Relationship between liver size and liver function in mice

Objectives and study: The mouse is a frequently used species in experimental models for human diseases. By using inbred mice under controlled conditions, the genetic and environmental variations are supposedly minimized. Recently, however, we discovered serendipitously a spontaneous bimodal variation in liver size in a frequently used mouse strain (C57BL/6JOlaHsd). We now determined if the spontaneous variation in liver weight is translated to metabolic differences with respect to bile acid (BA) homeostasis and Very Low Density Lipoprotein (VLDL) secretion. Methods: We fed male wildtype C57BL/6JOlaHsd mice a commonly used standardized semi-synthetic diet (AIN-93G) from birth to 10 weeks of age. We determined plasma BA concentration and composition, by LC-MS/MS, and VLDL secretion, for 5h after intraperitoneal injection of a lipoprotein lipase inhibitor (poloxamer-407). In separate mice, we measured fasting plasma lipids and hepatic mRNA expression of relevant genes. Values represent means±SD. Results: Liver weight distribution was bimodal, both with respect to absolute weight as to liver-to-body weight (Hartigans’ test; each p<0.01). Mice could be subdivided into two, non-overlapping groups based on liver weight: 1.0±0.1 (normal liver; NL) and 0.6±0.1 g (small liver; SL) (p<0.001). Liver weight differences were not associated with housing conditions or nests. Bodyweight of SL mice was slightly lower than that of NL mice (-7%, p=0.02). Plasma BA concentration was ~10-fold higher in SL (p<0.001). VLDL secretion was profoundly lower in SL mice: both in absolute amounts (-66%, p<0.001) and after correction for liver weight (-44%, p<0.001). Fasting plasma triglycerides (-70%, p<0.001), phospholipids (-50%; p=0.08) and cholesterol (-70%, p<0.001) were decreased in SL mice. Plasma AST (+17U/L; p<0.001) and ALT (+28U/L; p<0.001) were higher in SL mice, but still below upper limit of normal. Liver histology showed the presence of more inflammatory foci in SL. Hepatic mRNA expression of TNFα (inflammatory cytokine) was 3-fold higher in SL (p<0.001). Conclusion: Our data indicate that spontaneous phenotypical bimodality in liver size and function exists in wild type “C57/Black 6” mice, an inbred mouse strain commonly used for experimental models. The spontaneous heterogeneity in mice may help to identify underlying causes of heterogeneity in human liver function and metabolism, such as observed in non-alcoholic fatty liver disease and metabolic syndrome.