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

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.