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BACKGROUND: Tuberous sclerosis complex (TSC) is a multisystem hamartomatous disease caused by inactivating mutations in the TSC1/TSC2 genes leading to hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) in TSC tumors. Novel therapeutic regimens and imaging biomarkers remain critical unmet needs in TSC. Mitochondrial fatty acid oxidation (FAO) is a major cellular source of acetyl-CoA. Acetyl-CoA is a central metabolite in lipid anabolism and catabolism. The purpose of this study was to identify novel metabolic therapeutic targets, particularly involving lipid metabolism, to achieve durable responses in TSC. METHODS AND RESULTS: Fluoroacetate (FACE), an acetate derivative, is a surrogate biomarker of mitochondrial activity. It accumulates in the mitochondria without being oxidized to CO2, and it is converted to fluorocitrate, irreversibly inhibiting the TCA (tricarboxylic acid) cycle enzyme aconitase. Micro-positron emission tomography (PET) imaging of subcutaneous xenografts of TSC2-deficient Eker rat uterine leiomyoma-derived ELT3 cells showed rapid uptake of [18F]FACE that was maintained after 72-hour treatment with mTORC1 inhibitor rapamycin. This result suggests that mitochondrial oxidative metabolism is sustained in the presence of rapamycin. Consistent with this finding, treatment of TSC2-deficient cells with rapamycin led to a significant increase in FAO and a decrease in glucose oxidation in vitro as measured by a 14C-CO2 collection metabolic assay. Expression of the A isoform of carnitine palmitoyltransferase I (CPT1A; FAO rate-limiting enzyme) was selectively increased in TSC2-deficient cells. Pharmacological inhibition of CPT1A by ST1326 led to a decrease in FAO, as measured by a 14C-CO2 collection metabolic assay, and a decrease in mitochondrial ATP production, measured by the Seahorse analyzer. CONCLUSIONS: This study proposes a role for FAO in TSC tumor bioenergetics and for CPT1A as a potential therapeutic target in TSC.

acase@tulane.edu / TAp63, a member of the p53 family, has been shown to regulate energy metabolism. Here, we report coiled coil domain-containing 3 (CCDC3) as a new TAp63 target. TAp63, but not ΔNp63, p53 or p73, induces the expression of CCDC3 mRNA level by directly binding to the p63 consensus DNA binding sequence within the CCDC3 enhancer region. The CCDC3 expression is markedly reduced in TAp63-null mouse embryonic fibroblasts and brown adipose tissues and by tumor necrosis factor alpha that reduces p63 transcriptional activity but induced by metformin, an anti-diabetic drug that activates p63. Also, the expression of CCDC3 is positively correlated with TAp63 levels, but inversely with ΔNp63 levels, during adipocyte differentiation. Interestingly, CCDC3, as a secreted protein, targets liver cancer cells and increases long chain polyunsaturated fatty acids, but decreases ceramide in the cells. CCDC3 alleviates glucose intolerance, insulin resistance, and fatty liver (steatosis) formation in transgenic CCDC3 mice on the high-fat diet by markedly reducing hepatic PPARγ expression and consequently leading to a drastic decrease of the PPARγ target gene, CIDEA, and other genes involved in de novo lipogenesis and of lipid droplets formation in their livers. Similar results are reproduced by hepatic expression of ectopic CCDC3 in mice on high-fat diet. Altogether, these results demonstrate that CCDC3 modulates liver lipid metabolism by inhibiting liver de novo lipogenesis as a downstream player of the p63 network. / 1 / Wenjuan Liao

Thesis (doctoral)--Universitetet i Lund. / Reprints of journal articles inserted in pocket on back cover.