PMID- 33052067
OWN - NLM
STAT- MEDLINE
DCOM- 20210107
LR  - 20211204
IS  - 1522-1563 (Electronic)
IS  - 0363-6143 (Print)
IS  - 0363-6143 (Linking)
VI  - 319
IP  - 6
DP  - 2020 Dec 1
TI  - Inositol-requiring enzyme 1alpha links palmitate-induced mTOR activation and 
      lipotoxicity in hepatocytes.
PG  - C1130-C1140
LID - 10.1152/ajpcell.00165.2020 [doi]
AB  - Hepatic lipotoxicity, hepatocyte dysfunction/cell death induced by saturated 
      fatty acids (SFA), plays a central role in the pathogenesis of nonalcoholic fatty 
      liver disease (NAFLD); however, the underlying mechanisms remain unclear. 
      Palmitate is the most abundant SFA in the circulation. In this study, via a 
      small-scale screening of chemical inhibitors using AML12 hepatocytes, we 
      identified mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) to be a 
      culprit in palmitate-induced cell death in hepatocytes in that mTOR inhibition is 
      protective against palmitate-induced cell death. The protective effect of mTORC1 
      inhibition is independent of autophagy induction, as autophagy inhibition failed 
      to ablate the mTORC1 inhibitor-conferred protection. We have previously reported 
      that the endonuclease activity of inositol-requiring enzyme 1alpha (IRE1alpha), one of 
      three canonical signaling pathways of endoplasmic reticulum (ER) stress, was 
      implicated in palmitate-induced cell death in hepatocytes. The continuous 
      mechanistic investigation in this study uncovered that IRE1alpha is a downstream 
      target of mTORC1 activation upon palmitate exposure and the inhibition of either 
      its endonuclease activity or kinase activity protects against the lipotoxic 
      effect of palmitate. Our research further revealed that protein palmitoylation is 
      potentially involved in palmitate-induced mTORC1 activation and lipotoxicity in 
      hepatocytes. 2-Bromopalmitate, a protein palmitoylation inhibitor, ameliorated 
      palmitate-triggered mTORC1 activation, concomitant with the protection of 
      lipotoxicity in hepatocytes. Collectively, our data have identified that mTORC1 
      and ER stress are coordinately implicated in hepatocyte cell death in response to 
      palmitate exposure and suggest that this pathway may potentially serve as a 
      therapeutic target for the treatment of NAFLD as well as other metabolic 
      disorders involving lipotoxicity.
FAU - Chen, Yingli
AU  - Chen Y
AD  - Department of Kinesiology and Nutrition, University of Illinois at Chicago, 
      Chicago, Illinois.
AD  - College of Medical Laboratory Science and Technology, Harbin Medical University 
      (Daqing), Daqing, Heilongjiang, People's Republic of China.
FAU - Griffiths, Alexandra
AU  - Griffiths A
AD  - Department of Kinesiology and Nutrition, University of Illinois at Chicago, 
      Chicago, Illinois.
FAU - Wang, Jun
AU  - Wang J
AD  - Department of Kinesiology and Nutrition, University of Illinois at Chicago, 
      Chicago, Illinois.
AD  - Department of Gastroenterology, Tongji Medical College and Central Hospital of 
      Wuhan, Huazhong University of Science and Technology, Wuhan, Hubei, People's 
      Republic of China.
FAU - Zhang, Tingting
AU  - Zhang T
AD  - Department of Urology, Daqing Oilfield General Hospital, Daqing, Heilongjiang, 
      People's Republic of China.
FAU - Song, Qing
AU  - Song Q
AD  - Department of Kinesiology and Nutrition, University of Illinois at Chicago, 
      Chicago, Illinois.
FAU - Song, Zhenyuan
AU  - Song Z
AD  - Department of Kinesiology and Nutrition, University of Illinois at Chicago, 
      Chicago, Illinois.
LA  - eng
GR  - R01 AA026603/AA/NIAAA NIH HHS/United States
GR  - R21 AA025363/AA/NIAAA NIH HHS/United States
GR  - R21AA025363/NIH-NIAAA/International
GR  - R01AA026603/NIH-NIAAA/International
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20201014
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Palmitates)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (ERN1 protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.- (Endoribonucleases)
SB  - IM
MH  - Animals
MH  - Apoptosis/*physiology
MH  - Autophagy/physiology
MH  - Cell Line, Tumor
MH  - Endoplasmic Reticulum/pathology
MH  - Endoplasmic Reticulum Stress/*physiology
MH  - Endoribonucleases/*metabolism
MH  - Hep G2 Cells
MH  - Hepatocytes/*metabolism
MH  - Humans
MH  - Liver/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1/*metabolism
MH  - Mice
MH  - Non-alcoholic Fatty Liver Disease/pathology
MH  - Palmitates/*pharmacology
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC7792676
OTO - NOTNLM
OT  - ER stress
OT  - IRE1alpha
OT  - NAFLD
OT  - autophagy
OT  - lipotoxicity
OT  - mTORC1
COIS- No conflicts of interest, financial or otherwise, are declared by the authors.
EDAT- 2020/10/15 06:00
MHDA- 2021/01/08 06:00
PMCR- 2021/12/01
CRDT- 2020/10/14 12:43
PHST- 2020/10/15 06:00 [pubmed]
PHST- 2021/01/08 06:00 [medline]
PHST- 2020/10/14 12:43 [entrez]
PHST- 2021/12/01 00:00 [pmc-release]
AID - C-00165-2020 [pii]
AID - 10.1152/ajpcell.00165.2020 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2020 Dec 1;319(6):C1130-C1140. doi: 
      10.1152/ajpcell.00165.2020. Epub 2020 Oct 14.