Abstract
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.
Highlights
Type 2 diabetes mellitus (T2DM), characterized by insulin resistance (IR) and pancreatic β-cell dysfunction, is a heterogeneous metabolic disorder (Magliano et al 2020).Compelling evidence showed that T2DM was accompanied by hypertriglyceridemia-based lipid dysregulation (Zheng et al 2018; Xu et al 2018), one of the main factors leading to atherosclerosis and even death (McGuire et al 2016).Recently, an interesting dietary pattern, namely ketogenic diet (KD), has been proposed to attain a remarkable decline of hyperglycemia in T2DM (Abbasi 2018)
We aimed to evaluate the effects of KD on diabetic mice or of β-hydroxybutyric acid (β-HB) on liver cells via downregulating pescadillo 1 (PES1) expression, which may be associated with the amelioration of lipid metabolism in vivo and in vitro
Long‐term KD intervention improved the hyperglycemia and insulin resistance in diabetic mice After 16 weeks of KD intervention, murine body weights in KKAy-KD group showed no significant difference from those in the KKAy-standard diet (SD) groups, the similar results were observed in the C57BL6J mice (Fig. 1a)
Summary
Type 2 diabetes mellitus (T2DM), characterized by insulin resistance (IR) and pancreatic β-cell dysfunction, is a heterogeneous metabolic disorder (Magliano et al 2020).Compelling evidence showed that T2DM was accompanied by hypertriglyceridemia-based lipid dysregulation (Zheng et al 2018; Xu et al 2018), one of the main factors leading to atherosclerosis and even death (McGuire et al 2016).Recently, an interesting dietary pattern, namely ketogenic diet (KD), has been proposed to attain a remarkable decline of hyperglycemia in T2DM (Abbasi 2018). KD is typically characterized by low carbohydrates (5 to 10% of total caloric intake) and high fat consumption (more than 70% of total caloric intake) (Castellana et al 2020). 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. Liver-conditional knockout (CKO) of Pes in vivo was applied
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