LuHui Derivative, A Novel Compound That Inhibits the Fat Mass and Obesity-Associated (FTO), Alleviates the Inflammatory Response and Injury in Hyperlipidemia-Induced Cardiomyopathy
Hyperlipidemia is a major risk factor for metabolic disorders and cardiovascular injury. The excessive deposition of saturated fatty acids in the heart leads to chronic cardiac inflammation, which in turn causes myocardial damage and systolic dysfunction. However, the effective suppression of cardia...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:0b5983ffb2e04518a5e1ee71e86c44e22021-11-22T11:05:08ZLuHui Derivative, A Novel Compound That Inhibits the Fat Mass and Obesity-Associated (FTO), Alleviates the Inflammatory Response and Injury in Hyperlipidemia-Induced Cardiomyopathy2296-634X10.3389/fcell.2021.731365https://doaj.org/article/0b5983ffb2e04518a5e1ee71e86c44e22021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.731365/fullhttps://doaj.org/toc/2296-634XHyperlipidemia is a major risk factor for metabolic disorders and cardiovascular injury. The excessive deposition of saturated fatty acids in the heart leads to chronic cardiac inflammation, which in turn causes myocardial damage and systolic dysfunction. However, the effective suppression of cardiac inflammation has emerged as a new strategy to reduce the impact of hyperlipidemia on cardiovascular disease. In this study, we identified a novel monomer, known as LuHui Derivative (LHD), which reduced the serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and reduced lipid deposition in cardiomyocytes. In addition, LHD treatment improved cardiac function, reduced hyperlipidemia-induced inflammatory infiltration in cardiomyocytes and suppressed the release of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). From a mechanistic perspective, cluster of differentiation 36 (CD36), an important cell surface receptor, was identified as a downstream target following the LHD treatment of palmitic acid-induced inflammation in cardiomyocytes. LHD specifically binds the pocket containing the regulatory sites of RNA methylation in the fat mass and obesity-associated (FTO) protein that is responsible for elevated intracellular m6A levels. Moreover, the overexpression of the N6-methyladenosine (m6A) demethylase FTO markedly increased CD36 expression and suppressed the anti-inflammatory effects of LHD. Conversely, loss-of-function of FTO inhibited palmitic acid-induced cardiac inflammation and altered CD36 expression by diminishing the stability of CD36 mRNA. Overall, our results provide evidence for the crucial role of LHD in fatty acid-induced cardiomyocyte inflammation and present a new strategy for the treatment of hyperlipidemia and its complications.Ying YuYumiao PanZiyi FanSilun XuZhiyuan GaoZijing RenJie YuWen LiFangtong LiuJintao GuYe YuanYe YuanZhimin DuZhimin DuZhimin DuFrontiers Media S.A.articlehyperlipidemiainflammationLuHui derivativeFTOCD36m6ABiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021) |
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| collection |
DOAJ |
| language |
EN |
| topic |
hyperlipidemia inflammation LuHui derivative FTO CD36 m6A Biology (General) QH301-705.5 |
| spellingShingle |
hyperlipidemia inflammation LuHui derivative FTO CD36 m6A Biology (General) QH301-705.5 Ying Yu Yumiao Pan Ziyi Fan Silun Xu Zhiyuan Gao Zijing Ren Jie Yu Wen Li Fangtong Liu Jintao Gu Ye Yuan Ye Yuan Zhimin Du Zhimin Du Zhimin Du LuHui Derivative, A Novel Compound That Inhibits the Fat Mass and Obesity-Associated (FTO), Alleviates the Inflammatory Response and Injury in Hyperlipidemia-Induced Cardiomyopathy |
| description |
Hyperlipidemia is a major risk factor for metabolic disorders and cardiovascular injury. The excessive deposition of saturated fatty acids in the heart leads to chronic cardiac inflammation, which in turn causes myocardial damage and systolic dysfunction. However, the effective suppression of cardiac inflammation has emerged as a new strategy to reduce the impact of hyperlipidemia on cardiovascular disease. In this study, we identified a novel monomer, known as LuHui Derivative (LHD), which reduced the serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and reduced lipid deposition in cardiomyocytes. In addition, LHD treatment improved cardiac function, reduced hyperlipidemia-induced inflammatory infiltration in cardiomyocytes and suppressed the release of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). From a mechanistic perspective, cluster of differentiation 36 (CD36), an important cell surface receptor, was identified as a downstream target following the LHD treatment of palmitic acid-induced inflammation in cardiomyocytes. LHD specifically binds the pocket containing the regulatory sites of RNA methylation in the fat mass and obesity-associated (FTO) protein that is responsible for elevated intracellular m6A levels. Moreover, the overexpression of the N6-methyladenosine (m6A) demethylase FTO markedly increased CD36 expression and suppressed the anti-inflammatory effects of LHD. Conversely, loss-of-function of FTO inhibited palmitic acid-induced cardiac inflammation and altered CD36 expression by diminishing the stability of CD36 mRNA. Overall, our results provide evidence for the crucial role of LHD in fatty acid-induced cardiomyocyte inflammation and present a new strategy for the treatment of hyperlipidemia and its complications. |
| format |
article |
| author |
Ying Yu Yumiao Pan Ziyi Fan Silun Xu Zhiyuan Gao Zijing Ren Jie Yu Wen Li Fangtong Liu Jintao Gu Ye Yuan Ye Yuan Zhimin Du Zhimin Du Zhimin Du |
| author_facet |
Ying Yu Yumiao Pan Ziyi Fan Silun Xu Zhiyuan Gao Zijing Ren Jie Yu Wen Li Fangtong Liu Jintao Gu Ye Yuan Ye Yuan Zhimin Du Zhimin Du Zhimin Du |
| author_sort |
Ying Yu |
| title |
LuHui Derivative, A Novel Compound That Inhibits the Fat Mass and Obesity-Associated (FTO), Alleviates the Inflammatory Response and Injury in Hyperlipidemia-Induced Cardiomyopathy |
| title_short |
LuHui Derivative, A Novel Compound That Inhibits the Fat Mass and Obesity-Associated (FTO), Alleviates the Inflammatory Response and Injury in Hyperlipidemia-Induced Cardiomyopathy |
| title_full |
LuHui Derivative, A Novel Compound That Inhibits the Fat Mass and Obesity-Associated (FTO), Alleviates the Inflammatory Response and Injury in Hyperlipidemia-Induced Cardiomyopathy |
| title_fullStr |
LuHui Derivative, A Novel Compound That Inhibits the Fat Mass and Obesity-Associated (FTO), Alleviates the Inflammatory Response and Injury in Hyperlipidemia-Induced Cardiomyopathy |
| title_full_unstemmed |
LuHui Derivative, A Novel Compound That Inhibits the Fat Mass and Obesity-Associated (FTO), Alleviates the Inflammatory Response and Injury in Hyperlipidemia-Induced Cardiomyopathy |
| title_sort |
luhui derivative, a novel compound that inhibits the fat mass and obesity-associated (fto), alleviates the inflammatory response and injury in hyperlipidemia-induced cardiomyopathy |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/0b5983ffb2e04518a5e1ee71e86c44e2 |
| work_keys_str_mv |
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