Principal Investigator

Awardee Organization

University Of Iowa
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

E-FABP mediates n-3 fatty acid-induced tumor prevention through epigenetic control of immune cell differentiation and function

Despite therapeutic advances, over 600,000 people in the US will die from cancer in 2019. Preventing cancer eliminates the risk of mortality and/or morbidity that may occur with the development of cancer. Thus, cancer prevention represents the most effective way for addressing cancer challenges. Healthy diet is considered be essential to reduce cancer risk by maintaining and improving immunity, but recent VITAL trials did not show beneficial effects of these supplements. The negative results reflect the mechanistic knowledge gap of how dietary factors modulate health. The objectives of this renewal application are to determine cellular and molecular mechanisms by which epithelial fatty acid binding protein (E-FABP) promotes n-3 fatty acidmediated tumor prevention by enhancing immune cell differentiation and anti-tumor activity. Data collected in the last funding cycle have successfully established E-FABP as a new host-derived cancer prevention factor in non-obese subjects. During our studies, we observed that different types of high fat diets (HFD, 45% fat), including cocoa butter (rich in saturated fatty acids, FAs), safflower oil (rich in 18:2 linoleic acid), fish oil (rich in n-3 FAs), all induced similar degree of obesity in mouse models. However, tumor growth in these obese mice was dramatically different with the fastest growth in cocoa butter group and slowest in the fish oil group. In analyzing the immunophenotype of these obese mice, we found an atypical population of CD8+ γδ T cells that was specifically upregulated in the fish oil group. More interestingly, fish oil diet-induced CD8+ γδ T differentiation and anti-tumor effects were blunted in mice lacking E-FABP, suggesting a novel molecular mechanism mediated by E-FABP. Thus, we hypothesized that host expression of E-FABP plays a critical role in n-3 FA-induced immune cell differentiation and anti-tumor function. Three specific aims are proposed to address the central hypothesis in this renewal application. Specific Aim 1 will determine the mechanisms by which E-FABP promotes n-3 FA-induced immune cell differentiation. Experiments are designed to elucidate molecular mechanisms by which consumption of dietary n-3 FAs regulate CD8+ γδ T cell differentiation via EFABP-dependent epigenetic reprogramming. Specific Aim 2 will delineate how E-FABP mediates n-3 FAinduced anti-tumor activity. Results of Aim 2 are expected to reveal that E-FABP promotes host anti-tumor activity through targeting both immune cells and tumor-derived epithelial cells. Specific Aim 3 will evaluate whether targeting E-FABP with optimized n-3 FA diets results in effective tumor prevention. In summary, successful completion of this proposal will offer E-FABP as a new cancer prevention target and have significant mechanistic and clinical implications for healthy diet-mediated cancer prevention.


