Hepatosteatosis and hepatic insulin resistance are blunted by argirein, an anti-inflammatory agent, through normalizing endoplasmic reticulum stress and apoptosis in diabetic liver.

Abstract

OBJECTIVES:

Insulin resistance represents a mechanism underlying defect metabolism of carbohydrate and lipid linked to inflammatory reactions in diabetic liver. We hypothesized that the changes may be secondary to endoplasmic reticulum (ER) stress, which could be alleviated by either argirein or valsartan.

METHODS:

Hepatosteatosis in diabetic liver was induced in rats fed with a high-fat diet (HFD) for 12 weeks combined with a single low dose of streptozotocin (STZ 35 mg/kg, ip). Interventions (mg/kg/d, po)with either argirein (50, 100 and 200) or valsartan (12) were conducted in the last 4 weeks.

KEY FINDINGS:

In diabetic liver fat was significantly accumulated in association with elevated hepatic glucose, serum insulin and homeostasis model assessment of insulin resistance value. Downregulated glucose transporter 4, insulin receptor substrate-1 and leptin receptor (P < 0.01) were found relative to normal, where DNA ladder, downregulated B cell lymphoma/leukemia-2, upregulated B cell lymphoma/leukemia-2 Associated X protein and upregulated ER stress chaperones such as Bip/GRP78 (also known as Binding Protein, BiP), PKR-like ER kinase (PERK), p-PERK/PERK and C/EBP homologous protein were significant. These abnormalities were significantly ameliorated by argirein and valsartan.

CONCLUSIONS:

Hepatosteatosis induced by HFD/low STZ manifests insulin resistance and apoptosis, linked to an entity of low-grade inflammation due to activated ER stress sensors. With anti-inflammatory activity either argirein or valsartan blunts hepatosteatosis through normalizing ER stress and apoptosis in the diabetic liver.

• Authors: Fang-Hong Shi, You Wu, De-Zai Dai, Xiao-Dong Cong, Yu-Mao Zhang, Yin Dai
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 65 Issue 6 Pg. 916-27 (Jun 2013) ISSN: 2042-7158 [Electronic] England
• PMID: 23647685 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Royal Pharmaceutical Society.

Chemical References

• Anthraquinones
• Anti-Inflammatory Agents
• Ddit3 protein, rat
• Drug Combinations
• GRP78 protein, rat
• Glucose Transporter Type 4
• Heat-Shock Proteins
• Insulin
• Insulin Receptor Substrate Proteins
• Irs1 protein, rat
• PPAR alpha
• PPAR gamma
• Receptors, Leptin
• Slc2a4 protein, rat
• Tetrazoles
• argirein
• Transcription Factor CHOP
• Valsartan
• Glycogen
• Arginine
• Glutathione Peroxidase
• PERK kinase
• eIF-2 Kinase
• Valine
• Glucose

Topics

• Animals
• Anthraquinones (pharmacology)
• Anti-Inflammatory Agents (pharmacology)
• Apoptosis (drug effects)
• Arginine (pharmacology)
• Diabetes Mellitus, Experimental (blood, drug therapy, metabolism)
• Diet, High-Fat (adverse effects)
• Drug Combinations
• Endoplasmic Reticulum Stress (drug effects)
• Glucose (metabolism)
• Glucose Transporter Type 4 (metabolism)
• Glutathione Peroxidase (blood, metabolism)
• Glycogen (metabolism)
• Heat-Shock Proteins (metabolism)
• Insulin (blood, metabolism)
• Insulin Receptor Substrate Proteins (metabolism)
• Insulin Resistance (physiology)
• Liver (drug effects, metabolism)
• Male
• PPAR alpha (metabolism)
• PPAR gamma (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Leptin (metabolism)
• Tetrazoles (pharmacology)
• Transcription Factor CHOP (metabolism)
• Valine (analogs & derivatives, pharmacology)
• Valsartan
• eIF-2 Kinase (metabolism)