FABP7 Regulates Acetyl-CoA Metabolism Through the Interaction with ACLY in the Nucleus of Astrocytes

Abstract

Fatty acid binding protein 7 (FABP7) is an intracellular fatty acid chaperon that is highly expressed in astrocytes, oligodendrocyte-precursor cells, and malignant glioma. Previously, we reported that FABP7 regulates the response to extracellular stimuli by controlling the expression of caveolin-1, an important component of lipid raft. Here, we explored the detailed mechanisms underlying FABP7 regulation of caveolin-1 expression using primary cultured FABP7-KO astrocytes as a model of loss of function and NIH-3T3 cells as a model of gain of function. We discovered that FABP7 interacts with ATP-citrate lyase (ACLY) and is important for acetyl-CoA metabolism in the nucleus. This interaction leads to epigenetic regulation of several genes, including caveolin-1. Our novel findings suggest that FABP7-ACLY modulation of nuclear acetyl-CoA has more influence on histone acetylation than cytoplasmic acetyl-CoA. The changes to histone structure may modify caveolae-related cell activity in astrocytes and tumors, including malignant glioma.

Glioma glycolipid metabolism: MSI2–SNORD12B–FIP1L1–ZBTB4 feedback loop as a potential treatment target

“…[24][25][26] A recent study demonstrated that ACLY expression is significantly upregulated in GBM cells and that it participates in the regulation of energy metabolism and cell proliferation. 27,28 In this study, we explored the endogenous expression of MSI2, SNORD12B, and ZBTB4 in GBM tissues and cells. Further, we evaluated the interactive model of these molecules and clarified their roles in glycolipid metabolism and the proliferation of GBM cells.…”

“…ACLY is generally overexpressed in tumor cells, and its knockdown inhibits lipid synthesis in lung and prostate cancer cells, as well as tumor growth 24–26 . A recent study demonstrated that ACLY expression is significantly upregulated in GBM cells and that it participates in the regulation of energy metabolism and cell proliferation 27,28 …”

Nuclear FABP7 regulates cell proliferation of wild‐type IDH1 glioma through caveolae formation

“…So far, the functional significance of lipid rafts or their related proteins in the regulation of tumor cell biology have Nuclear acetyl-CoA, generated by the citrate-ACLY pathway, is an essential molecule for signaling and epigenetics, acting as an acetyl donor for histone lysine acetylation [41,42]. Previously, we demonstrated that FABP7 interacts with ACLY and regulates nuclear acetyl-CoA levels in astrocytes [15]. In this study, we have explored the role of FABP7 in the production of nuclear acetyl-CoA in pathophysiological condition.…”

“…Chromatin immunoprecipitation was performed as reported previously [ 15 ]. The relative levels of histone modifications of each target sequence were analyzed by qPCR using SYBR® Premix Ex Taq™ II (Takara) and Light Cycler 1.5® Carousel‐based system (Roche).…”

“…Previously, we found that FABP7 in astrocytes controls the function of caveolae, which are the main source of cellular activity in response to external stimuli, via regulating the expression of caveolin‐1, a specific scaffold protein in caveolae [ 14 ]. Further mechanistic analysis revealed that nuclear FABP7 in astrocytes regulates nuclear acetyl‐CoA production via interacting with ATP citrate lyase (ACLY), followed by epigenetically controlling caveolin‐1 expression [ 15 ]. These results suggest that nuclear FABP7‐regulated caveolae function may influence cellular activity in physiological astrocytes and possibly in pathophysiological tumors.…”