氢杨梅素改善高脂饮食诱导的肥胖小鼠肝脏脂肪沉积及机制

doi:10.5246/jcps.2022.11.070

中国药学(英文版) ›› 2022, Vol. 31 ›› Issue (11): 824-839.DOI: 10.5246/jcps.2022.11.070

氢杨梅素改善高脂饮食诱导的肥胖小鼠肝脏脂肪沉积及机制

吕慧婕¹^,²^,^#, 许拓²^,^#, 彭俊³^,⁴^,^#, 罗刚³, 何剑琴², 杨丝丝², 张天成¹^,^*(), 奉水东⁵^,^*(), 凌宏艳²^,^*()

1. 吉首大学体育科学学院, 湖南吉首 416000
2. 南华大学衡阳医学院生理教研室, 湖南衡阳 421001
3. 吉首大学医学院, 湖南吉首 416000
4. 湘西土家族苗族自治州人民医院, 湖南吉首 416000
5. 南华大学公共卫生学院社会医学与卫生事业管理学教研室, 湖南衡阳 421001

收稿日期:2022-08-16 修回日期:2022-11-19 接受日期:2022-11-20 出版日期:2022-11-30 发布日期:2022-11-30
通讯作者: 张天成, 奉水东, 凌宏艳
作者简介:
+ Tel.: +86-13007348439, E-mail: linghongyan0203@126.com
+ Tel.: +86-18397728940, E-mail: shuidong_f@hotmail.com
+ Tel.: +86-13974321940, E-mail: jdzhangtiancheng@163.com
基金资助:
Natural Science Foundation of Hunan Province (Grant No. 2018JJ2347, 2021JJ30595), Hunan Provincial Postgraduate Scientific Research Innovation Project (Grant No. CX20211061), and the Jishou University School-level Scientific Research Project (Grant No. Jdzd21028).

Dihydromyricetin improves liver fat deposition in high-fat diet-induced obese mice

Huijie Lv¹^,²^,^#, Tuo Xv²^,^#, Jun Peng³^,⁴^,^#, Gang Luo³, Jianqin He², Sisi Yang², Tiancheng Zhang¹^,^*(), Shuidong Feng⁵^,^*(), Hongyan Ling²^,^*()

1 College of Sports Science, Jishou University, Jishou 416000, Hunan, China
2 Department of Physiology, Hengyang Medical College, Nanhua University, Hengyang 421001, Hunan, China
3 Medical College of Jishou University, Jishou 416000, Hunan, China
4 Xiangxi Tujia and Miao Autonomous Prefecture People’s Hospital, Jishou 416000, Hunan, China
5 Teaching and Research Section of Social Medicine and Health Management, School of Public Health, Nanhua University Hengyang 421001, Hunan, China

Received:2022-08-16 Revised:2022-11-19 Accepted:2022-11-20 Online:2022-11-30 Published:2022-11-30
Contact: Tiancheng Zhang, Shuidong Feng, Hongyan Ling
About author:
# Huijie Lv, Tuo Xv and Jun Peng contributed equally to this work.

