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Bile acid sequestrants activate novel signaling pathways in the kidney and prevent obesity‐induced renal disease (767.10)
Author(s) -
Luo Yuhuan,
Wang Xiaoxin,
Levi Moshe
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.767.10
Subject(s) - medicine , endocrinology , kidney , insulin resistance , diabetes mellitus , chemistry
Bile acid sequestrants (BAS) are orally administered nonabsorbable polymers that decrease serum cholesterol and serum glucose in patients and animal models with type 2 diabetes mellitus. The effects of BAS on renal dysfunction in obesity and insulin resistance or type 2 diabetes mellitus have not been studied. Our goal was to evaluate the effect of BAS on metabolic and renal parameters in diet induced obesity. Our studies were performed in C57BL/6J male mice fed a control low fat (LF) diet (10 kcal% fat) or high fat (HF) diet (60 kcal% fat). The diets were supplemented with a) no addition or b) 2% sevelamer a BAS. Treatment with BAS prevented HF diet induced body weight gain, improved fasting blood glucose and glucose tolerance, and prevented the increases in serum cholesterol as well as insulin and leptin levels in HF mice. BAS prevented the increase in urine albumin excretion and decreased the PAS staining in the kidney of HF mice. Treatment with BAS decreased the renal lipid accumulation as shown by oil red O staining. HF diet induced upregulation of profibrotic genes (TGF‐β, CTGF, and PAI‐1) and proinflammatory genes (MCP‐1, TLR2, and TLR4) in the kidney which were decreased by treatment with BAS. In addition BAS induced downregulation of extracellular matrix protein fibronectin and macrophage marker CD68 expression in the kidney. The beneficial effects of BAS were also associated with decreases in renal gluconeogenic gene expression (PEPCK and G6Pase) and renal glucose transporter (SGLT2). Treatment with BAS also and most notably increased renal expression of Nrf1, SIRT1, PGC‐1a,SIRT3, ERRa, that mediate mitochondrial biogenesis, MCAD and LCAD, that mediate fatty acid oxidation, and Nrf2, HO‐1, and SOD, that mediate anti‐oxidative stress. In summary, our study showed a novel renoprotective role for bile acid sequestrant treatment in mice with diet induced obesity, insulin and leptin resistance. Grant Funding Source : NIH, VA, Genzyme, Daiichi Sankyo