PMID- 33819629
OWN - NLM
STAT- MEDLINE
DCOM- 20210830
LR  - 20210830
IS  - 1879-1220 (Electronic)
IS  - 0960-0760 (Linking)
VI  - 211
DP  - 2021 Jul
TI  - Elucidation of the mechanism of NEFA-induced PERK-eIF2alpha signaling pathway 
      regulation of lipid metabolism in bovine hepatocytes.
PG  - 105893
LID - S0960-0760(21)00086-8 [pii]
LID - 10.1016/j.jsbmb.2021.105893 [doi]
AB  - During the periparturient transition period, negative energy balance (NEB) 
      characterized by high concentrations of non-esterified fatty acids (NEFA) may 
      cause fatty liver and ketosis in dairy cows. Previous studies have shown that the 
      protein kinase R-like endoplasmic reticulum kinase (PERK) branch of the 
      endoplasmic reticulum stress (ERS) response plays an important role in lipid 
      metabolism in hepatocytes. This study, therefore, investigated the role of the 
      PERK-branch in NEFA-induced fatty liver. Different concentrations of NEFA or 
      GSK2656157 (a novel catalytic inhibitor of PERK) were used to treat hepatocytes 
      isolated from calves. The NEFA treatment significantly increased the 
      triacylglycerol (TG) content, the phosphorylation level of PERK and eukaryotic 
      initiation factor 2alpha (eIF2alpha), and the abundance of glucose-regulated protein 78 
      (Grp78), C/EBP homologous protein (CHOP), sterol regulatory element-binding 
      protein 1c (SREBP-1c), fatty acid synthase (FASN), peroxisome 
      proliferator-activated receptor-alpha (PPARalpha), carnitine palmitoyltransferase 1A 
      (CPT1A), apolipoprotein B (APOB), and the low-density lipoprotein receptor 
      (LDLR). Compared with the 1.2 mM NEFA group, inhibition of PERK activity further 
      increased the TG content in hepatocytes, the very-low-density lipoprotein (VLDL) 
      content in the supernatant and the protein abundance of APOB while reducing the 
      expression and nuclear levels of SREBP-1c and PPARalpha, as well as the expression of 
      CPT1A and CPT2. In conclusion, the results showed that the NEFA-induced 
      PERK-eIF2alpha signaling pathway promotes lipid synthesis, lipid oxidation, but 
      inhibits the assembly and secretion of VLDL. Therefore, during the transition 
      period, the activation of the PERK-eIF2alpha signaling pathway in the liver of dairy 
      cows could defeat the acid-induced lipotoxicity and provide energy to alleviate 
      NEB.
CI  - Copyright (c) 2021. Published by Elsevier Ltd.
FAU - Huang, Yan
AU  - Huang Y
AD  - College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 
      712100, PR China.
FAU - Zhao, Chenxu
AU  - Zhao C
AD  - College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 
      712100, PR China.
FAU - Kong, Yezi
AU  - Kong Y
AD  - College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 
      712100, PR China.
FAU - Tan, Panpan
AU  - Tan P
AD  - College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 
      712100, PR China.
FAU - Liu, Siqi
AU  - Liu S
AD  - College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 
      712100, PR China.
FAU - Liu, Yaoquan
AU  - Liu Y
AD  - College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 
      712100, PR China.
FAU - Zeng, Fangyuan
AU  - Zeng F
AD  - College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 
      712100, PR China.
FAU - Yuan, Yang
AU  - Yuan Y
AD  - College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 
      712100, PR China.
FAU - Zhao, Baoyu
AU  - Zhao B
AD  - College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 
      712100, PR China.
FAU - Wang, Jianguo
AU  - Wang J
AD  - College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 
      712100, PR China. Electronic address: jgwang0625@nwsuaf.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210402
PL  - England
TA  - J Steroid Biochem Mol Biol
JT  - The Journal of steroid biochemistry and molecular biology
JID - 9015483
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 0 (Fatty Acids, Nonesterified)
RN  - 0 (Peroxisome Proliferator-Activated Receptors)
SB  - IM
MH  - Animals
MH  - Cattle
MH  - Cells, Cultured
MH  - Endoplasmic Reticulum/*drug effects/metabolism
MH  - Eukaryotic Initiation Factor-2/*metabolism
MH  - Fatty Acids, Nonesterified/*pharmacology
MH  - Hepatocytes/*drug effects/metabolism
MH  - *Lipid Metabolism
MH  - Peroxisome Proliferator-Activated Receptors/*metabolism
MH  - Phosphorylation
OTO - NOTNLM
OT  - Dairy cows
OT  - Lipid metabolism
OT  - Non-esterified fatty acids
OT  - Protein kinase R-like endoplasmic reticulum kinase
EDAT- 2021/04/06 06:00
MHDA- 2021/08/31 06:00
CRDT- 2021/04/05 20:11
PHST- 2020/12/14 00:00 [received]
PHST- 2021/03/25 00:00 [revised]
PHST- 2021/03/31 00:00 [accepted]
PHST- 2021/04/06 06:00 [pubmed]
PHST- 2021/08/31 06:00 [medline]
PHST- 2021/04/05 20:11 [entrez]
AID - S0960-0760(21)00086-8 [pii]
AID - 10.1016/j.jsbmb.2021.105893 [doi]
PST - ppublish
SO  - J Steroid Biochem Mol Biol. 2021 Jul;211:105893. doi: 
      10.1016/j.jsbmb.2021.105893. Epub 2021 Apr 2.