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Epidermal growth factor receptor plays a role in the regulation of liver and plasma lipid levels in adult male mice.

Scheving LA, Zhang X, Garcia OA, Wang RF, Stevenson MC, Threadgill DW, Russell WE
Am J Physiol Gastrointest Liver Physiol. 2014 306 (5): G370-81

PMID: 24407590 · PMCID: PMC3949019 · DOI:10.1152/ajpgi.00116.2013

Dsk5 mice have a gain of function in the epidermal growth factor receptor (EGFR), caused by a point mutation in the kinase domain. We analyzed the effect of this mutation on liver size, histology, and composition. We found that the livers of 12-wk-old male Dsk5 heterozygotes (+/Dsk5) were 62% heavier compared with those of wild-type controls (+/+). The livers of the +/Dsk5 mice compared with +/+ mice had larger hepatocytes with prominent, polyploid nuclei and showed modestly increased cell proliferation indices in both hepatocytes and nonparenchymal cells. An analysis of total protein, DNA, and RNA (expressed relative to liver weight) revealed no differences between the mutant and wild-type mice. However, the livers of the +/Dsk5 mice had more cholesterol but less phospholipid and fatty acid. Circulating cholesterol levels were twice as high in adult male +/Dsk5 mice but not in postweaned young male or female mice. The elevated total plasma cholesterol resulted mainly from an increase in low-density lipoprotein (LDL). The +/Dsk5 adult mouse liver expressed markedly reduced protein levels of LDL receptor, no change in proprotein convertase subtilisin/kexin type 9, and a markedly increased fatty acid synthase and 3-hydroxy-3-methyl-glutaryl-CoA reductase. Increased expression of transcription factors associated with enhanced cholesterol synthesis was also observed. Together, these findings suggest that the EGFR may play a regulatory role in hepatocyte proliferation and lipid metabolism in adult male mice, explaining why elevated levels of EGF or EGF-like peptides have been positively correlated to increased cholesterol levels in human studies.

MeSH Terms (19)

Adipose Tissue Alleles Animals Chondroitin Sulfates Dermatan Sulfate ErbB Receptors Female Gene Expression Regulation, Developmental Heparitin Sulfate Kidney Lipid Metabolism Lipids Liver Male Mice Sarcoma, Small Cell Signal Transduction Spleen Testis

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