Zac1 and the Imprinted Gene Network program juvenile NAFLD in response to maternal metabolic syndrome.

BACKGROUND AND AIMS: Within the next decade, NAFLD is predicted to become the most prevalent cause of childhood liver failure in developed countries. Predisposition to juvenile NAFLD can be programmed during early life in response to maternal metabolic syndrome (MetS), but the underlying mechanisms are poorly understood. We hypothesized that imprinted genes, defined by expression from a single parental allele, play a key role in maternal MetS-induced NAFLD, due to their susceptibility to environmental stressors and their functions in liver homeostasis. We aimed to test this hypothesis and determine the critical periods of susceptibility to maternal MetS. APPROACH AND RESULTS: We established a mouse model to compare the effects of MetS during prenatal and postnatal development on NAFLD. Postnatal but not prenatal MetS exposure is associated with histological, biochemical, and molecular signatures of hepatic steatosis and fibrosis in juvenile mice. Using RNA sequencing, we show that the Imprinted Gene Network (IGN), including its regulator Zac1, is up-regulated and overrepresented among differentially expressed genes, consistent with a role in maternal MetS-induced NAFLD. In support of this, activation of the IGN in cultured hepatoma cells by overexpressing Zac1 is sufficient to induce signatures of profibrogenic transformation. Using chromatin immunoprecipitation, we demonstrate that Zac1 binds the TGF-ß1 and COL6A2 promoters, forming a direct pathway between imprinted genes and well-characterized pathophysiological mechanisms of NAFLD. Finally, we show that hepatocyte-specific overexpression of Zac1 is sufficient to drive fibrosis in vivo. CONCLUSIONS: Our findings identify a pathway linking maternal MetS exposure during postnatal development to the programming of juvenile NAFLD, and provide support for the hypothesis that imprinted genes play a central role in metabolic disease programming.

Exotic electronic structures of SmxCe3-xOy (x = 0-3; y = 2-4) clusters and the effect of high neutral density of low-lying states on photodetachment transition intensities.

Lanthanide (Ln) oxide clusters have complex electronic structures arising from the partially occupied Ln 4f subshell. New anion photoelectron (PE) spectra of SmxCe3-xOy- (x = 0-3; y = 2-4) along with supporting results of density functional theory (DFT) calculations suggest interesting x and y-dependent Sm 4f subshell occupancy with implications for Sm-doped ionic conductivity of ceria, as well as the overall electronic structure of the heterometallic oxides. Specifically, the Sm centers in the heterometallic species have higher 4f subshell occupancy than the homonuclear Sm3Oy-/Sm3Oy clusters. The higher 4f subshell occupancy both weakens Sm-O bonds and destabilizes the 4f subshell relative to the predominantly O 2p bonding orbitals in the clusters. Parallels between the electronic structures of these small cluster systems with bulk oxides are explored. In addition, unusual changes in the excited state transition intensities, similar to those observed previously in the PE spectra of Sm2O- and Sm2O2- [J. O. Kafader et al., J. Chem. Phys. 146, 194310 (2017)], are also observed in the relative intensities of electronic transitions to excited neutral state bands in the PE spectra of SmxCe3-xOy- (x = 1-3; y = 2, 4). The new spectra suggest that the effect is enhanced with lower oxidation states and with an increasing number of Sm atoms, implying that the prevalence of electrons in the diffuse Sm 6s-based molecular orbitals and a more populated 4f subshell both contribute to this phenomenon. Finally, this work identifies challenges associated with affordable DFT calculations in treating the complex electronic structures exhibited by these systems, including the need for a more explicit treatment of strong coupling between the neutral and PE.

The electron shuffle: Cerium influences samarium 4f orbital occupancy in heteronuclear Ce-Sm oxide clusters.

The anion photoelectron (PE) spectra along with supporting results of density functional theory (DFT) calculations on SmO-, SmCeOy-, and Sm2Oy- (y = 1, 2) are reported and compared to previous results on CeO- [M. Ray et al., J. Chem. Phys. 142, 064305 (2015)] and Ce2Oy- (y = 1, 2) [J. O. Kafader et al., J. Chem. Phys. 145, 154306 (2016)]. Similar to the results on CexOy- clusters, the PE spectra of SmO-, SmCeOy-, and Sm2Oy- (y = 1, 2) all exhibit electronic transitions to the neutral ground state at approximately 1 eV e-BE. The Sm centers in SmO and Sm2O2 neutrals can be described with the 4f56s superconfiguration, which is analogous to CeO and Ce2O2 neutrals in which the Ce centers can be described with the 4f 6s superconfiguration (ZCe = ZSm - 4). The Sm center in CeSmO2, in contrast, has a 4f6 occupancy, while the Ce center maintains the 4f 6s superconfiguration. The less oxidized Sm centers in both Sm2O and SmCeO have 4f6 6s occupancies. The 4f6 subshell occupancy results in relatively weak Sm-O bond strengths. If this extra 4f occupancy also occurs in bulk Sm-doped ceria, it may play a role in the enhanced O2- ionic conductivity in Sm-doped ceria. Based on the results of DFT calculations, the heteronuclear Ce-Sm oxides have molecular orbitals that are distinctly localized Sm 4f, Sm 6s, Ce 4f, and Ce 6s orbitals. The relative intensity of two electronic bands in the PE spectrum of Sm2O- exhibits an unusual photon energy-dependence, and the PE spectrum of Sm2O2- exhibits a photon energy-dependent continuum signal between two electronic transitions. Several explanations, including the high magnetic moment of these suboxide species and the presence of low-lying quasi-bound anion states, are considered.