title: Fenofibrate improves renal lipotoxicity through activation of AMPK-PGC-1α in db/db mice.
abstract: 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.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Korea.
authors.forename: Yu Ah
authors.initials: YA
authors.lastname: Hong
authors.affiliation: Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Ji Hee
authors.initials: JH
authors.lastname: Lim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Min Young
authors.initials: MY
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Yaeni
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Keun Suk
authors.initials: KS
authors.lastname: Yang
authors.affiliation: Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hoon Suk
authors.initials: HS
authors.lastname: Park
authors.affiliation: Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Sun Ryoung
authors.initials: SR
authors.lastname: Choi
authors.affiliation: Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Sungjin
authors.initials: S
authors.lastname: Chung
authors.affiliation: Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hyung Wook
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Department of Rehabilitation Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Bum Soon
authors.initials: BS
authors.lastname: Choi
authors.affiliation: Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Yoon Sik
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Cheol Whee
authors.initials: CW
authors.lastname: Park
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D050171:Dyslipidemias / Q000188:drug therapy* / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology* / Q000627:therapeutic use; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014157:Transcription Factors / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D000960:Hypolipidemic Agents; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019869:Phosphatidylinositol 3-Kinases; D055372:AMP-Activated Protein Kinases; D011345:Fenofibrate