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

Abstract

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.

Urine-based Detection of Congenital Portosystemic Shunt in C57BL/6 Mice

“… 3–7 On one hand, PSS may present a significant confounding variable that should be excluded, or at least stratified from many studies to yield more precise and reliable conclusion. Of note, PSS mice may pose as confounders due to their abnormal neurochemical profile, 1 altered drug and toxicological response, 5 , 8 metabolic perturbations (eg, hypocholesterolemia, hypotriglyceridemia, and hypoglycemia), 2 , 9 and an intolerance to purified diets that trigger rapid onset of cholestatic liver injury 10 and cancer. 2 , 3 On the other hand, murine PSS can be harnessed as the sought-after animal model for understanding the mechanisms and pathophysiology of human PSS.…”

“…Screening for PSS in mice, however, remains challenging due to its asymptomatic nature and the lack of diagnostic tests that allow its identification in a high-throughput manner. 2 , 10 …”

Response to Spontaneous Cholemia in C57BL/6 Mice Predisposes to Liver Cancer in NASH

“…It is tempting to speculate that the various observations of a spontaneous phenotypic heterogeneity are related to PSS in a subset of the mice. 2 , 3 , 4 PSS leads to a small liver and elevated plasma bile acids in dogs. 5 In humans, unresolved congenital PSS can eventually result in liver adenomas and carcinomas.…”

“…Recently, we did describe spontaneous phenotypic heterogeneity related to serum TBA in the C57BL/6JOlaHsd strain fed the AIN-93G semisynthetic diet. 2 This semisynthetic diet contains all known nutritional requirements for mice, and 7% (weight/weight) fat. In approximately 25% of mice, we observed substantially elevated serum TBA, which coincided with increased serum liver damage markers, lower serum cholesterol and triglyceride levels (likely caused by decreased VLDL-secretion rates), and small livers (measured in weights).…”

“…High-TBA was a common feature in the cited references. 1 , 2 , 4 It has not yet been tested whether high-TBA is caused by a congenital PSS. Another feature described by Gallage et al 1 that is compatible with a PSS is the high concentration of not only total but also unconjugated bile acids.…”