4‐O‐methylhonokiol protects against diabetic cardiomyopathy in type 2 diabetic mice by activation of AMPK‐mediated cardiac lipid metabolism improvement

Aim: Vildagliptin (vild) improves diastolic dysfunction and is associated with a lower relative risk of major adverse cardiovascular events in younger patients. The present study aimed to evaluate whether vild prevents the development of diabetic cardiomyopathy in type 2 diabetic mice and identify its underlying mechanisms.Methods: Type 2 diabetic mouse model was generated using wild-type (WT) (C57BL/6J) and miR-21 knockout mice by treatment with HFD/STZ. Cardiomyocyte-specific miR-21 overexpression was achieved using adeno-associated virus 9. Echocardiography was used to evaluate cardiac function in mice. Morphology, autophagy, and proteins levels in related pathway were analyzed. qRT-PCR was used to detect miR-21. Rat cardiac myoblast cell line (H9c2) cells were transfected with miR-21 mimics and inhibitor to explore the related mechanisms of miR-21 in diabetic cardiomyopathy.Results: Vild restored autophagy and alleviated fibrosis, thereby enhancing cardiac function in DM mice. In addition, miR-21 levels were increased under high glucose conditions. miR-21 knockout DM mice with miR-21 knockout had reduced cardiac hypertrophy and cardiac dysfunction compared to WT DM mice. Overexpression of miR-21 aggravated fibrosis, reduced autophagy, and attenuated the protective effect of vild on cardiac function. In high-glucose-treated H9c2 cells, the downstream effectors of sprouty homolog 1 (SPRY1) including extracellular signal-regulated kinases (ERK) and mammalian target of rapamycin showed significant changes following transfection with miR-21 mimics or inhibitor.Conclusion: The results of our study indicate that vild prevents DCM by restoring autophagy through the miR-21/SPRY1/ERK/mTOR pathway. Therefore, miR-21 is a target in the development of DCM, and vild demonstrates significant potential for clinical application in prevention of DCM.

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Anti-inflammatory effects of hederagenin on diabetic cardiomyopathy via inhibiting NF-κB and Smads signaling pathways in a type-2 diabetic mice model

RSC Advances ◽

10.1039/c9ra02043h ◽

2019 ◽

Vol 9 (45) ◽

pp. 26238-26247

Author(s):

Ying Li ◽

Junli Dong ◽

Yinghui Shang ◽

Qiangqiang Zhao ◽

Pengcheng Li ◽

...

Keyword(s):

Medicinal Plants ◽

Signaling Pathways ◽

Diabetic Cardiomyopathy ◽

Natural Compound ◽

Diabetic Mice ◽

Mice Model ◽

Pentacyclic Triterpenes ◽

Anti Inflammatory ◽

Type 2 Diabetic

Hederagenin (HED) is a bioactive natural compound of pentacyclic triterpenes extracted from many medicinal plants.

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Ketogenic diet ameliorates lipid dysregulation in type 2 diabetic mice by downregulating hepatic pescadillo 1

Molecular Medicine ◽

10.1186/s10020-021-00429-6 ◽

2022 ◽

Vol 28 (1) ◽

Author(s):

Jielin Zhou ◽

Yao Lu ◽

Yajing Jia ◽

Jing Lu ◽

Zhengxuan Jiang ◽

...

Keyword(s):

