[HTML][HTML] Fenofibrate Improves Renal Lipotoxicity through Activation of AMPK-PGC-1α in db/db Mice

YA Hong, JH Lim, MY Kim, TW Kim, Y Kim, KS Yang… - PloS one, 2014 - journals.plos.org
YA Hong, JH Lim, MY Kim, TW Kim, Y Kim, KS Yang, HS Park, SR Choi, S Chung, HW Kim…
PloS one, 2014journals.plos.org
Peroxisome proliferator-activated receptor (PPAR)-α, a lipid-sensing transcriptional factor,
serves an important role in lipotoxicity. We evaluated whether fenofibrate has a
renoprotective effect by ameliorating lipotoxicity in the kidney. Eight-week-old male
C57BLKS/J db/m control and db/db mice, divided into four groups, received fenofibrate for
12 weeks. In db/db mice, fenofibrate ameliorated albuminuria, mesangial area expansion
and inflammatory cell infiltration. Fenofibrate inhibited accumulation of intra-renal free fatty …
Peroxisome proliferator-activated receptor (PPAR)-α, a lipid-sensing transcriptional factor, serves an important role in lipotoxicity. We evaluated whether fenofibrate has a renoprotective effect by ameliorating lipotoxicity in the kidney. Eight-week-old male C57BLKS/J db/m control and db/db mice, divided into four groups, received fenofibrate for 12 weeks. In db/db mice, fenofibrate ameliorated albuminuria, mesangial area expansion and inflammatory cell infiltration. Fenofibrate inhibited accumulation of intra-renal free fatty acids and triglycerides related to increases in PPARα expression, phosphorylation of AMP-activated protein kinase (AMPK), and activation of Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-estrogen-related receptor (ERR)-1α-phosphorylated acetyl-CoA carboxylase (pACC), and suppression of sterol regulatory element-binding protein (SREBP)-1 and carbohydrate regulatory element-binding protein (ChREBP)-1, key downstream effectors of lipid metabolism. Fenofibrate decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and FoxO3a phosphorylation in kidneys, increasing the B cell leukaemia/lymphoma 2 (BCL-2)/BCL-2-associated X protein (BAX) ratio and superoxide dismutase (SOD) 1 levels. Consequently, fenofibrate recovered from renal apoptosis and oxidative stress, as reflected by 24 hr urinary 8-isoprostane. In cultured mesangial cells, fenofibrate prevented high glucose-induced apoptosis and oxidative stress through phosphorylation of AMPK, activation of PGC-1α-ERR-1α, and suppression of SREBP-1 and ChREBP-1. Our results suggest that fenofibrate improves lipotoxicity via activation of AMPK-PGC-1α-ERR-1α-FoxO3a signaling, showing its potential as a therapeutic modality for diabetic nephropathy.
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