title: Hepatosteatosis and hepatic insulin resistance are blunted by argirein, an anti-inflammatory agent, through normalizing endoplasmic reticulum stress and apoptosis in diabetic liver.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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: China Pharmaceutical University, Research Division of Pharmacology, Nanjing, China.
authors: Fang-Hong
authors: FH
authors: Shi
authors: You
authors: Y
authors: Wu
authors: De-Zai
authors: DZ
authors: Dai
authors: Xiao-Dong
authors: XD
authors: Cong
authors: Yu-Mao
authors: YM
authors: Zhang
authors: Yin
authors: Y
authors: Dai
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001120:Arginine / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004338:Drug Combinations; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000097:blood / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054411:Receptors, Leptin / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D019892:eIF-2 Kinase / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D000880:Anthraquinones; D000893:Anti-Inflammatory Agents; D001120:Arginine; D004338:Drug Combinations; D005947:Glucose; D051275:Glucose Transporter Type 4; D005979:Glutathione Peroxidase; D006003:Glycogen; D006360:Heat-Shock Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047493:PPAR alpha; D047495:PPAR gamma; D054411:Receptors, Leptin; D013777:Tetrazoles; D051742:Transcription Factor CHOP; D014633:Valine; D000068756:Valsartan; D019892:eIF-2 Kinase; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C526296:Irs1 protein, rat; C495694:Slc2a4 protein, rat; C576350:argirein