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

Molecular Medicine

Yao Lu¹  Yajing Jia²  Jielin Zhou³  Jing Lu³  Keyang Chen⁴  Zhengxuan Jiang⁵ 

[1] Department of Anesthesiology, The First Affiliated Hospital, Anhui Medical University, 230032, Hefei, Anhui, China;Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, 230032, Hefei, Anhui, China;Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, 230032, Hefei, Anhui, China;Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, 230032, Hefei, Anhui, China;Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, 230032, Hefei, Anhui, China;Department of Ophthalmology, The Second Affiliated Hospital, Anhui Medical University, 230021, Hefei, Anhui, China;

关键词: Ketogenic diet (KD);    β-Hydroxybutyrate (β-HB);    PES1;    Lipid metabolism;    Inflammation;   

DOI  :  10.1186/s10020-021-00429-6

来源: Springer

【 摘 要 】

BackgroundPrevious 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.MethodsMale 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.ResultsHepatic 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.ConclusionKD may improve lipid dysregulation in type 2 diabetic mice by downregulating hepatic PES1 expression.

【 授权许可】

CC BY