摘要/Abstract

摘要：

有文献报道, SIRT1-AMPK信号通路可能在DHM改善肝脏细胞甘油三酯蓄积、胰岛素抵抗等作用中发挥作用。为此, 本课题拟进一步观察DHM对高脂饮食诱导的肥胖小鼠肝脏脂肪沉积的影响, 并探讨其可能机制。C57BL/6J小鼠采用普通饲料和高脂饲料喂养, 同时分别用或不用低剂量(125 mg/kg)或高剂量(250 mg/kg)的DHM处理16周。实验期间, 每两周检测体重一次。16周后, 眼眶静脉取血并处死动物, 同时取肩胛下、附睾与腹股沟的脂肪并用电子秤进行称重, 并记录脂肪重量。全自动生化分析仪检测: 血清甘油三酯(triglyceride, TG)、血清总胆固醇(total cholesterol, TC)、血清高密度脂蛋白(high-density lipoprotein, HDL)、血清低密度脂蛋白(low-density lipoprotein, LDL)。取肝脏甲醛固定、HE和油红O染色检测肝脏脂肪沉积情况; 比色法检测肝脏MDA和SOD含量; Realtime PCR检测相关指标的基因表达: IL-6、IL-8、TNF-α、乙酰辅酶A羧化酶(acetyl-CoA carboxylase, ACC)、固醇调节元件结合蛋白(sterol regulatory element binding protein-1c, SREBP-1)、脂肪酸合成酶(fatty acid synthetase, FAS)、过氧化物酶体增殖物激活受体α(peroxisome proliferator-activated receptor alpha, PPARα)、棕榈酰转移酶1(carnitine palmitoyltransferase 1, CPT1)、SIRT1和AMPK。Western Blot检测SIRT1、AMPK、SIRT1-AMPK、ACC、SREBP-1、FAS、PPARα和CPT1的蛋白表达水平。与ND组相比, HFD组小鼠体重、体脂显著增加; TG、TC、LDL水平增加, HDL水平降低, 肝细胞体积增大, 脂滴数量、脂肪沉积、MDA、IL-6、IL-8、TNF-α、SREBP-1c、FAS、ACC1水平显著增加, SOD活力、PPARα、CPT1、SIRT1mRNA和AMPKmRNA、SIRT1、AMPK PPARα、CPT1蛋白水平显著下降。DHM能显著逆转HFD组小鼠上述指标的改变; 但DHM对ND小鼠上述指标无显著影响。总之, DHM改善高脂饮食诱导的肥胖小鼠肝脏脂肪沉积, 其机制可能与抑制氧化应激、炎症和脂质合成, 促进脂质分解有关。

关键词: 二氢杨梅素, 肥胖小鼠, 肝脏脂肪沉积, 氧化应激, 炎症, 脂质合成, 脂质分解

Abstract:

It has been reported that the histone/protein deacetylase SIRT1-AMP-activated protein kinase (SIRT1-AMPK) signaling pathway may play a role in the effects of dihydromyricetin (DHM) on improving triglyceride (TG) accumulation and insulin resistance in liver cells. Therefore, we aimed to further observe the effect of DHM on liver fat deposition in high-fat diet (HFD)-induced obese mice and explore its possible mechanism. C57BL/6J mice were fed with a normal diet (ND) and HFD and were treated with or without low-dose (125 mg/kg) or high-dose (250 mg/kg) DHM for 16 weeks, respectively. During the experiment, body weight was checked every 2 weeks. After 16 weeks, the orbital vein was bled, the animals were sacrificed, and the subscapular, epididymal, and inguinal fat were collected and weighed with an electronic scale. An automatic biochemical analyzer was used to determine the levels of serum triglyceride (TG), serum total cholesterol (TC), serum high-density lipoprotein (HDL), and serum low-density lipoprotein (LDL). The livers were stained with hematoxylin-eosin staining (H&E) and Oil Red O to detect liver fat deposition. A colorimetric method was used to detect liver MDA and SOD contents. Quantitative real-time PCR (qRT-PCR) was used to detect the gene expressions of related indicators, such as interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), acetyl-CoA carboxyl acetyl-CoA carboxylase (ACC), sterol regulatory element-binding protein-1c (SREBP-1), fatty acid synthetase (FAS), peroxisome proliferator activation receptor alpha (peroxisome proliferator-activated receptor-alpha, PPARα), palmitoyltransferase 1 (carnitine palmitoyltransferase 1, CPT1), SIRT1, and AMPK. Western blotting analysis was used to detect the protein expression levels of SIRT1, AMPK, SIRT1-AMPK, ACC, SREBP-1, FAS, PPARα, and CPT1. Results showed that compared with the ND group, the weight and body fat of the mice in the HFD group were increased significantly. The levels of TG, TC, and LDL were increased, the level of HDL was decreased, the volume of hepatocytes was increased, the number of lipid droplets, fat deposition, MDA, IL-6, IL-8, TNF-α, SREBP-1c, FAS, ACC1, SIRT1, and AMPK protein levels were significantly increased, and the SOD activity, PPARα, CPT1, SIRT1 mRNA, AMPK mRNA, PPARα, CPT1 levels were significantly decreased. DHM could significantly reverse the changes of the above indexes in HFD mice, while DHM had no significant effect on the above indexes in ND mice. Collectively, our findings revealed that DHM improved liver fat deposition in HFD-induced obese mice, and the mechanism might be related to inhibition of oxidative stress, inflammation, lipid synthesis, and promotion of lipid decomposition.

