Disrupting Hepatocyte Cyp51 from Cholesterol Synthesis Leads to Progressive Liver Injury in the Developing Mouse and Decreases RORC Signalling
SCIENTIFIC REPORTS
Authors: Urlep, Ziga; Lorbek, Gregor; Perse, Martina; Jeruc, Jera; Juvan, Peter; Matz-Soja, Madlen; Gebhardt, Rolf; Bjorkhem, Ingemar; Hall, Jason A.; Bonneau, Richard; Littman, Dan R.; Rozman, Damjana
Abstract
Development of mice with hepatocyte knockout of lanosterol 14 alpha-demethylase (HCyp51-/-) from cholesterol synthesis is characterized by the progressive onset of liver injury with ductular reaction and fibrosis. These changes begin during puberty and are generally more aggravated in the knockout females. However, a subgroup of (pre) pubertal knockout mice (runts) exhibits a pronounced male prevalent liver dysfunction characterized by downregulated amino acid metabolism and elevated Casp12. RORC transcriptional activity is diminished in livers of all runt mice, in correlation with the depletion of potential RORC ligands subsequent to CYP51 disruption. Further evidence for this comes from the global analysis that identified a crucial overlap between hepatic Cyp51(-/-) and Rorc(-/-) expression profiles. Additionally, the reduction in RORA and RORC transcriptional activity was greater in adult HCyp51-/- females than males, which correlates well with their downregulated amino and fatty acid metabolism. Overall, we identify a global and sex-dependent transcriptional de-regulation due to the block in cholesterol synthesis during development of the Cyp51 knockout mice and provide in vivo evidence that sterol intermediates downstream of lanosterol may regulate the hepatic RORC activity.
Polymorphisms in twelve candidate genes are associated with growth, muscle lipid profile and meat quality traits in eleven European cattle breeds
MOLECULAR BIOLOGY REPORTS
Authors: Sevane, N.; Armstrong, E.; Wiener, P.; Wong, R. Pong; Dunner, S.
Abstract
Current customers' demands focus on the nutritional and sensory quality of cattle meat. Candidate gene approach allows identification of genetic polymorphisms that have a measurable effect on traits of interest. The aim of this work is to identify new molecular markers for beef production through an association study using 27 candidate genes and 314 purebred bulls from 11 European cattle breeds. Twelve genes were found associated with different lipid and meat quality traits, and among these stand out the considerable effect of CAST on fatness score, CGGBP1 on growth traits, HSPB1 on the percentage of lauric acid (12:0) and phospholipid docosahexaenoic acid (DHA 22:6 n - 3), RORA on the ratio of light absorption (K) to light scattering (S) (K/S), and TNFA on lightness (L*). Most of these traits are related to post-mortem muscle biochemical changes, which are key factors controlling meat quality and consumers' acceptance. Also, the variations produced on muscle fatty acid profiles, such as those of AANAT, CRH, CSN3, HSPB1, and TNFA, give insights into the genetic networks controlling these complex traits and the possibility of future improvement of meat nutritional quality.