血紅素代謝與非酒精性脂肪肝疾病：內質網壓力抑制游離血紅素回收及血基質降解改變血紅素代謝

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題名:	血紅素代謝與非酒精性脂肪肝疾病：內質網壓力抑制游離血紅素回收及血基質降解改變血紅素代謝 Endoplasmic Reticulum Stress Contributes to Altered Hemoglobin Metabolism via Attenuating Cell Free Hemoglobin Uptake and Downregulating Heme Degradation in Non Alcoholic Fatty Liver Disease
作者:	張丁允 Chang, Ting-Yun
貢獻者:	保健營養學研究所張榮素
關鍵詞:	非酒精性脂肪肝疾病;內質網壓力;血紅素 Nonalcoholic Fatty Liver Disease (NAFLD);Endoplasmic Reticulum stress (ER stress);Hemoglobin (Hb)
日期:	2016
上傳時間:	2021-08-13 14:17:25 (UTC+8)
摘要:	非酒精性脂肪肝病(Nonalcoholic fatty liver disease, NAFLD)患者常伴隨著血鐵下降但肝臟鐵含量卻增加。鐵質代謝異常會增加內質網代謝壓力，而內質網壓力的增加又與NAFLD的病程發展有關。CD163+巨噬細胞主要負責回收人體紅血球中的血色素鐵，而回收的血色素鐵提供成年人90%的造血來源。本研究主要探討：(1) NAFLD誘發的內質網壓力是否會干擾血紅素回收機制以及血紅素回收異常是否與NAFLD有關；(2)評估鐵劑補充對高脂誘發NAFLD大鼠的血紅素回收機制效益。研究模式：(1) 招募33位正常、202位非酒精性脂肪肝病受試者；(2) 大鼠投予50%高脂或添加0.25、1、2克三價鐵/每公斤飼料餵養12週；(3) 衣黴素(Tunicamycin)誘發急性內質網壓力之大鼠。結果：(1) 和正常受試者相比較，中、重度NAFLD患者紅血球變形程度、血清游離血紅素及CD163 含量顯著較高；(2) 大鼠肝臟病理結果顯示：高脂誘發脂肪肝及血清AST、ALT濃度增加。鐵劑補充之大鼠有輕度肝臟鐵沉積。和正常鼠相比較，高脂飲食導致紅血球聚集有增高傾向及血清LVV-hemorphin7降低，但鐵劑補充有改善此現象。(3) 和正常鼠相比，高脂飲食增加內質網壓力指標Grp78表現，但血紅素代謝並無異常。鐵補充(1、2克)增加抗氧化蛋白(SOD2、catalase)　及內質網壓力指標ATF4、ATF6在細胞核內的表現量。但高劑量鐵劑補充(2克)降低血紅素代謝相關蛋白。(4)內質網壓力抑制游離血紅素回收、增加血清游離CD163及降低LVV-hemorphin7含量。在誘發內質網壓力狀況下再注射血紅素，血紅素蛋白質分解酵素cathepsin D (CatD)、glyoxalase-1 (GLO-1)、HO-1及血清膽紅素含量皆降低。結論：紅血球代謝異常與非酒精性脂肪肝疾病嚴重程度有相關性。內質網壓力可藉由抑制血紅素蛋白分解酵素CatD、GLO-1與HO-1抑制血紅素代謝。高劑量鐵補充(2克/kg diet)抑制血紅素的代謝並可能加速鐵沉積於肝臟。 Nonalcoholic fatty liver disease (NAFLD) is associated with dysregulated iron metabolism. Recent literature suggests that unresolved endoplasmic reticulum (ER) stress can alter iron metabolism and contribute to the pathogenesis of NAFLD. The aim of this study was to investigate: (1) effects of ER stress on CD163-Hb recycling pathways in relation to NAFLD and (2) efficacy of iron supplementation to high fat diet (HFD) induced NAFLD rats. Models: (1) 202 adults (control=33; NAFLD=169); (2) Rat model of NAFLD: 50% HFD induced liver steatosis supplemented with or without ferric citrate (0.25g, 1g, 2g ferric iron/kg diet); and (3) tunicamycin (TM) induced acute ER stress rat model. Results: (1) Compared to controls, patients with moderate and severe NAFLD had impaired RBC rheology (aggregation and deformability), elevated serum free Hb and soluble CD163 levels; (2) Rat NAFLD model: Liver pathological examination showed that HFD induced liver steatosis. Iron supplementation caused mild liver iron overload but did not alter pathological score. Compared to controls, HFD slightly increased RBC aggregation but decreased serum LVV-hemorphin-7 levels. These effects were reversed by the iron supplementation. Iron supplementation, in particular at 2 g iron/kg diet, decreased total serum bilirubin, cathepsin D (CatD), glyoxalase-1 (GLO-1), and heme oxygesnase-1 (HO-1) expression. (3) Acute ER stress model: ER stress attenuated serum free Hb recycling; increased shedding of surface CD163 and decreased serum LVV-hemorphin-7 levels. Western blot analysis revealed that Hb proteolytic enzymes CatD, GLO-1, full-length HO-1 and serum bilirubin levels were decreased in rats received TM and Hb injection compared to Hb alone. Conclusion: Human study showed that impaired RBC metabolism is associated with NAFLD severity. ER stress attenuated cell free Hb uptake and impaired Hb degradation via downregulating hemoprotein degradation enzymes (CatD and GLO-1) and heme degradation enzyme HO-1. Our animal study also highlights the cautious of use of high dosages iron supplementation (2g ferric iron/kg diet) to obese rats.
描述:	碩士指導教授：張榮素
資料類型:	thesis
顯示於類別:	[保健營養學系暨研究所] 碩博士論文

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