title: Endoplasmic reticulum stress induces hepatic steatosis via increased expression of the hepatic very low-density lipoprotein receptor.
abstract: Recent evidence suggests that obese animals exhibit increased endoplasmic reticulum (ER) stress in the liver and adipose tissue. Although ER stress is closely associated with lipid homeostasis, it is largely unknown how ER stress contributes to hepatic steatosis. In this study, we demonstrate that the induction of ER stress stimulates hepatic steatosis through increased expression of the hepatic very low-density lipoprotein receptor (VLDLR). Among the unfolded protein response sensors, the protein kinase RNA-like ER kinase-activating transcription factor 4 signaling pathway was required for hepatic VLDLR up-regulation. In primary hepatocytes, ER stress-dependent VLDLR expression induced intracellular triglyceride accumulation in the presence of very low-density lipoprotein. Moreover, ER stress-dependent hepatic steatosis was diminished in the livers of VLDLR-deficient and apolipoprotein E-deficient mice compared with wild-type mice. In addition, the VLDLR-deficient mice exhibited decreased hepatic steatosis upon high-fat diet feeding.
  
  
  CONCLUSIONS
  These data suggest that ER stress-dependent expression of hepatic VLDLR leads to hepatic steatosis by increasing lipoprotein delivery to the liver, which might be a novel mechanism explaining ER stress-induced hepatic steatosis.
authors.affiliation: School of Biological Sciences, Institute of Molecular Biology and Genetics, University of Ulsan, Ulsan, Korea.
authors.forename: Hyunsun
authors.initials: H
authors.lastname: Jo
authors.forename: Sung Sik
authors.initials: SS
authors.lastname: Choe
authors.forename: Kyung Cheul
authors.initials: KC
authors.lastname: Shin
authors.forename: Hagoon
authors.initials: H
authors.lastname: Jang
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Je Kyung
authors.initials: JK
authors.lastname: Seong
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Back
authors.forename: Jae Bum
authors.initials: JB
authors.lastname: Kim
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005234:Fatty Liver / Q000378:metabolism / Q000503:physiopathology*; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D001057:Apolipoproteins E; C081452:Atf4 protein, mouse; D008074:Lipoproteins; D011973:Receptors, LDL; D014280:Triglycerides; C036053:VLDL receptor; D051701:Activating Transcription Factor 4