Cysteine-rich 61 inhibition attenuates hepatic insulin resistance and improves lipid metabolism in high-fat diet fed mice and HepG2 cells

被引:1
|
作者
Heo, Yu Jung [1 ]
Park, Jieun [2 ]
Lee, Nami [2 ]
Choi, Sung-E [2 ]
Jeon, Ja Young [2 ]
Han, Seung Jin [2 ]
Kim, Dae Jung [2 ]
Lee, Kwan Woo [2 ]
Kim, Hae Jin [2 ]
机构
[1] Ajou Univ, Inst Med Sci, Sch Med, Suwon, South Korea
[2] Ajou Univ, Dept Endocrinol & Metab, Sch Med, 206 World Cup Ro, Suwon 16499, South Korea
来源
FASEB JOURNAL | 2024年 / 38卷 / 15期
基金
新加坡国家研究基金会;
关键词
AMP-activated protein kinase; Cyr61; inflammation; insulin resistance; lipid metabolism; Sirt6; OVEREXPRESSION; EXPRESSION;
D O I
10.1096/fj.202400860R
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with insulin resistance development. Hepatic lipid accumulation and inflammation are considered the main drivers of hepatic insulin resistance in MASLD. Cysteine-rich 61 (Cyr61 also called CCN1), a novel secretory matricellular protein, is implicated in liver inflammation, and its role in MASLD is not clearly understood. Therefore, we investigated the role of Cyr61 in hepatic insulin resistance and lipid metabolism as major factors in MASLD pathogenesis. In high-fat diet (HFD)-fed C57BL/6J mice, Cyr61 was downregulated or upregulated via viral transduction. Measurements of glucose homeostasis, histological assessment of liver tissues, and gene expression and signaling pathways of lipogenesis, fatty acid oxidation, and inflammation were performed using liver samples from these mice. Cyr61 levels in HepG2 cells were reduced using RNAi-mediated gene knockdown. Inflammation and insulin resistance were evaluated using real-time polymerase chain reaction and western blotting. HFD/AAV-shCyr61 mice exhibited enhanced glucose tolerance via the protein kinase B pathway, reduced hepatic inflammation, decreased lipogenesis, and increased fatty acid oxidation. Notably, HFD/AAV-shCyr61 mice showed elevated protein expression of sirtuin 6 and phosphorylated-AMP-activated protein kinase. In vitro experiments demonstrated that inhibition of Cyr61 downregulated pro-inflammatory cytokines such as interleukin-1 beta, IL-6, and tumor necrosis factor-alpha via the nuclear factor kappa B/c-Jun N-terminal kinase pathway, and alleviated insulin resistance. Cyr61 affected hepatic inflammation, lipid metabolism, and insulin resistance. Inhibition of Cyr61 reduced inflammation, recovered insulin resistance, and altered lipid metabolism in vivo and in vitro. Therefore, Cyr61 is a potential therapeutic target in MASLD.
引用
收藏
页数:15
相关论文
共 50 条
  • [21] Bardoxolone methyl prevents insulin resistance and the development of hepatic steatosis in mice fed a high-fat diet
    Camer, Danielle
    Yu, Yinghua
    Szabo, Alexander
    Dinh, Chi H. L.
    Wang, Hongqin
    Cheng, Licai
    Huang, Xu-Feng
    MOLECULAR AND CELLULAR ENDOCRINOLOGY, 2015, 412 (0C) : 36 - 43
  • [22] Effect of Konjac Oligosaccharide on Lipid Metabolism in Mice Fed High-Fat Diet
    Zhou, Zhongkai
    Zhao, Yali
    Yang, Xingyue
    Shipin Kexue/Food Science, 2019, 40 (01): : 149 - 154
  • [23] Oleanolic acid attenuates obesity through modulating the lipid metabolism in high-fat diet-fed mice
    Zhang, Guangjie
    Zhang, Huiying
    Dong, Ruiyi
    Zhao, Hongmei
    Li, Junfeng
    Yue, Weiming
    Ma, Zheng
    FOOD SCIENCE & NUTRITION, 2024, 12 (10): : 8243 - 8254
  • [24] Amaranth Supplementation Improves Hepatic Lipid Dysmetabolism and Modulates Gut Microbiota in Mice Fed a High-Fat Diet
    Yang, Yongshou
    Fukui, Rikako
    Jia, Huijuan
    Kato, Hisanori
    FOODS, 2021, 10 (06)
  • [25] Korean Pine Nut Oil Replacement decreases intestinal lipid uptake while improves hepatic lipid metabolism in High-Fat Diet Fed Mice
    Shuang, Zhu
    Park, Soyoung
    Lim, Yeseo
    Shin, Sunhye
    Han, Sung Nim
    FASEB JOURNAL, 2016, 30
  • [26] Asiatic Acid Ameliorates Hepatic Lipid Accumulation and Insulin Resistance in Mice Consuming a High-Fat Diet
    Yan, Sheng-Lei
    Yang, Hui-Ting
    Lee, Yi-Ju
    Lin, Chun-Che
    Chang, Ming-Hui
    Yin, Mei-Chin
    JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 2014, 62 (20) : 4625 - 4631
  • [27] Asiatic acid ameliorates hepatic lipid accumulation and insulin resistance in mice consuming a high-fat diet
    Yin, M.-C. (mcyin@mail.cmu.edu.tw), 1600, American Chemical Society (62):
  • [28] Supplementation of a High-Fat Diet with Chlorogenic Acid Is Associated with Insulin Resistance and Hepatic Lipid Accumulation in Mice
    Mubarak, Aidilla
    Hodgson, Jonathan M.
    Considine, Michael J.
    Croft, Kevin D.
    Matthews, Vance B.
    JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 2013, 61 (18) : 4371 - 4378
  • [29] Relaxin Treatment Reverses Insulin Resistance in Mice Fed a High-Fat Diet
    Bonner, Jeffrey S.
    Lantier, Louise
    Hocking, Kyle M.
    Kang, Li
    Owolabi, Mark
    James, Freyja D.
    Bracy, Deanna P.
    Brophy, Colleen M.
    Wasserman, David H.
    DIABETES, 2013, 62 (09) : 3251 - 3260
  • [30] Alginate oligosaccharide improves lipid metabolism and inflammation by modulating gut microbiota in high-fat diet fed mice
    Yuting Wang
    Lili Li
    Changqing Ye
    Jingyi Yuan
    Song Qin
    Applied Microbiology and Biotechnology, 2020, 104 : 3541 - 3554