Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, Anhui, China.
Department of Ophthalmology, The Second Affiliated Hospital, Anhui Medical University, Hefei, 230021, Anhui, China.
Eur J Nutr. 2022 Aug;61(5):2775-2797. doi: 10.1007/s00394-022-02850-x. Epub 2022 Mar 15.
A possible link between pescadillo 1 (PES1) and lipid metabolism has been reported. However, whether PES1 is involved in the effects of daily caloric restriction (CR) and alternate-day fasting (ADF) interventions on diabetes-related lipid dysregulation is not elucidated. The current study aims are to explore the role of PES1 in effects of CR and ADF on diabetic mice and related mechanism.
Eight-week-old male db/db mice with type 2 diabetes mellitus (T2DM) were randomly divided into untreated T2DM, CR and ADF groups. McArdle hepatocytes were treated with 48 h high glucose (HG), 48 h normal glucose (NG) and 24 h HG plus 24 h NG, respectively. Pes1 siRNA and overexpression plasmid were, respectively, transfected into liver cells, and AAV-Pes1-shRNA was injected into db/db mice.
After 12-week interventions, the peroxisome proliferator-activated receptor alpha (PPAR-α) and carnitine palmitoyltransferase 1A (CPT1A) levels in livers of T2DM mice were enhanced by CR and ADF interventions with reductions of hepatic and plasma triglycerides. Unexpectedly, hepatic PES1 levels were downregulated by two interventions, consistent with the results of 48 h NG and 24 h HG plus 24 h NG-treated cells. Moreover, CPT1A level was upregulated in Pes1-siRNA-treated cells and AAV-Pes1-shRNA injected murine livers, in contrast to Pes1 overexpression in cultured cells. Mechanistically, 48 h NG or 24 h HG plus 24 h NG treatment increased PPAR-α binding to Pes1 promoter, suppressing the PES1 expression, thereby lowering the PES1-mediated ubiquitination of CPT1A.
The present study suggests that CR and ADF may improve lipid dysregulation in diabetic mice by downregulating hepatic PES1.
有研究报道称，pescadillo 1（PES1）与脂代谢之间可能存在关联。然而，PES1 是否参与了热量限制（CR）和隔日禁食（ADF）干预对糖尿病相关脂质失调的影响尚不清楚。本研究旨在探讨 PES1 在 CR 和 ADF 对糖尿病小鼠的作用及其相关机制。
将 8 周龄的 2 型糖尿病（T2DM）雄性 db/db 小鼠随机分为未治疗 T2DM、CR 和 ADF 组。McArdle 肝细胞分别用 48 h 高葡萄糖（HG）、48 h 正常葡萄糖（NG）和 24 h HG 加 24 h NG 处理。PES1 siRNA 和过表达质粒分别转染入肝细胞，AAV-Pes1-shRNA 注射入 db/db 小鼠。
经过 12 周的干预，CR 和 ADF 干预使 T2DM 小鼠肝脏中的过氧化物酶体增殖物激活受体α（PPAR-α）和肉碱棕榈酰转移酶 1A（CPT1A）水平升高，肝和血浆甘油三酯减少。出乎意料的是，两种干预措施均使肝脏 PES1 水平下调，与 48 h NG 和 24 h HG 加 24 h NG 处理的细胞结果一致。此外，Pes1-siRNA 处理的细胞和 AAV-Pes1-shRNA 注射的鼠肝中 CPT1A 水平升高，而在培养细胞中 PES1 过表达则相反。机制上，48 h NG 或 24 h HG 加 24 h NG 处理增加了 PPAR-α 与 Pes1 启动子的结合，抑制了 PES1 的表达，从而降低了 PES1 介导的 CPT1A 泛素化。
本研究表明，CR 和 ADF 可能通过下调肝 PES1 改善糖尿病小鼠的脂质失调。
