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.