adipocytes 31
刍3-adrenoreceptor agonist activates HSL to induce lipolysis through ERK and PKA signaling pathway 32
HMGB1 attenuates 刍3-adrenergic-induced lipolysis through reducing ERK and PKA-mediated HSL phosphorylation 33
Role of HMGB1 in MEF and in vivo 34
Discussion 35
References 43
Figures 87
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