Key words: Dihydromyricetin, Obese mice, Hepatic fat deposition, Oxidative stress, Inflammation, Lipid synthesis, Lipid breakdown

Supporting:

吕慧婕, 许拓, 彭俊, 罗刚, 何剑琴, 杨丝丝, 张天成, 奉水东, 凌宏艳. 氢杨梅素改善高脂饮食诱导的肥胖小鼠肝脏脂肪沉积及机制[J]. 中国药学(英文版), 2022, 31(11): 824-839.

Huijie Lv, Tuo Xv, Jun Peng, Gang Luo, Jianqin He, Sisi Yang, Tiancheng Zhang, Shuidong Feng, Hongyan Ling. Dihydromyricetin improves liver fat deposition in high-fat diet-induced obese mice[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(11): 824-839.

图/表 9

Figure 1. DHM reduces the body weight of HFD-induced obese mice (x ± s, n = 13). ND: normal control group; ND + L-DHM: normal control + 125 mg/kg/d DHM group; ND + H-DHM: normal control + 250 mg/kg/d DHM group; HFD: high-fat diet group; HFD + L-DHM: HFD + 125 mg/kg/d DHM group; HFD + H-DHM: HFD + 250 mg/kg/d DHM group. #P < 0.05, vs. ND group; *P < 0.05, vs. HFD group.

Figure 2. DHM reduces body fat in HFD-induced obese mice (x ± s, n = 13). #P < 0.05, vs. ND group; *P < 0.05, vs. HFD group.

Figure 3. The effect of DHM on blood lipids in HFD-induced obese mice (x ± s, n = 13). (A) The TG levels; (B) The TC level; (C) The LDL level; (D) The HDL level. #P < 0.05, vs. ND group; *P < 0.05, vs. HFD group.

Figure 4. DHM reduces liver lipid deposition in HFD-induced obese mice. (A) H&E staining (20×); (B) and Oil Red O staining (20×). ND: normal control group; HFD: high-fat diet group.

Figure 5. The effect of DHM on MDA and SOD in the liver of obese mice fed an HFD (x ± s, n = 5). (A) The liver MDA level; (B) The liver SOD level. #P < 0.05, vs. ND group; *P < 0.05, vs. HFD group.

Figure 6. DHM reduces the levels of inflammatory factors IL-6, IL-8, and TNF-α in the liver of obese mice fed an HFD (x ± s, n = 4). (A) The liver IL-6 level; (B) The liver IL-8 level; (C) The liver TNF-α level. #P < 0.05, vs. ND group; *P < 0.05, vs. HFD group.

Figure 7. The effect of DHM on the mRNA and protein expressions of SIRT1 and AMPK in the liver of obese mice fed an HFD (x ± s, n = 4–5). (A) Sirt1 mRNA expression level; (B) AMPK mRNA expression level; (C) Sirt1 protein expression level; (D) AMPK protein expression level. #P < 0.05, vs. ND group; *P < 0.05, vs. HFD group.

Figure 8. The effect of DHM on the gene and protein expressions of SREBP1, ACC1, and FAS in the liver of HFD-fed obese mice (x ± s, n = 4–5). (A) SREBP1 mRNA expression level; (B) ACC1 mRNA expression level; (C) FAS mRNA expression level; (D) SREBP1 protein expression level; (E) ACC1 protein expression level; (F) FAS protein expression level. #P < 0.05, vs. ND group; *P < 0.05, vs. HFD group.

Figure 9. The effect of DHM on gene and protein expressions of PPARα and CPT1 in the liver of obese mice fed an HFD (x ± s, n = 4–5). (A) PPARα mRNA expression level; (B) CPT1 mRNA expression level; (C) PPARα protein expression level; (D) CPT1 protein expression level. #P < 0.05, vs. ND group; *P < 0.05, vs. HFD group.

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氢杨梅素改善高脂饮食诱导的肥胖小鼠肝脏脂肪沉积及机制

Dihydromyricetin improves liver fat deposition in high-fat diet-induced obese mice

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