The farnesoid X receptor modulates renal lipid metabolism and diet-induced renal inflammation, fibrosis, and proteinuria

Abstract

Diet-induced obesity is associated with proteinuria and glomerular disease in humans and rodents. We have shown that in mice fed a high-fat diet, increased renal expression of the transcriptional factor sterol-regulatory element binding protein-1 (SREBP-1) plays a critical role in renal lipid accumulation and increases the activity of proinflammatory cytokines and profibrotic growth factors. In the current study, we have determined a key role of the farnesoid X receptor (FXR) in modulating renal SREBP-1 activity, glomerular lesions, and proteinuria. We found that feeding a Western-style diet to DBA/2J mice results in proteinuria, podocyte loss, mesangial expansion, renal lipid accumulation, and increased expression of proinflammatory factors, oxidative stress, and profibrotic growth factors. Treatment of these mice with the highly selective and potent FXR-activating ligand 6-alpha-ethyl-chenodeoxycholic acid (INT-747) ameliorates triglyceride accumulation by modulating fatty acid synthesis and oxidation, improves proteinuria, prevents podocyte loss, mesangial expansion, accumulation of extracellular matrix proteins, and increased expression of profibrotic growth factors and fibrosis markers, and modulates inflammation and oxidative stress. Our results therefore indicate that FXR activation could represent an effective therapy for treatment of abnormal renal lipid metabolism with associated inflammation, oxidative stress, and kidney pathology in patients affected by obesity.

Farnesoid X receptor (FXR) gene deficiency impairs urine concentration in mice

“…The present study demonstrates that the kidney has constitutively high expression of FXR, with a ubiquitous expression pattern along renal tubules, suggesting that FXR may play an important role in renal physiology and pathophysiology. In support, recent studies by Levi Moshe's group have demonstrated that FXR modulates renal lipid metabolism and is involved in the pathogenesis of diabetic nephropathy and represents an attractive therapeutic target for this disease (16,36).…”

Differential regulation of bile acid and cholesterol metabolism by the farnesoid X receptor in Ldlr −/− mice versus hamsters

“…Also, lower doses of 6-ECDCA have been shown to reduce hepatic and/or plasma cholesterol in apoE Ϫ / Ϫ and Western diet-fed DBA/2J mice ( 56,57 ). It is possible then that the adverse effects associated with the higher dose of 6-ECDCA may have counteracted its potential for reducing plasma cholesterol.…”

Transcription Factors Potentially Involved in Regulation of Cytochrome P450 Gene Expression

“…FXR inhibits expression of SREBP-1 (Sterol Regulatory Element-Binding Protein 1) and ChREBP (Carbohydrate Response Element-Binding Protein), transcription factors that regulate gene expression of lipogenic and glycolytic enzymes, especially in the liver and adipose tissue (X. Wang et al, 2009). PPAR regulates renal fatty acid -oxidation, preventing at the same time the accumulation of lipids and lipotoxicity phenomenon, and also controls the formation of foam cells (Rigamonti et al, 2008).…”

“…FXR, through the CYP3A11 gene induction, CYP7A1 gene repression, and induction of expression of ileal bile acid binding protein (IBABP), inhibits the biosynthesis of bile acids and increases their transport from the intestine to the liver. High content of FXR in tissues associated with enterohepatic circulation makes it a regulator of drug distribution in the body (Gnerre et al, 2004;X. Wang et al, 2009 www.intechopen.com LXR, after joining the ligand, heterodimerization with RXR and binding of the complex with the promoter of CYP7 gene coding element of steroid 7 -hydroxylase, acts as a 'sensor' of cholesterol concentration, by stimulating its removal from the liver.…”