PMID- 24726883
OWN - NLM
STAT- MEDLINE
DCOM- 20140724
LR  - 20220318
IS  - 0006-3002 (Print)
IS  - 0006-3002 (Linking)
VI  - 1842
IP  - 7
DP  - 2014 Jul
TI  - Fatty acids are novel nutrient factors to regulate mTORC1 lysosomal localization 
      and apoptosis in podocytes.
PG  - 1097-108
LID - S0925-4439(14)00088-X [pii]
LID - 10.1016/j.bbadis.2014.04.001 [doi]
AB  - Podocyte apoptosis is a potent mechanism of proteinuria in diabetic nephropathy. 
      More detailed mechanistic insight into podocyte apoptosis is needed to better 
      understand the pathogenesis of diabetic nephropathy. An elevated level of serum 
      free fatty acid (FFA), as well as hyperglycemia, is a clinical characteristic in 
      diabetes, although its causal role in podocyte apoptosis remains unclear. This 
      study examined the effect of three types of FFAs, saturated, monounsaturated and 
      polyunsaturated FFAs, on podocyte apoptosis. Palmitate, a saturated FFA, induced 
      endoplasmic reticulum (ER) stress-dependent apoptosis in podocytes. Oleate, a 
      monounsaturated FFA, and eicosapentaenoic acid (EPA), an omega-3 polyunsaturated FFA 
      did not induce apoptosis; rather, they antagonized palmitate-induced apoptosis. 
      Palmitate activated mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a 
      nutrient-sensing kinase regulating a wide range of cell biology. Furthermore, 
      inhibition of mTORC1 activity by rapamycin or siRNA for Raptor, a component of 
      mTORC1, ameliorated palmitate-induced ER stress and apoptosis in podocytes. 
      Activity of mTORC1 is regulated by upstream kinases and Rag/Ragulator-dependent 
      recruitment of mTOR onto lysosomal membranes. Palmitate activated mTORC1 by 
      enhancing recruitment of mTOR onto lysosomal membranes, which was inhibited by 
      co-incubation with oleate or EPA. Inhibition of mTOR translocation onto lysosomes 
      by transfection with dominant-negative forms of Rag ameliorated palmitate-induced 
      apoptosis. This study suggests that saturated and unsaturated FFAs have opposite 
      effects on podocyte apoptosis by regulating mTORC1 activity via its translocation 
      onto lysosomal membranes, and the results provide a better understanding of the 
      pathogenesis in diabetic nephropathy and a novel role of mTORC1 in cell 
      apoptosis.
CI  - Copyright (c) 2014 Elsevier B.V. All rights reserved.
FAU - Yasuda, Mako
AU  - Yasuda M
AD  - Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
FAU - Tanaka, Yuki
AU  - Tanaka Y
AD  - Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
FAU - Kume, Shinji
AU  - Kume S
AD  - Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan. 
      Electronic address: skume@belle.shiga-med.ac.jp.
FAU - Morita, Yoshikata
AU  - Morita Y
AD  - Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
FAU - Chin-Kanasaki, Masami
AU  - Chin-Kanasaki M
AD  - Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
FAU - Araki, Hisazumi
AU  - Araki H
AD  - Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
FAU - Isshiki, Keiji
AU  - Isshiki K
AD  - Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
FAU - Araki, Shin-ichi
AU  - Araki S
AD  - Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
FAU - Koya, Daisuke
AU  - Koya D
AD  - Division of Diabetology and Endocrinology, Kanazawa Medical University, 
      Kahoku-Gun, Ishikawa, Japan.
FAU - Haneda, Masakazu
AU  - Haneda M
AD  - Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
FAU - Kashiwagi, Atsunori
AU  - Kashiwagi A
AD  - Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
FAU - Maegawa, Hiroshi
AU  - Maegawa H
AD  - Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
FAU - Uzu, Takashi
AU  - Uzu T
AD  - Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140413
PL  - Netherlands
TA  - Biochim Biophys Acta
JT  - Biochimica et biophysica acta
JID - 0217513
RN  - 0 (Fatty Acids)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Palmitates)
RN  - 2UMI9U37CP (Oleic Acid)
RN  - AAN7QOV9EA (Eicosapentaenoic Acid)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Apoptosis/*physiology
MH  - Cell Line
MH  - Diabetic Nephropathies/metabolism
MH  - Eicosapentaenoic Acid/metabolism
MH  - Endoplasmic Reticulum Stress/physiology
MH  - Fatty Acids/*metabolism
MH  - Food
MH  - HEK293 Cells
MH  - Humans
MH  - Lysosomes/*metabolism
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Multiprotein Complexes/*metabolism
MH  - Oleic Acid/metabolism
MH  - Palmitates/metabolism
MH  - Podocytes/*metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
OTO - NOTNLM
OT  - Diabetic nephropathy
OT  - Free fatty acid
OT  - Lysosome
OT  - Podocyte apoptosis
OT  - mTORC1
EDAT- 2014/04/15 06:00
MHDA- 2014/07/25 06:00
CRDT- 2014/04/15 06:00
PHST- 2013/09/25 00:00 [received]
PHST- 2014/03/03 00:00 [revised]
PHST- 2014/04/02 00:00 [accepted]
PHST- 2014/04/15 06:00 [entrez]
PHST- 2014/04/15 06:00 [pubmed]
PHST- 2014/07/25 06:00 [medline]
AID - S0925-4439(14)00088-X [pii]
AID - 10.1016/j.bbadis.2014.04.001 [doi]
PST - ppublish
SO  - Biochim Biophys Acta. 2014 Jul;1842(7):1097-108. doi: 
      10.1016/j.bbadis.2014.04.001. Epub 2014 Apr 13.