  • Jin R, Hao J, Yi Y, Sauter E, Li B. Regulation of macrophage functions by FABP-mediated inflammatory and metabolic pathways. Biochimica et biophysica acta. Molecular and cell biology of lipids. 2021 Aug;1866(8):158964. Epub 2021 May 10. PMID: 33984518
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  • Zhang Y, Rao E, Zeng J, Hao J, Sun Y, Liu S, Sauter ER, Bernlohr DA, Cleary MP, Suttles J, Li B. Adipose Fatty Acid Binding Protein Promotes Saturated Fatty Acid-Induced Macrophage Cell Death through Enhancing Ceramide Production. Journal of immunology (Baltimore, Md. : 1950). 2017 Jan 15;198(2):798-807. Epub 2016 Dec 5. PMID: 27920274
  • Li B, Hao J, Yan X, Kong M, Sauter ER. A-FABP and oestrogens are independently involved in the development of breast cancer. Adipocyte. 2019 Dec;8(1):379-385. PMID: 31755351
  • Yan F, Shen N, Pang JX, Zhang YW, Rao EY, Bode AM, Al-Kali A, Zhang DE, Litzow MR, Li B, Liu SJ. Fatty acid-binding protein FABP4 mechanistically links obesity with aggressive AML by enhancing aberrant DNA methylation in AML cells. Leukemia. 2017 Jun;31(6):1434-1442. Epub 2016 Nov 25. PMID: 27885273
  • Zhang Y, Li Q, Rao E, Sun Y, Grossmann ME, Morris RJ, Cleary MP, Li B. Epidermal Fatty Acid binding protein promotes skin inflammation induced by high-fat diet. Immunity. 2015 May 19;42(5):953-964. PMID: 25992864
  • Zhang Y, Hao J, Sun Y, Li B. Saturated Fatty Acids Induce Ceramide-associated Macrophage Cell Death. Journal of visualized experiments : JoVE. 2017 Oct 31;(128). PMID: 29155746
  • Hao J, Zhang Y, Yan X, Yan F, Sun Y, Zeng J, Waigel S, Yin Y, Fraig MM, Egilmez NK, Suttles J, Kong M, Liu S, Cleary MP, Sauter E, Li B. Circulating Adipose Fatty Acid Binding Protein Is a New Link Underlying Obesity-Associated Breast/Mammary Tumor Development. Cell metabolism. 2018 Nov 6;28(5):689-705.e5. Epub 2018 Aug 9. PMID: 30100196
  • Rao E, Singh P, Li Y, Zhang Y, Chi YI, Suttles J, Li B. Targeting epidermal fatty acid binding protein for treatment of experimental autoimmune encephalomyelitis. BMC immunology. 2015 May 12;16:28. PMID: 25962726
  • Liu L, Jin R, Hao J, Zeng J, Yin D, Yi Y, Zhu M, Mandal A, Hua Y, Ng CK, Egilmez NK, Sauter ER, Li B. Consumption of the Fish Oil High-Fat Diet Uncouples Obesity and Mammary Tumor Growth through Induction of Reactive Oxygen Species in Protumor Macrophages. Cancer research. 2020 Jun 15;80(12):2564-2574. Epub 2020 Mar 25. PMID: 32213543
  • Yan F, Shen N, Pang JX, Zhao N, Zhang YW, Bode AM, Al-Kali A, Litzow MR, Li B, Liu SJ. A vicious loop of fatty acid-binding protein 4 and DNA methyltransferase 1 promotes acute myeloid leukemia and acts as a therapeutic target. Leukemia. 2018 Apr;32(4):865-873. Epub 2017 Oct 10. PMID: 28993705
  • Hao J, Jin R, Zeng J, Hua Y, Yorek MS, Liu L, Mandal A, Li J, Zheng H, Sun Y, Yi Y, Yin D, Zheng Q, Li X, Ng CK, Rouchka EC, Egilmez NK, Jabbari A, Li B. Consumption of fish oil high-fat diet induces murine hair loss via epidermal fatty acid binding protein in skin macrophages. Cell reports. 2022 Dec 13;41(11):111804. PMID: 36516778
  • Li B, Hao J, Zeng J, Sauter ER. SnapShot: FABP Functions. Cell. 2020 Aug 20;182(4):1066-1066.e1. PMID: 32822569
  • Zhang Y, Hao J, Zeng J, Li Q, Rao E, Sun Y, Liu L, Mandal A, Landers VD, Morris RJ, Cleary MP, Suttles J, Li B. Epidermal FABP Prevents Chemical-Induced Skin Tumorigenesis by Regulation of TPA-Induced IFN/p53/SOX2 Pathway in Keratinocytes. The Journal of investigative dermatology. 2018 Sep;138(9):1925-1934. Epub 2018 Mar 17. PMID: 29559340
  • Zeng J, Zhang Y, Hao J, Sun Y, Liu S, Bernlohr DA, Sauter ER, Cleary MP, Suttles J, Li B. Stearic Acid Induces CD11c Expression in Proinflammatory Macrophages via Epidermal Fatty Acid Binding Protein. Journal of immunology (Baltimore, Md. : 1950). 2018 May 15;200(10):3407-3419. Epub 2018 Apr 6. PMID: 29626089
  • Jin R, Hao J, Yu J, Wang P, Sauter ER, Li B. Role of FABP5 in T Cell Lipid Metabolism and Function in the Tumor Microenvironment. Cancers. 2023 Jan 20;15. (3). PMID: 36765614
  • Zeng J, Sauter ER, Li B. FABP4: A New Player in Obesity-Associated Breast Cancer. Trends in molecular medicine. 2020 May;26(5):437-440. Epub 2020 Apr 8. PMID: 32359475
  • Yin D, Hao J, Jin R, Yi Y, Bodduluri SR, Hua Y, Anand A, Deng Y, Haribabu B, Egilmez NK, Sauter ER, Li B. Epidermal Fatty Acid‒Binding Protein Mediates Depilatory-Induced Acute Skin Inflammation. The Journal of investigative dermatology. 2022 Jul;142(7):1824-1834.e7. Epub 2021 Dec 21. PMID: 34942197