scholarly journals Pre-emptive pharmacological inhibition of fatty acid–binding protein 4 attenuates kidney fibrosis by reprogramming tubular lipid metabolism

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Yuting Chen ◽  
Yue Dai ◽  
Kaixin Song ◽  
Yi Huang ◽  
Le Zhang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Binding Protein ◽  
Kidney Diseases ◽  
Binding Protein ◽  
Acid Oxidation ◽  
Fatty Acid Binding ◽  
Kidney Fibrosis ◽  
Pharmacological Inhibition ◽  
Acid Binding Protein

AbstractKidney fibrosis is a hallmark of chronic kidney disease (CKD) progression that is caused by tubular injury and dysregulated lipid metabolism. Genetic abolition fatty acid-binding protein 4 (FABP4), a key lipid transporter, has been reported to suppress kidney interstitial fibrosis. However, the role and underlying mechanism of chemical inhibition of FABP4 in fibrotic kidney have not been well-documented. Here, we examined preemptive the effect of a FABP4 inhibitor, BMS309403, on lipid metabolism of tubular epithelial cells (TECs) and progression of kidney fibrosis. The expression of FABP4 was significantly elevated, concomitated with the accumulation of lipid droplets in TECs during kidney fibrosis. Treatment with BMS309403 alleviated lipid deposition of TECs, as well as interstitial fibrotic responses both in unilateral ureteral obstruction (UUO)-engaged mice and TGF-β-induced TECs. Moreover, BMS309403 administration enhanced fatty acid oxidation (FAO) in TECs by regulating peroxisome proliferator-activated receptor γ (PPARγ) and restoring FAO-related enzyme activities; In addition, BMS309403 markedly reduced cell lipotoxicity, such as endoplasmic reticulum (ER) stress and apoptosis in fibrotic kidney. Taken together, our results suggest that preemptive pharmacological inhibition of FABP4 by BMS309403 rebalances abnormal lipid metabolism in TECs and attenuates the progression of kidney fibrosis, thus may hold therapeutic potential for the treatment of fibrotic kidney diseases.

Role of Fatty Acid Binding Protein 4 (FABP4) in Kidney Disease

2020 ◽  
Vol 27 (22) ◽  
pp. 3657-3664 ◽  
Author(s):  
Min Shi ◽  
Liang Ma ◽  
Ping Fu
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Binding Protein ◽  
Current Knowledge ◽  
Kidney Diseases ◽  
Binding Protein ◽  
Experimental Studies ◽  
Protective Effects ◽  
Fatty Acid Binding ◽  
Acid Binding Protein

Accumulating evidences indicated that obesity and metabolic syndrome were independent risk factors for the development and progression of kidney diseases. Apart from inflammation, lipotoxicity, and hemodynamic factors, adipokines have been proposed to play crucial roles in the relationship between kidney diseases and metabolic disorders. As one of the key adipokines, fatty acid binding protein 4 (FABP4), which is mainly expressed in adipocytes and macrophages, has recently been shown to be associated with renal dysfunction and kidney damage. Both clinical and experimental studies have proposed circulating FABP4 as a novel predictor for renal injuries, and it might also be a predictor for cardiovascular events in patients with end stage renal disease (ESRD). FABP4 has also been detected in the glomerular cells and epithelial tubular cells in mouse and human kidneys, and the expression of FABP4 in these cells has been involved in the pathogenesis of kidney diseases. In addition, experimental studies suggested that inhibition of FABP4 had protective effects on renal damage. Here, we reviewed current knowledge regarding the role of FABP4 in pathophysiological insights as well as its potential function as a predictor and therapeutic target for kidney diseases.

scholarly journals The involvement of fatty acid binding protein in peroxisomal fatty acid oxidation

FEBS Letters ◽  
1990 ◽  
Vol 267 (2) ◽  
pp. 229-230 ◽  
Author(s):  
F.A.G. Reubsaet ◽  
J.H. Veerkamp ◽  
M.L.P. Brückwilder ◽  
J.M.F. Trijbels ◽  
L.A.H. Monnens
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fatty Acid Binding Protein ◽  
Binding Protein ◽  
Acid Oxidation ◽  
Fatty Acid Binding ◽  
Acid Binding Protein ◽  
Peroxisomal Fatty Acid Oxidation ◽  
Peroxisomal Fatty Acid