Lipid Metabolism ◽

Ketogenic Diet ◽

Conditional Knockout ◽

Standard Diet ◽

Diabetic Mice ◽

Cultured Hepatocytes ◽

Type 2 Diabetic

Abstract Background Previous reports implied a possible link between PES1 and lipid metabolism. However, the role of PES1 in regulating T2DM related lipid metabolism and the effect of ketogenic diet (KD) on PES1 have not been reported. The aim of present study is to explore the role of PES1 in effects of KD on diabetic mice and its mediated mechanism. Methods Male C57BL/6J and KKAy mice were fed with standard diet (SD) and KD, respectively. Simultaneously, McArdle 7777 cells were treated by β-hydroxybutyric acid (β-HB), Pes1 siRNA or Pes1 overexpression plasmid, respectively. Additionally, liver-conditional knockout (CKO) of Pes1 in vivo was applied. Results Hepatic PES1 expression in diabetic mice was markedly increased, which was suppressed by KD feeding with an accompanying reduction of hepatic and plasma triglycerides (TG). In mice with CKO of Pes1, the protein levels of p300, SREBP1c, FASN, SCD1, Caspase1, NLRP3 and GSDMD were dramatically downregulated in livers, and the plasma and hepatic TG, IL-1β and IL-18 were decreased as well. The similar outcomes were also observed in β-HB and Pes1 knockdown treated hepatocytes. By contrast, Pes1 overexpression in cultured hepatocytes showed that these levels were significantly enhanced, which were, however reduced under β-HB treatment. Mechanistically, we discovered that β-HB decreased CHOP binding to the Pes1 promoters, resulting in the downregulation of PES1, thereby reducing PES1 binding to p300 and Caspase1 promoters. The inhibition of p300 and Caspase1 expression elicited the dramatic suppression of acetylation of SREBP1c via its interaction with p300, and the decreased GSDMD levels. Besides, knockdown of Caspase1 also alleviated the TG levels in cultured hepatocytes. Conclusion KD may improve lipid dysregulation in type 2 diabetic mice by downregulating hepatic PES1 expression.

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Ketogenic Diet Ameliorates Lipid Dysregulation in Type 2 Diabetic Mice by Downregulating Hepatic Pescadillo 1

10.21203/rs.3.rs-951448/v1 ◽

2021 ◽

Author(s):

Jielin Zhou ◽

Yao Lu ◽

Yajing Jia ◽

Jing Lu ◽

Zhengxuan Jiang ◽

...

Keyword(s):

Lipid Metabolism ◽

Ketogenic Diet ◽

Conditional Knockout ◽

Standard Diet ◽

Diabetic Mice ◽

Cultured Hepatocytes ◽

Type 2 Diabetic

Abstract Background: Previous reports implied a possible link between PES1 and lipid metabolism. However, the role of PES1 in regulation of T2DM related lipid metabolism and the effect of KD on PES1 have not been reported. The aim of present study is to explore the role of PES1 in effects of ketogenic diet (KD) on diabetic mice and its mediated mechanism.Methods: Male C57BL/6J and KKAy mice were fed with standard diet (SD) and KD, respectively. Simultaneously, McArdle 7777 cells were treated by β-hydroxybutyric acid (β-HB), Pes1 siRNA or Pes1 overexpression plasmid, respectively. Additionally, liver-conditional knockout (CKO) of Pes1 in vivo were used.Results: We unexpectedly found that hepatic PES1 expression in T2DM patients was markedly elevated, but the elevated PES1 was suppressed by KD feeding in T2DM mice with the reduction of hepatic and plasma triglycerides (TG). In mice with CKO of Pes1, the protein levels of p300, SREBP1c, FASN, SCD1, caspase1, NLRP3 and GSDMD were dramatically downregulated in livers, and the plasma and hepatic TG, IL-1β and IL-18 were decreased as well. The similar phenomena were also observed in β-HB and Pes1 knockdown treated hepatocytes. By contrast, Pes1 overexpression in cultured hepatocytes showed that these levels were significantly enhanced, which however were reduced under β-HB treatment. Mechanistically, we discovered that β-HB decreased CHOP binding to the Pes1 promoters, resulting in the downregulation of PES1, thereby reducing PES1 binding to p300 and caspase1 promoters. The inhibition of p300 and caspase1 expressions elicited the dramatic suppression of acetylation of SREBP1c via its interaction with p300, and the decreased GSDMD levels. Besides, knockdown of caspase1 also alleviated the TG levels in cultured hepatocytes.Conclusion: KD may improve lipid dysregulation in type 2 diabetic mice by downregulating hepatic PES1 expression.

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