Hepatic retinaldehyde deficiency is involved in diabetes deterioration by enhancing PCK1- and G6PC-mediated gluconeogenesis

Hanyu Yang; Mengxiang Su; Ming Liu; Yun Sheng; Liang Zhu; Lu Yang; Ruijing Mu; Jianjun Zou; Xiaodong Liu; Li Liu

doi:10.1016/j.apsb.2023.06.014

Hepatic retinaldehyde deficiency is involved in diabetes deterioration by enhancing PCK1- and G6PC-mediated gluconeogenesis

Acta Pharm Sin B. 2023 Sep;13(9):3728-3743. doi: 10.1016/j.apsb.2023.06.014. Epub 2023 Jun 27.

Authors

Hanyu Yang^{1

2}, Mengxiang Su³, Ming Liu², Yun Sheng², Liang Zhu², Lu Yang^{1

2}, Ruijing Mu^{1

2}, Jianjun Zou⁴, Xiaodong Liu^{1

2}, Li Liu^{1

2}

Affiliations

¹ State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
² Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
³ Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
⁴ Department of Clinical Pharmacology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.

Abstract

Type 2 diabetes (T2D) is often accompanied with an induction of retinaldehyde dehydrogenase 1 (RALDH1 or ALDH1A1) expression and a consequent decrease in hepatic retinaldehyde (Rald) levels. However, the role of hepatic Rald deficiency in T2D progression remains unclear. In this study, we demonstrated that reversing T2D-mediated hepatic Rald deficiency by Rald or citral treatments, or liver-specific Raldh1 silencing substantially lowered fasting glycemia levels, inhibited hepatic glucogenesis, and downregulated phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6-phosphatase (G6PC) expression in diabetic db/db mice. Fasting glycemia and Pck1/G6pc mRNA expression levels were strongly negatively correlated with hepatic Rald levels, indicating the involvement of hepatic Rald depletion in T2D deterioration. A similar result that liver-specific Raldh1 silencing improved glucose metabolism was also observed in high-fat diet-fed mice. In primary human hepatocytes and oleic acid-treated HepG2 cells, Rald or Rald + RALDH1 silencing resulted in decreased glucose production and downregulated PCK1/G6PC mRNA and protein expression. Mechanistically, Rald downregulated direct repeat 1-mediated PCK1 and G6PC expression by antagonizing retinoid X receptor α, as confirmed by luciferase reporter assays and molecular docking. These results highlight the link between hepatic Rald deficiency, glucose dyshomeostasis, and the progression of T2D, whilst also suggesting RALDH1 as a potential therapeutic target for T2D.

Keywords: Gluconeogenesis; Glucose-6-phosphatase; Oleic acid; Phosphoenolpyruvate carboxykinase 1; Retinaldehyde; Retinaldehyde dehydrogenase 1; Retinoid X receptor; Type 2 diabetes.