補充維生素K2改善高脂飲食誘發小鼠肝臟脂肪變性與高血糖

Vitamin K2 Supplementation Improve High-Fat-Diet Induced Mice Hepatic Steatosis and Hyperglycemia

邱芸鋆(Yun-Yun Qiu)

指導教授 ： 劉德中

中山醫學大學/健康管理學院/營養學系/碩士(2021年)

https://doi.org/10.6834/csmu202100130

摘要

非酒精性脂肪肝疾病(Non-alcoholic fatty liver diseases, NAFLD)，是全球最常見的慢性肝臟疾病，除了有肝臟脂肪堆積發炎及纖維化外，易常伴隨胰島素阻抗及高血糖症狀。已有文獻指出維生素K2 (Menaquinone-7)能改善第2型糖尿病小鼠肝臟中胰島素敏感性，具有調控血糖的作用，而本研究探討維生素K2是否能改善餵食高脂飲食小鼠非酒精性脂肪肝疾病與高血糖及相關可能機制。結果顯示，管灌餵食維生素K2可顯著降低高脂飲食誘發小鼠肝臟中油脂含量，發炎以及纖維化的狀況。補充維生素K2可改善高脂飲食造成減少小鼠肝臟荷爾蒙敏感性脂解酶(Hormone-sensitive lipase, HSL)蛋白質表現與增加肪合成酵素包括脂肪酸合酶(Fatty acid synthase, FAS)和硬脂醯輔酶A去飽和酶(Stearoyl-CoA desaturase 1, SCD-1)及羥甲基戊二酸單醯輔酶A還原酶(Hydroxymethylglutaryl-CoA reductase, HMGCR)表現增。此外，補充維生素K2降低高脂飲食造成高血糖和增加空腹胰島素值、胰島素抗性指標(Homeostasis Model Assessment-Insulin Resistance Index, HOMA-IR)與胰島素阻抗相關的胰島素受體底物1 (Phosphate-insulin receptor substrate 1, pser307IRS1)表現等胰島素阻抗指標。餵食維生素K2亦可顯著降低高脂飲食誘發肝臟中脂質過氧化物丙二醛(Malondialdehyde, MDA)及發炎相關指標，腫瘤壞死因子-α (Tumor necrosis factor-α)、白介素-1β(T Interleukin 1β, IL-1β)、單核細胞趨化蛋白-1(Monocyte chemoattractant protein-1, Ccl2)、血小板醣蛋白靶點(Cluster of differentiation 36, CD36)及NLRP3(NLR family pyrin domain containing 3, NLRP3)表現。補充維生素K2可改善高脂飲食小鼠肝臟單磷酸腺苷活化蛋白質激酶(AMP-activated protein kinase, AMPK)的活化，NAD-依賴性去乙醯化酶(Sirtuin-1, SirT-1)/過氧化物酶體增殖物激活受體γ共激活因子1α (Peroxisome proliferator activated receptor γ coactivator 1 α, PGC1α)、固醇調節元件結合轉錄因子1 (Sterol regulatory element-binding transcription factor 1, SREBF1)及過氧化物酶體增殖物激活受體γ (Peroxisome proliferator activated receptor γ, PPARγ)表現等與血糖和脂肪代謝相關因子表現。此外，補充維生素K2可能經由改善高脂飲食小鼠肝臟增加38絲裂原活化蛋白激酶(p38 mitogen-activated protein kinase, p38 MAPK)及轉錄因子NF-кB活化(Nuclear factor kappa-light-chain-enhancer of activated B)，降低肝臟發炎。綜合以上可知，補充維生素K2有助於改善高脂飲食誘發高血糖與小鼠肝臟脂肪變性高血糖，延緩非酒精性脂肪肝病的進展。

關鍵字

非酒精性脂肪肝疾病 ； 脂質變性 ； 高血糖 ； 維生素K2 ； 胰島素阻抗

並列摘要

Non-alcoholic fatty liver diseases (NAFLD) is the most common chronic liver disease in the world. In addition to liver fat accumulation, inflammation and fibrosis, NAFLD is often accompanied by insulin resistance and hyperglycemia. It has been pointed out in the literature that vitamin K2 (Menaquinone-7) through an increase of insulin sensitivity in the liver could improve blood sugar in type 2 diabetic mice. This study was explored the effect and possible mechanisms of vitamin K2 on high-fat diet induced NAFLD and hyperglycemia in mice. The results show that vitamin K2 supplementation can significantly reduce the lipid amount, inflammation and fibrosis in the liver of mice fed with high-fat diet. Vitamin K2 supplementation can improve the high-fat diet caused an decrease in expression of hormone-sensitive lipase (HSL) and increases in expression of fatty acid synthase (FAS) and stearyl coenzyme Stearoyl-CoA desaturase (SCD-1) and Hydroxymethylglutaryl-CoA reductase (HMGCR)in mouse liver In addition, vitamin K2 supplementation can improve high-fat diet induced high blood sugar and insulin resistance as an evidence by decreases in fasting insulin concentration, insulin resistance index (Homeostasis Model Assessment-Insulin Resistance Index,) and ser307phosphylation of insulin receptor substrate 1. vitamin K2 supplementation also can significantly reduce high-fat diet induced the lipid peroxide malondialdehyde and expression of inflammation-related indicators such as tumor necrosis factor-α, interleukin-1β, monocyte chemoattractant protein-1, Cluster of differentiation 36 and NLR family pyrin domain containing 3, NLRP3. Vitamin K2 supplementation can increase the expression of phosphorylated AMP-activated protein kinase, Sirtuin-1, Peroxisome proliferator activated receptor γ coactivator 1 α, Sterol regulatory element-binding transcription factor 1, and Peroxisome proliferator activated receptor γ which are related to regulation of carbohydrate and fat metabolism in liver of mice fed with high fat diet. In addition, vitamin K2 supplementation may through decreases in activation of p38 mitogen-activated protein kinase and transcription factor NF-кB diminished liver inflammation in mice fed with high fat diet. Based on the above findings, vitamin K2 supplementation improves the high fat diet induced the hyperglycemia and lipid accumulation as well as delays the progression of non-alcoholic fatty liver disease in mice.

並列關鍵字

Nonalcoholic fatty liver diseases ； Steatosis ； Inflammation ； Vitamin K2 ； Insulin resistance

參考文獻

1. Zobair, M.,et al., The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. Journal of Hepatology, 2019. (71):p.793-801.

2. Chris, E.,et al., Modelling NAFLD disease burden in four Asian regions—2019-2030. Alimentary Pharmacology Therapeutics. 2020.(51): p.801-811.

3. Yuan, L.,et al., Activation of liver x receptors attenuates endotoxin-induced liver injury in mice with nonalcoholic fatty liver disease. Digestive Diseases and Sciences, 2012.(57): p.390-398.

4. Katherine, J.,et al., Clinical approaches to non-alcoholic fatty liver disease. World Journal of Gastroenterology, 2014.(7): p.1712-1723.

5. Machado, M.,et al., Hepatic histology in obese patients undergoing bariatric surgery. Journal of Hepatology, 2006.(45): p.600-606.