title: Infusion of glucose and lipids at physiological rates causes acute endoplasmic reticulum stress in rat liver.
abstract: Endoplasmic reticulum (ER) stress has recently been implicated as a cause for obesity-related insulin resistance; however, what causes ER stress in obesity has remained uncertain. Here, we have tested the hypothesis that macronutrients can cause acute (ER) stress in rat liver. Examined were the effects of intravenously infused glucose and/or lipids on proximal ER stress sensor activation (PERK, eIF2-α, ATF4, Xbox protein 1 (XBP1s)), unfolded protein response (UPR) proteins (GRP78, calnexin, calreticulin, protein disulphide isomerase (PDI), stress kinases (JNK, p38 MAPK) and insulin signaling (insulin/receptor substrate (IRS) 1/2 associated phosphoinositol-3-kinase (PI3K)) in rat liver. Glucose and/or lipid infusions, ranging from 23.8 to 69.5 kJ/4 h (equivalent to between ~17% and ~50% of normal daily energy intake), activated the proximal ER stress sensor PERK and ATF6 increased the protein abundance of calnexin, calreticulin and PDI and increased two GRP78 isoforms. Glucose and glucose plus lipid infusions induced comparable degrees of ER stress, but only infusions containing lipid activated stress kinases (JNK and p38 MAPK) and inhibited insulin signaling (PI3K). In summary, physiologic amounts of both glucose and lipids acutely increased ER stress in livers 12-h fasted rats and dependent on the presence of fat, caused insulin resistance. We conclude that this type of acute ER stress is likely to occur during normal daily nutrient intake.
authors.affiliation: Division of Endocrinology/Diabetes/Metabolism and the Clinical Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA. bodengh@tuhs.temple.edu
authors.forename: Guenther
authors.initials: G
authors.lastname: Boden
authors.forename: Weiwei
authors.initials: W
authors.lastname: Song
authors.forename: Xunbao
authors.initials: X
authors.lastname: Duan
authors.forename: Peter
authors.initials: P
authors.lastname: Cheung
authors.forename: Karen
authors.initials: K
authors.lastname: Kresge
authors.forename: Carlos
authors.initials: C
authors.lastname: Barrero
authors.forename: Salim
authors.initials: S
authors.lastname: Merali
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D004655:Emulsions / Q000008:administration & dosage / Q000009:adverse effects; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005217:Fat Emulsions, Intravenous / Q000008:administration & dosage* / Q000009:adverse effects; D005947:Glucose / Q000008:administration & dosage* / Q000009:adverse effects; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010743:Phospholipids / Q000008:administration & dosage* / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013024:Soybean Oil / Q000008:administration & dosage* / Q000009:adverse effects; D013312:Stress, Physiological; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D004655:Emulsions; D000091342:Endoplasmic Reticulum Chaperone BiP; D005217:Fat Emulsions, Intravenous; D005947:Glucose; D006360:Heat-Shock Proteins; D007328:Insulin; D058539:Phosphatidylinositol 3-Kinase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010743:Phospholipids; D013024:Soybean Oil; D019892:eIF-2 Kinase; C497113:Atf6 protein, rat; C545823:soybean oil, phospholipid emulsion