Role of fatty acid-binding protein in lipid metabolism of insect flight muscle

1993 ◽  
Vol 123 (1-2) ◽  
pp. 145-152 ◽  
Author(s):  
Dick J. van der Horst ◽  
Jan M. van Doorn ◽  
Paul C. C. M. Passier ◽  
Michael M. Vork ◽  
Jan F. C. Glatz
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Binding Protein ◽  
Flight Muscle ◽  
Insect Flight ◽  
Binding Protein ◽  
Insect Flight Muscle ◽  
Fatty Acid Binding ◽  
Acid Binding Protein

Role of fatty acid-binding protein in lipid metabolism of insect flight muscle

1993 ◽  
pp. 145-152
Author(s):  
Dick J. van der Horst ◽  
Jan M. van Doorn ◽  
Paul C. C. M. Passier ◽  
Michael M. Vork ◽  
Jan F. C. Glatz
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Binding Protein ◽  
Flight Muscle ◽  
Insect Flight ◽  
Binding Protein ◽  
Insect Flight Muscle ◽  
Fatty Acid Binding ◽  
Acid Binding Protein

Adipocyte Fatty Acid Binding Protein Promotes Multiple Myeloma through Regulating Bone Marrow Microenvironment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-32
Author(s):  
Lingling Shu ◽  
Jinyuan Li ◽  
Weida Wang ◽  
Xiaoping Wu ◽  
Hanying Huang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Binding Protein ◽  
Binding Protein ◽  
Bone Marrow Microenvironment ◽  
Fatty Acid Binding ◽  
Myeloma Cells ◽  
Acid Binding Protein

Multiple myeloma (MM) is a plasma cell malignancy in bone marrow, which often occurs in middle-aged and elderly people and also obese patients. Aging and obesity can lead to the ectopic accumulation of adipocytes in bone marrow, which can cause the change of bone marrow microenvironment. Bone marrow adipocyte (BMA) displays distinct immune regulatory properties rather than provides energy substrates. Despite BMA accounts for 70% of the entire volume of bone marrow microenvironment, while the mechanisms still remain elusive. The present study aims to investigate the precise mechanism of BMA promoting myeloma pathogenesis and new potential therapeutic strategies targeting bone marrow microenvironment. Newly diagnosed MM patients and their relative healthy control in our cancer center were recruited. We found that the quantity of BMA increased significantly in multiple myeloma patients, accompanied with the elevated level of adipocyte fatty acid binding protein (A-FABP) by flow cytometry and immunohistochemistry staining. A-FABP is a fatty acid chaperone, which abundantly expressed in adipocytes, playing a critical role in lipid metabolism and immune response. To further explore the role of A-FABP in the pathogenesis of MM, A-FABP knockout (KO) mice and their wide type (WT) littermates were employed and fed with stand chow or high fat diet (HFD). Tumor burden and MM-related osteolytic lesions were significantly lower in A-FABP KO mice comparing to their WT littermates fed with HFD. It was observed that A-FABP deficiency did not change the content of BMA in bone marrow, but cytokines levels in bone marrow such as TNFα, IL-6, RANKL, DPP4 were significantly reduced. The infiltration and pro-inflammatory polarization (M1/M2) of macrophages (MΦ) decreased significantly. Moreover, A-FABP promotes the expression of Th1 and Th17 cells, while the percentage of Th2 and Treg cells are significantly declined. Furthermore, pharmacological inhibition of A-FABP by administration BMS309403 also alleviates the invasion and metastasis of MM in mouse. In addition, co-culture of myeloma cells with pharmacological inhibition or genetic depletion of A-FABP in adipocytes significantly decreased the uptake of free fatty acid and oxygen consumption of myeloma cells. In conclusion, A-FABP increased in BMA in response to aging or obesity, remodeled the energy and lipid metabolism of myeloma cells, and manipulated bone marrow microenvironment to a pro-tumor environment, promoting the proliferation and migration of myeloma cells. This study will shed light on the potential of A-FABP specific inhibitor BMS309403 as the therapeutic strategy of multiple myeloma targeting bone marrow microenvironment. Disclosures No relevant conflicts of interest to declare.

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