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Liver size and lipid content differences between BALB/c and BALB/cJ mice on a high-fat diet are due, in part, to Zhx2

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Abstract

BALB/cJ mice exhibit considerable phenotypic differences with other BALB/c substrains. Some of these traits involve the liver, including persistent postnatal expression of genes that are normally expressed only in the fetal liver and reduced expression of major urinary proteins. These traits are due to a mutation that dramatically reduces expression of the gene encoding the transcription factor Zinc fingers and homeoboxes 2 (Zhx2). BALB/cJ mice also exhibit reduced serum lipid levels and resistance to atherosclerosis compared to other mouse strains when placed on a high-fat diet. This trait is also due, at least in part, to the Zhx2 mutation. Microarray analysis identified many genes affecting lipid homeostasis, including Lipoprotein lipase, that are dysregulated in BALB/cJ liver. This led us to investigate whether hepatic lipid levels would be different between BALB/cJ and BALB/c mice when placed on a normal chow or a high-fat chow diet. On the high-fat chow, BALB/cJ mice had increased weight gain, increased liver:body weight ratio, elevated hepatic lipid accumulation and markers of liver damage when compared to BALB/c mice. These traits in BALB/cJ mice were only partially reversed by a hepatocyte-specific Zhx2 transgene. These data indicate that Zhx2 reduces liver lipid levels and is hepatoprotective in mice on a high-fat diet, but the partial rescue by the Zhx2 transgene suggests a contribution by both parenchymal and non-parenchymal cells. A model to account for the cardiovascular and liver phenotype in mice with reduced Zhx2 levels is provided.

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Acknowledgements

We thank Sean Thatcher, Ryan Temel and Eun Lee, University of Kentucky, for their assistance. This study was supported by Public Health Service Grants DK059866 and DK074816 from the National Institute of Diabetes and Digestive and Kidney Diseases.

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Author notes

  1. Erica L. Clinkenbeard

    Present address: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

Authors and Affiliations

  1. Department of Microbiology, Immunology & Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY, 40536, USA

    Erica L. Clinkenbeard, Jieyun Jiang, Martha L. Peterson & Brett T. Spear

  2. Department of Pharmacology & Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40536, USA

    Courtney Turpin

  3. Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA

    Martha L. Peterson & Brett T. Spear

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Correspondence to Brett T. Spear.

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Clinkenbeard, E.L., Turpin, C., Jiang, J. et al. Liver size and lipid content differences between BALB/c and BALB/cJ mice on a high-fat diet are due, in part, to Zhx2. Mamm Genome 30, 226–236 (2019). https://doi.org/10.1007/s00335-019-09811-6

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