Regulation of Liver and Plasma Lipid Levels in Adult Male Mice

29 Dsk5 mice have a gain-of-function in the epidermal growth factor receptor (EGFR), caused by a point 30 mutation in the kinase domain. We analyzed the effect of this mutation on liver size, histology, and 31 composition. We found that the livers of 12-week old male Dsk5 heterozygotes (+/Dsk5) were 62% 32 heavier compared to those of wild-type controls (+/+). The livers of the +/Dsk5 mice compared to +/+ 33 mice had larger hepatocytes with prominent, polyploid nuclei and showed modestly increased cell 34 proliferation indices in both hepatocytes and non-parenchymal cells. An analysis of total protein, DNA, 35 and RNA (expressed relative to liver weight) revealed no differences between the mutant and wild-type 36 mice. However, the livers of the +/Dsk5 mice had more cholesterol but less phospholipid and fatty acid. 37 Circulating cholesterol levels were twice as high in adult male +/Dsk5 mice, but not in post-weaned 38 young male or female mice. The elevated total plasma cholesterol resulted mainly from an increase in 39 low-density lipoprotein (LDL). The +/Dsk5 adult mouse liver expressed markedly reduced protein levels 40 of low-density lipoprotein receptor (LDLR), no change in proprotein convertase subtilisin/kexin type 9 41 (PCSK9), and a markedly increased fatty acid synthase (FAS) and 3-hydroxy-3-methyl-glutaryl-CoA 42 reductase (HMG-CoA R). Increased expression of transcription factors associated with enhanced 43 cholesterol synthesis was also observed. Together, these findings suggest that the EGFR may play a 44 regulatory role in hepatocyte proliferation and lipid metabolism in adult male mice, explaining why 45 elevated levels of EGF or EGF-like peptides have been positively correlated to increased cholesterol 46 levels in human studies. 47