Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death.
Prolonged endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) have been linked to apoptosis via several mechanisms, including increased expression of C/EBP homologous protein (Chop). Increased long-chain fatty acids, in particular saturated fatty acids, induce ER stress, Chop expression, and apoptosis in liver cells. The first aim of the present study was to determine the role of Chop in lipid-induced hepatocyte cell death and liver injury induced by a methionine-choline-deficient diet. Albumin-bound palmitate increased Chop gene and protein expression in a dose-dependent fashion in H4IIE liver cells. siRNA-mediated silencing of Chop in H4IIE liver cells reduced thapsigargin-mediated cell death by approximately 40% and delayed palmitate-mediated cell death, but only at high concentrations of palmitate (400-500 microM). Similar results were observed in primary hepatocytes isolated from Chop-knockout mice. Indices of liver injury were also not reduced in Chop-knockout mice provided a methionine-choline-deficient diet. To ascertain whether ER stress was linked to palmitate-induced cell death, primary hepatocytes were incubated in the absence or presence of the chemical chaperones taurine-conjugated ursodeoxycholic acid or 4-phenylbutyric acid. The presence of either of these chemical chaperones protected liver cells from palmitate-mediated ER stress and cell death, in part, via inhibition of JNK activation. These data suggest that ER stress is linked to palmitate-mediated cell death via mechanisms that include JNK activation.
Pfaffenbach
Kyle T
KT
Colorado State University, Department of Food Science and Human Nutrition, Gifford 234, Fort Collins, CO 80523-1571, USA.
Gentile
Christopher L
CL
Nivala
Angela M
AM
Wang
Dong
D
Wei
Yuren
Y
Pagliassotti
Michael J
MJ
D000818:Animals; D001786:Blood Glucose; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002796:Choline Deficiency; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D008715:Methionine / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000378:metabolism; D019308:Palmitic Acid / Q000633:toxicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects / Q000502:physiology*
D001786:Blood Glucose; D007328:Insulin; D018832:Molecular Chaperones; D051742:Transcription Factor CHOP; D019308:Palmitic Acid; D008715:Methionine