👤 Michael Kluge

The α-tocopherol-derived long-chain metabolite (α-LCM) α-13'-carboxychromanol (α-13'-COOH) is formed via enzymatic degradation of α-tocopherol (α-TOH) in the liver. In the last decade, α-13'-COOH has emerged as a new regulatory metabolite revealing more potent or even different effects compared with its vitamin precursor α-TOH. The detection of α-13'-COOH in human serum has further strengthened the concept of its physiological relevance as a potential regulatory molecule. Here, we present a new facet on the interaction of α-13'-COOH with macrophage foam cell formation. We found that α-13'-COOH (5 μM) increases angiopoietin-like 4 (ANGPTL4) mRNA expression in human THP-1 macrophages in a time- and dose-dependent manner, while α-TOH (100 μM) showed no effects. Interestingly, the mRNA level of lipoprotein lipase (LPL) was not influenced by α-13'-COOH, but α-TOH treatment led to a reduction of LPL mRNA expression. Both compounds also revealed different effects on protein level: while α-13'-COOH reduced the secreted amount of LPL protein via induction of ANGPTL4 cleavage, i.e. activation, the secreted amount of LPL in the α-TOH-treated samples was diminished due to the inhibition of mRNA expression. In line with this, both compounds reduced the catalytic activity of LPL. However, α-13'-COOH but not α-TOH attenuated VLDL-induced lipid accumulation by 35%. In conclusion, only α-13'-COOH revealed possible antiatherogenic effects due to the reduction of VLDL-induced foam cell formation in THP-1 macrophages. Our results provide further evidence for the role of α-13'-COOH as a functional metabolite of its vitamin E precursor. Show less

Mammalian-wide interspersed repeats (MIRs) are retrotransposed elements of mammalian genomes. Here, we report the specific binding of zinc finger protein ZNF768 to the sequence motif GCTGTGTG (N20) CCTCTCTG in the core region of MIRs. ZNF768 binding is preferentially associated with euchromatin and promoter regions of genes. Binding was observed for genes expressed in a cell type-specific manner in human B cell line Raji and osteosarcoma U2OS cells. Mass spectrometric analysis revealed binding of ZNF768 to Elongator components Elp1, Elp2 and Elp3 and other nuclear factors. The N-terminus of ZNF768 contains a heptad repeat array structurally related to the C-terminal domain (CTD) of RNA polymerase II. This array evolved in placental animals but not marsupials and monotreme species, displays species-specific length variations, and possibly fulfills CTD related functions in gene regulation. We propose that the evolution of MIRs and ZNF768 has extended the repertoire of gene regulatory mechanisms in mammals and that ZNF768 binding is associated with cell type-specific gene expression. Show less