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

Abstract

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.

Polychlorinated biphenyls disrupt hepatic epidermal growth factor receptor signaling

“…For example, 39.6% of chemotherapy patients on gefitinib, a small molecule EGFR inhibitor, developed abnormal liver function (Wang and others 2016). Further, loss of EGFR function in humans and mice is implicated in the development of steatosis (Collin de l’Hortet and others 2014; Scheving and others 2014). EGFR activation was shown to be hepatoprotective against chemical-induced liver injury and EGF supplementation attenuated alcohol-induced liver disease (Deaciuc and others 2002; Scheving and others 2015).…”

“…Akt and mTOR are effector kinases downstream of EGFR that regulate lipid metabolism, and glycogen synthesis (Caron and others 2015; Taniguchi and others 2006). Decreased EGFR signaling has been implicated in metabolic diseases such as type II diabetes (Bernal-Mizrachi and others 2014; Miettinen and others 2008) and NASH (Collin de l’Hortet and others 2014; Deaciuc and others 2002; Komposch and Sibilia 2016; Scheving and others 2014; Scheving and others 2015), both of which have been associated with PCB exposures (Cave and others 2010; Li and others 2013; Taylor and others 2013; Wahlang and others 2016; Wahlang and others 2014b; Yu and others 1997). Thus, we hypothesised that if PCBs antagonised EGFR like phenobarbital, this mechanism could account for both indirect CAR activation and the associated ‘off target’ effects contributing to PCB-related NASH.…”

Neuregulin-activated ERBB4 induces the SREBP-2 cholesterol biosynthetic pathway and increases low-density lipoprotein uptake

“…ERBBs were linked to metabolic regulation as early as 1965, when Stanley Cohen found that injection of EGF into newborn rodents induces fatty liver (including some elevation in cholesteryl esters) ( 44 ), and now reinforced with the finding that the Dsk5 gain-of-function mutation in the EGFR induces fatty liver with elevated HMGCR and FAS in mice ( 45 ).…”

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

“…These mice have more cholesterol and decreased phospholipid and fatty acid in the livers and an elevated total plasma cholesterol resulting mainly from an increase in low-density lipoprotein, suggesting that the EGFR may play a regulatory role in hepatocyte function and lipid metabolism in adult male mice (481). Moreover, recent studies in a transgenic mouse model expressing a hepatocyte-specific dominant-negative EGFR indicate that liver regeneration is markedly delayed in response to partial hepatectomy by inhibition of both cell proliferation and lipid synthesis (316).…”