Gerding, A. | Search bioRxiv

bioRxiv2020

Spontaneous liver disease in wild-type C57BL/6JOlaHsd mice fed semisynthetic diet

Mouse models are frequently used to study mechanisms of human diseases. Recently, we observed a spontaneous bimodal variation in liver weight in C57BL/6JOlaHsd mice fed a semisynthetic diet. We now characterized the spontaneous variation in liver weight and its relationship with parameters of hepatic lipid and bile acid (BA) metabolism. In male C57BL/6JOlaHsd mice fed AIN-93G from birth to postnatal day (PN)70, we measured plasma BA, lipids, Very low-density lipoprotein (VLDL)-triglyceride (TG) secretion, and hepatic mRNA expression patterns. Mice were sacrificed at PN21, PN42, PN63 and PN70. Liver weight distribution was bimodal at PN70. Mice could be subdivided into two nonoverlapping groups based on liver weight: 0.6 SD 0.1 g (approximately one-third of mice, small liver; SL), and 1.0 SD 0.1 g (normal liver; NL; p<0.05). Liver histology showed a higher steatosis grade, inflammation score, more mitotic figures and more fibrosis in the SL versus the NL group. Plasma BA concentration was 14-fold higher in SL (p<0.001). VLDL-TG secretion rate was lower in SL mice, both absolutely (-66%, p<0.001) and upon correction for liver weight (-44%, p<0.001). Mice that would later have the SL-phenotype showed lower food efficiency ratios during PN21-28, suggesting the cause of the SL phenotype is present at weaning (PN21). Our data show that approximately one-third of C57BL/6JOlaHsd mice fed semisynthetic diet develop spontaneous liver disease with aberrant histology and parameters of hepatic lipid, bile acid and lipoprotein metabolism. Study designs involving this mouse strain on semisynthetic diets need to take the SL phenotype into account. Plasma lipids may serve as markers for the identification of the SL phenotype.

pathology↗

bioRxiv2019

Fibroblast-specific genome-scale modelling predicts an imbalance in amino acid metabolism in Refsum disease

Refsum disease is an inborn error of metabolism that is characterised by a defect in peroxisomal -oxidation of the branched-chain fatty acid phytanic acid. The disorder presents with late-onset progressive retinitis pigmentosa and polyneuropathy and can be diagnosed biochemically by elevated levels of phytanic acid in plasma and tissues of patients. To date, no cure exists for Refsum disease, but phytanic acid levels in patients can be reduced by plasmapheresis and a strict diet.\n\nIn this study, we reconstructed a fibroblast-specific genome-scale model based on the recently published, FAD-curated model, based on Recon3D reconstruction. We used transcriptomics (available via GEO database with identifier GSE138379), metabolomics, and proteomics data (available via ProteomeXchange with identifier PXD015518), which we obtained from healthy controls and Refsum disease patient fibroblasts incubated with phytol, a precursor of phytanic acid.\n\nOur model correctly represents the metabolism of phytanic acid and displays fibroblast-specific metabolic functions. Using this model, we investigated the metabolic phenotype of Refsum disease at the genome-scale, and we studied the effect of phytanic acid on cell metabolism. We identified 53 metabolites that were predicted to discriminate between Healthy and Refsum disease patients, several of which with a link to amino acid metabolism. Ultimately, these insights in metabolic changes may provide leads for pathophysiology and therapy.

systems biology↗