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

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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Bone Marrow Adipocyte Shapes Metabolism and Immunity in Tumor Microenvironment to Promote Multiple Myeloma

Blood ◽

10.1182/blood-2021-150208 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 892-892

Author(s):

Lingling Shu ◽

Jinyuan Li ◽

Shuzhao Chen ◽

Han-Ying Huang ◽

Yang Li ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Fatty Acid ◽

Lipid Metabolism ◽

Lipid Binding ◽

Bone Marrow Microenvironment ◽

Acid Uptake ◽

Fatty Acid Binding ◽

Myeloma Cells

Abstract Multiple myeloma (MM) often occurs in middle-aged, elderly and obese patients with ectopic accumulation of fat cells in the bone marrow. Bone marrow adipocytes (BMAs) display unique immunomodulatory properties instead of simply providing energy substrates, which can cause distinct change of bone marrow microenvironment. Although BMA accounts for 70% of the total volume of bone marrow, the mechanism on how BMA affects tumor progression remains elusive. This study aims to explore the pathogenesis of BMA in promoting myeloma and new potential treatment strategies targeting bone marrow microenvironment. Newly diagnosed MM patients in our cancer center and their relative healthy controls are recruited. A significant increase of BMA quantity in multiple myeloma patients was observed. Moreover, analysis of transcriptome sequencing data of BMA derived from MM patients demonstrated a distinctive gene expression profiles (Fig A). It worth to note that, expression of fatty acid-binding protein 4 (FABP4, also known as A-FABP or aP2), a member of the FABP family abundantly expressed in adipocytes, functions as a lipid-binding chaperone that regulates trafficking and cellular signaling of fatty acids, and plays an important role in linking lipid metabolism with immunity and inflammation, was increased significantly in BMA of MM patients (Fig B). To further explore the role of FABP4 in pathogenesis in MM, FABP4 knockout (KO) mice and their wide-type (WT) littermates were adopted, and fed with standard chow (STC) or high-fat diet (HFD, 45 kcal % Fat, D12451). FABP4 deficiency significantly attenuated the tumor burden and MM-related osteolytic lesions in mice fed with HFD (Fig C-D). Moreover, levels of pro-inflammatory cytokines including TNFα, IL-6, RANKL and DPP4 were significantly reduced in FABP4 deficient adipocytes (Fig E). Flow cytometry analysis showed that the infiltration and pro-inflammatory polarization (M1/M2) of macrophages (MΦ) decreased significantly in FABP4 KO bone marrow (Fig F). In addition, FABP4 promoted the infiltration of Th1 and Th17 cells, while impaired the recruitment of Th2 and Treg cells (Fig G). Furthermore, administration of exogenous FABP4 recombinant protein significantly increased the fatty acid uptake and oxygen consumption of myeloma cells (Fig H). In contrast, pharmacological inhibition of FABP4 with BMS309403 alleviated the invasion and metastasis of MM in mice fed with HFD (Fig I-J). In summary, BMA increased in MM patients, reshapes the metabolism and immunity in bone marrow microenvironment through regulating FABP4 functions. FABP4 enhanced the energy and lipid metabolism of myeloma cells, and manipulated the bone marrow microenvironment to pro-tumor environment, therefore promoted the proliferation and migration of myeloma cells. This study will not only clarify the critical role of BMA in MM pathogenesis, but also provide therapeutic potential of FABP4 selective inhibitor BMS309403 for multiple myeloma treatment, especially for obese MM patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Effect of liver fatty acid binding protein (L-FABP) gene ablation on lipid metabolism in high glucose diet (HGD) pair-fed mice

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ◽

10.1016/j.bbalip.2019.03.009 ◽

2019 ◽

Vol 1864 (7) ◽

pp. 985-1004 ◽

Cited By ~ 5

Author(s):

Avery L. McIntosh ◽

Barbara P. Atshaves ◽

Gregory G. Martin ◽

Danilo Landrock ◽

Sherrelle Milligan ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

High Glucose ◽

Fatty Acid Binding Protein ◽

Binding Protein ◽

Liver Fatty Acid ◽

Fatty Acid Binding ◽

Acid Binding Protein ◽

Gene Ablation ◽

Fabp Gene

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

Molecular and Cellular Biochemistry ◽

10.1007/bf01076486 ◽

1993 ◽

Vol 123 (1-2) ◽

pp. 145-152 ◽

Cited By ~ 30

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

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

Cell Death and Disease ◽

10.1038/s41419-021-03850-1 ◽

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.

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

Cellular Fatty Acid-Binding Proteins II ◽

10.1007/978-1-4615-3096-1_19 ◽

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

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Localization of a portion of the liver isoform of fatty-acid-binding protein (L-FABP) to peroxisomes

Biochemical Journal ◽

10.1042/bj20051058 ◽

2006 ◽

Vol 394 (2) ◽

pp. 475-484 ◽

Cited By ~ 27

Author(s):

Vasily D. Antonenkov ◽

Raija T. Sormunen ◽

Steffen Ohlmeier ◽

Leen Amery ◽

Marc Fransen ◽

...

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Binding Protein ◽

Binding Capacity ◽

Binding Protein ◽

Matrix Proteins ◽

Protein L ◽

Fatty Acid Binding ◽

Acid Binding Protein

The liver isoform of fatty-acid-binding protein (L-FABP) facilitates the cellular uptake, transport and metabolism of fatty acids and is also involved in the regulation of gene expressions and cell differentiation. Consistent with these functions, L-FABP is predominantly present in the cytoplasm and to a lesser extent in the nucleus; however, a significant portion of this protein has also been detected in fractions containing different organelles. More recent observations, notably on L-FABP-deficient mice, indicated a possible direct involvement of L-FABP in the peroxisomal oxidation of long-chain fatty acids. In order to clarify the links between L-FABP and peroxisomal lipid metabolism, we reinvestigated the subcellular distribution of the protein. Analytical subcellular fractionation by a method preserving the intactness of isolated peroxisomes, two-dimensional gel electrophoresis of peroxisomal matrix proteins combined with MS analysis, and immunoelectron microscopy of liver sections demonstrate the presence of L-FABP in the matrix of peroxisomes as a soluble protein. Peroxisomal L-FABP was highly inducible by clofibrate. The induction of L-FABP was accompanied by a marked increase in the binding capacity of peroxisomal matrix proteins for oleic acid and cis-parinaric acid. The peroxisomal β-oxidation of palmitoyl-CoA and acyl-CoA thioesterase activity were stimulated by L-FABP, indicating that the protein modulates the function of peroxisomal lipid-metabolizing enzymes. The possible role of intraperoxisomal L-FABP in lipid metabolism is discussed.

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