Contribution of Hepatic Retinaldehyde Dehydrogenase Induction to Impairment of Glucose Metabolism by High-Fat-Diet Feeding in C57BL/6J Mice.

Abstract

Obesity and insulin resistance are associated with overexpression of retinaldehyde dehydrogenase 1 (RALDH1). We aimed to investigate the roles of hepatic RALDH1 induction in glucose metabolism impairment using mice fed with high-fat-diet (HFD). Mice were fed with HFD for 8 weeks and treated with RALDH inhibitor citral for another 4 weeks. Oral glucose tolerance test (OGTT), pyruvate tolerance test (PTT) and insulin tolerance test were performed. Expressions of phosphoenolpyruvate carboxykinase 1 (PCK1), glucokinase (GCK) and RALDH1 were measured. Therapeutic effects of citral were also documented in diabetic rats. Effects of retinaldehyde on PCK1 and GCK expressions were examined in rat primary hepatocytes and HepG2 cells. The results showed that HFD mice were characterized by hyperlipidaemia and insulin resistance, accompanied by significantly increased RALDH1 activity and expression. Citral (10 and 50 mg/kg) ameliorated HFD-induced hyperlipidaemia and insulin resistance, as demonstrated by the improved fasting glucose, insulin levels and lipid profiles. OGTT and PTT demonstrated that citral reversed HFD-induced glucose disposal impairment and glucose production enhancement. Citral also reversed the increased PCK1 expression and decreased GCK expression by HFD. Citral therapeutic effects were reconfirmed in diabetic rats. In vitro data indicated that retinaldehyde had the strongest PCK1 induction in primary hepatocytes of diabetic rats compared with HFD rats and control rats, in line with the increased RALDH1 expression. Citral reversed the retinaldehyde-induced PCK1 expression in primary rat hepatocytes and HepG2 cells. In conclusion, RALDH1 induction impaired glucose metabolism partly via modulating PCK1 and GCK expressions. Citral improved glucose metabolism through inhibiting RALDH activity.

• Authors: Jiong Xu, Mian Zhang, Xiangping Zhang, Hanyu Yang, Binbin Sun, Zhongjian Wang, Yaqian Zhou, Shuting Wang, Xiaodong Liu, Li Liu
• Journal: Basic & clinical pharmacology & toxicology (Basic Clin Pharmacol Toxicol) Vol. 123 Issue 5 Pg. 539-548 (Nov 2018) ISSN: 1742-7843 [Electronic] England
• PMID: 29753302 (Publication Type: Journal Article)
• Copyright: © 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Chemical References

• Acyclic Monoterpenes
• Insulin
• Intracellular Signaling Peptides and Proteins
• Isoenzymes
• Monoterpenes
• Aldehyde Dehydrogenase 1 Family
• ALDH1A1 protein, human
• ALDH1A1 protein, mouse
• Aldh1a1 protein, rat
• Retinal Dehydrogenase
• Glucokinase
• Pck1 protein, rat
• Phosphoenolpyruvate Carboxykinase (GTP)
• Glucose
• citral

Topics

• Acyclic Monoterpenes
• Aldehyde Dehydrogenase 1 Family
• Animals
• Diabetes Mellitus, Experimental (etiology, metabolism)
• Diet, High-Fat (methods)
• Glucokinase (metabolism)
• Glucose (metabolism)
• Glucose Tolerance Test (methods)
• Hep G2 Cells
• Hepatocytes (drug effects, metabolism)
• Humans
• Hyperlipidemias (etiology, metabolism)
• Insulin (blood)
• Insulin Resistance
• Intracellular Signaling Peptides and Proteins (metabolism)
• Isoenzymes (antagonists & inhibitors, metabolism)
• Lipid Metabolism (drug effects)
• Mice
• Mice, Inbred C57BL
• Monoterpenes (pharmacology)
• Phosphoenolpyruvate Carboxykinase (GTP) (metabolism)
• Rats
• Retinal Dehydrogenase (antagonists & inhibitors, metabolism)