Disrupting Hepatocyte Cyp51 from Cholesterol Synthesis Leads to Progressive Liver Injury in the Developing Mouse and Decreases RORC Signalling

Abstract

Development of mice with hepatocyte knockout of lanosterol 14α-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.

Retinal Cholesterol Content Is Reduced in Simvastatin-Treated Mice Due to Inhibited Local Biosynthesis Albeit Increased Uptake of Serum Cholesterol

“…The mechanism for this increase is currently unclear but could involve the retinoic acid receptor-related orphan nuclear receptor g (RORg), a transcription factor. The Cd36 expression seems to negatively correlate with RORg activation in nonretinal tissues (Raichur et al, 2007;Urlep et al, 2017), and specific cholesterol precursors downstream of lanosterol could be the RORg-activating ligands (Hu et al, 2015;Santori et al, 2015). We quantified retinal lanosterol and two potential RORg ligands (zymosterol and desmosterol) and showed that the levels of lanosterol and zymosterol, but not desmosterol, were decreased in simvastatin-treated mice (Fig.…”

Zebrafish models of skeletal dysplasia induced by cholesterol biosynthesis deficiency

“…Intriguingly, CDP is observed in patients with a deficit in the initial steps of the post-squalene cholesterol biosynthesis pathway (Rossi et al, 2015), pointing to a potential active role of sterol intermediates in the first steps of biosynthesis in bone pathology. Recently, sterol intermediates were implicated in interactions with numerous signaling pathways by acting as ligands for LXRs (also known as NR1Hs), RORγ (also known as RORC) and EGFR (Gabitova et al, 2015;Hu et al, 2015;Santori et al, 2015;Sukhanova et al, 2013;Urlep et al, 2017;Yang et al, 2006). These data highlight the importance of sterol intermediates in the cholesterol biosynthesis pathway and the role these intermediates may play in skeletal dysplasia.…”

Computational Modelling of Liver Metabolism and its Applications in Research and the Clinics

“…9 Cholesterol synthesis mutations may cause severe defects such as Antley-Bixler syndrome, Smith-Lemli-Opitz syndrome and several other genetic diseases. 10 There are still no approved therapies for NAFLD, which is becoming a major health concern due to increas-ing incidence of obesity in Europe. The problem of NAFLD is its multifactorial nature, with a largely uncharacterized genetic basis and only a few known associated genes.…”