Ioannis Evangelakos, Germany
University Medical Center Hamburg-Eppendorf Department of Biochemistry and Molecular Cell BiologyPresenter of 1 Presentation
The role of the Cyp7b1-derived cholesterol metabolites in NASH development
Abstract
Background and Aims
Aim:
Brown adipose tissue (BAT) activation by cold exposure induces hepatic Cyp7b1 expression, promoting cholesterol conversion to bile acids (BA) and intermediate oxysterols, mainly through the alternative synthesis pathway. Increased BAT activity inversely correlates with NAFLD progression and since BA exert anti-inflammatory properties, we aim to investigate the role of Cyp7b1 derived-metabolites during NAFLD to NASH progression.
Methods
Methods:
Cyp7b1-/- and wild type (WT) mice fed a choline-deficient high-fat diet for 8 months (diet-induced NASH model) were housed either at 30°C (thermoneutral conditions, control) or at 22°C (mild-cold exposure) to stimulate BAT and the hepatic Cyp7b1 overexpression. Metabolic parameters, histology, gene expression and protein levels were analyzed. BA/oxysterol species were determined by LC-MS/MS-based methods.
Results
Results:
Prolonged mild-cold exposure induced Cyp7b1 expression in WT mice and attenuated NASH development compared to 30oC in both genotypes (decreased plasma lipids, ALT activity, hepatic inflammation / fibrosis). Conversely, Cyp7b1-/- mice housed at thermoneutrality have an aggravated NASH phenotype compared to controls (elevated ALT activity, hepatic fibrosis, inflammatory / fibrotic gene markers, hyperlipidemia and hyperinsulinemia). Interestingly, mild cold exposure increased hepatic Cyp27a1, Ldlr and Lrp1 expression of Cyp7b1-/- mice, accompanied by ameliorated disease phenotype.
Conclusions
Conclusion:
Deletion of Cyp7b1 augments the disease’s phenotype at 30oC, suggesting that the downstream metabolites exert beneficial features during NASH manifestation at thermoneutral conditions. Upon mild cold exposure and BAT activation, the compensatory hepatic upregulation of Cyp27a1 in the Cyp7b1-/- mice together with this of Ldlr and Lrp1 indicate an enhanced lipoprotein metabolism and could, in part, explain the improved disease state.