Susceptibility of podocytes to palmitic acid is regulated by stearoyl-CoA desaturases 1 and 2
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Susceptibility of podocytes to palmitic acid is regulated by stearoyl-CoA desaturases 1 and 2. / Sieber, Jonas; Weins, Astrid; Kampe, Kapil; Gruber, Stefan; Lindenmeyer, Maja T; Cohen, Clemens D; Orellana, Jana M; Mundel, Peter; Jehle, Andreas W.
in: AM J PATHOL, Jahrgang 183, Nr. 3, 09.2013, S. 735-44.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Susceptibility of podocytes to palmitic acid is regulated by stearoyl-CoA desaturases 1 and 2
AU - Sieber, Jonas
AU - Weins, Astrid
AU - Kampe, Kapil
AU - Gruber, Stefan
AU - Lindenmeyer, Maja T
AU - Cohen, Clemens D
AU - Orellana, Jana M
AU - Mundel, Peter
AU - Jehle, Andreas W
N1 - Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
PY - 2013/9
Y1 - 2013/9
N2 - Type 2 diabetes mellitus is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are highly susceptible to saturated FFAs but not to protective, monounsaturated FFAs. We report that patients with diabetic nephropathy develop alterations in glomerular gene expression of enzymes involved in fatty acid metabolism, including induction of stearoyl-CoA desaturase (SCD)-1, which converts saturated to monounsaturated FFAs. By IHC of human renal biopsy specimens, glomerular SCD-1 induction was observed in podocytes of patients with diabetic nephropathy. Functionally, the liver X receptor agonists TO901317 and GW3965, two known inducers of SCD, increased Scd-1 and Scd-2 expression in cultured podocytes and reduced palmitic acid-induced cell death. Similarly, overexpression of Scd-1 attenuated palmitic acid-induced cell death. The protective effect of TO901317 was associated with a reduction of endoplasmic reticulum stress. It was lost after gene silencing of Scd-1/-2, thereby confirming that the protective effect of TO901317 is mediated by Scd-1/-2. TO901317 also shifted palmitic acid-derived FFAs into biologically inactive triglycerides. In summary, SCD-1 up-regulation in diabetic nephropathy may be part of a protective mechanism against saturated FFA-derived toxic metabolites that drive endoplasmic reticulum stress and podocyte death.
AB - Type 2 diabetes mellitus is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are highly susceptible to saturated FFAs but not to protective, monounsaturated FFAs. We report that patients with diabetic nephropathy develop alterations in glomerular gene expression of enzymes involved in fatty acid metabolism, including induction of stearoyl-CoA desaturase (SCD)-1, which converts saturated to monounsaturated FFAs. By IHC of human renal biopsy specimens, glomerular SCD-1 induction was observed in podocytes of patients with diabetic nephropathy. Functionally, the liver X receptor agonists TO901317 and GW3965, two known inducers of SCD, increased Scd-1 and Scd-2 expression in cultured podocytes and reduced palmitic acid-induced cell death. Similarly, overexpression of Scd-1 attenuated palmitic acid-induced cell death. The protective effect of TO901317 was associated with a reduction of endoplasmic reticulum stress. It was lost after gene silencing of Scd-1/-2, thereby confirming that the protective effect of TO901317 is mediated by Scd-1/-2. TO901317 also shifted palmitic acid-derived FFAs into biologically inactive triglycerides. In summary, SCD-1 up-regulation in diabetic nephropathy may be part of a protective mechanism against saturated FFA-derived toxic metabolites that drive endoplasmic reticulum stress and podocyte death.
KW - Benzoates
KW - Benzylamines
KW - Carnitine O-Palmitoyltransferase
KW - Cell Death
KW - Cells, Cultured
KW - Diabetic Nephropathies
KW - Fatty Acids, Monounsaturated
KW - Gene Expression Regulation
KW - Gene Knockdown Techniques
KW - Gene Silencing
KW - Humans
KW - Hydrocarbons, Fluorinated
KW - Kidney Glomerulus
KW - Models, Biological
KW - Oxidation-Reduction
KW - Palmitic Acid
KW - Podocytes
KW - Protective Agents
KW - Stearoyl-CoA Desaturase
KW - Sulfonamides
KW - Triglycerides
KW - Journal Article
KW - Research Support, N.I.H., Extramural
KW - Research Support, Non-U.S. Gov't
U2 - 10.1016/j.ajpath.2013.05.023
DO - 10.1016/j.ajpath.2013.05.023
M3 - SCORING: Journal article
C2 - 23867797
VL - 183
SP - 735
EP - 744
JO - AM J PATHOL
JF - AM J PATHOL
SN - 0002-9440
IS - 3
ER -