PMID- 34768836
OWN - NLM
STAT- MEDLINE
DCOM- 20220111
LR  - 20220111
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 21
DP  - 2021 Oct 22
TI  - 5-Aminolevulinic Acid Attenuates Glucose-Regulated Protein 78 Expression and 
      Hepatocyte Lipoapoptosis via Heme Oxygenase-1 Induction.
LID - 10.3390/ijms222111405 [doi]
LID - 11405
AB  - Endoplasmic reticulum (ER) stress plays a pivotal role in the progression of 
      steatohepatitis. 5-aminolevulinic acid (5-ALA), a precursor in the heme 
      biosynthetic pathway, has recently been reported to induce heme oxygenase (HO)-1. 
      HO-1 exerts important cytoprotective actions. In this study, we aimed to explore 
      the therapeutic potential of 5-ALA on palmitate-induced ER stress and 
      lipoapoptosis. Huh-7 cells were treated with palmitic acid (PA) (800 muM) to 
      induce steatosis for eight hours. Steatosis was evaluated by Lipi-green staining. 
      5-ALA (200 muM) was added with PA. The gene expression levels of the nuclear 
      factor erythroid 2-related factor 2 (NRF2), HO-1, Glucose-regulated protein 78 
      (GRP78), activating transcription factor 6 (ATF6), PKR-like endoplasmic reticulum 
      kinase (PERK), inositol-requiring enzyme 1 (IRE1), C/EBP homologous protein 
      (CHOP), and B-cell lymphoma 2 (BCL-2) were evaluated by RT-PCR. Caspase-3/7 
      activity was evaluated by fluorescein active Caspase-3/7 staining. Cell death was 
      evaluated by Annexin V/SYTOX green staining. PA significantly induced steatosis 
      and increased GRP78 expression in Huh-7 cells. 5-ALA significantly induced HO-1 
      and decreased GRP78 expression. ATF6 was subsequently decreased. However, NRF2 
      and CHOP expression were not altered. Anti-apoptotic BCL-2 expression 
      significantly increased, and Caspase 3/7 activity and cell death also decreased. 
      5-ALA has a therapeutic potential on hepatic steatosis by suppressing ER stress 
      and lipoapoptosis by attenuating GRP78 via HO-1 induction.
FAU - Hashimoto, Takaaki
AU  - Hashimoto T
AD  - Faculty of Medicine, School of Medicine, Tottori University, Yonago 683-8503, 
      Japan.
FAU - Sugihara, Takaaki
AU  - Sugihara T
AUID- ORCID: 0000-0003-0522-1884
AD  - Division of Medicine and Clinical Science, Department of Gastroenterology and 
      Nephrology, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan.
FAU - Kanda, Tsutomu
AU  - Kanda T
AUID- ORCID: 0000-0003-0409-9258
AD  - Division of Medicine and Clinical Science, Department of Gastroenterology and 
      Nephrology, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan.
FAU - Takata, Tomoaki
AU  - Takata T
AUID- ORCID: 0000-0003-2959-6015
AD  - Division of Medicine and Clinical Science, Department of Gastroenterology and 
      Nephrology, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan.
FAU - Isomoto, Hajime
AU  - Isomoto H
AD  - Division of Medicine and Clinical Science, Department of Gastroenterology and 
      Nephrology, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan.
LA  - eng
PT  - Journal Article
DEP - 20211022
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (ATF6 protein, human)
RN  - 0 (Activating Transcription Factor 6)
RN  - 0 (DDIT3 protein, human)
RN  - 0 (Endoplasmic Reticulum Chaperone BiP)
RN  - 0 (HSPA5 protein, human)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - 2V16EO95H1 (Palmitic Acid)
RN  - 88755TAZ87 (Aminolevulinic Acid)
RN  - EC 1.14.14.18 (HMOX1 protein, human)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (Caspase 3)
SB  - IM
MH  - Activating Transcription Factor 6/metabolism
MH  - Aminolevulinic Acid/metabolism/*pharmacology
MH  - Apoptosis/drug effects
MH  - Caspase 3/metabolism
MH  - Cell Line, Tumor
MH  - Endoplasmic Reticulum Chaperone BiP/genetics/*metabolism
MH  - Endoplasmic Reticulum Stress/drug effects/physiology
MH  - Fatty Liver/*metabolism/physiopathology
MH  - Heme Oxygenase-1/metabolism
MH  - Hepatocytes/drug effects/metabolism
MH  - Humans
MH  - Lipid Metabolism/drug effects
MH  - NF-E2-Related Factor 2/metabolism
MH  - Palmitic Acid/pharmacology
MH  - Transcription Factor CHOP/metabolism
PMC - PMC8584191
OTO - NOTNLM
OT  - 5-aminolevulinic acid
OT  - endoplasmic reticulum stress
OT  - glucose-regulated protein 78
OT  - heme oxygenase-1
OT  - steatohepatitis
COIS- The authors declare no conflict of interest.
EDAT- 2021/11/14 06:00
MHDA- 2022/01/12 06:00
PMCR- 2021/10/22
CRDT- 2021/11/13 01:03
PHST- 2021/09/29 00:00 [received]
PHST- 2021/10/13 00:00 [revised]
PHST- 2021/10/19 00:00 [accepted]
PHST- 2021/11/13 01:03 [entrez]
PHST- 2021/11/14 06:00 [pubmed]
PHST- 2022/01/12 06:00 [medline]
PHST- 2021/10/22 00:00 [pmc-release]
AID - ijms222111405 [pii]
AID - ijms-22-11405 [pii]
AID - 10.3390/ijms222111405 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Oct 22;22(21):11405. doi: 10.3390/ijms222111405.