Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, Anhui, China.
Department of Anesthesiology, The First Affiliated Hospital, Anhui Medical University, Hefei, 230032, Anhui, China.
Mol Med. 2022 Jan 3;28(1):1. doi: 10.1186/s10020-021-00429-6.
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.
Male C57BL/6J and KKA 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.
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.
KD may improve lipid dysregulation in type 2 diabetic mice by downregulating hepatic PES1 expression.
先前的报告表明 PES1 与脂质代谢之间可能存在联系。然而，PES1 在调节 2 型糖尿病相关脂质代谢中的作用以及生酮饮食（KD）对 PES1 的影响尚未得到报道。本研究旨在探讨 PES1 在 KD 对糖尿病小鼠影响中的作用及其介导机制。
雄性 C57BL/6J 和 KKA 小鼠分别给予标准饮食（SD）和 KD。同时，β-羟基丁酸（β-HB）、Pes1 siRNA 或 Pes1 过表达质粒分别处理 McArdle 7777 细胞，体内应用肝条件性敲除（CKO）Pes1。
糖尿病小鼠肝 PES1 表达明显增加，KD 喂养可抑制其表达，同时降低肝和血浆甘油三酯（TG）。在 Pes1 CKO 小鼠中，肝中 p300、SREBP1c、FASN、SCD1、Caspase1、NLRP3 和 GSDMD 蛋白水平显著下调，血浆和肝 TG、IL-1β 和 IL-18 也减少。在β-HB 和 Pes1 敲低处理的肝细胞中也观察到类似结果。相反，在培养的肝细胞中过表达 Pes1 时，这些水平显著增强，但在β-HB 处理下降低。机制上，我们发现β-HB 降低了 CHOP 与 Pes1 启动子的结合，导致 PES1 下调，从而减少了 PES1 与 p300 和 Caspase1 启动子的结合。p300 和 Caspase1 表达的抑制通过其与 p300 的相互作用引起 SREBP1c 的乙酰化显著减少，GSDMD 水平降低。此外，Caspase1 的敲低也减轻了培养的肝细胞中的 TG 水平。
KD 可能通过下调 2 型糖尿病小鼠肝 PES1 表达来改善脂质代谢紊乱。
