Abstract B25: Novel hepatic phenotypes caused by conditional c-Myc deletion

The transcription factor c-Myc (hereafter Myc) is among the most frequently deregulated oncoproteins. Inhibition of Myc triggers proliferative arrest of transformed cells and promotes tumor regression and/or apoptosis. Myc is also developmentally necessary and myc-/- embryos die at E9.5-10.5. However, Myc9s role in the maintenance of specific tissues has been shown to be of variable importance and necessity. For example, several studies of Myc9s role in promoting liver regeneration following partial hepatectomy (PH) have given conflicting results, although all show Myc to be generally dispensable for this function. We have used a conditional murine knockout (KO) model of Myc to study its role in liver regeneration. By employing a myc fl/fl ;Alb-Cre+ model in which loss of Myc occurs perinatally, we studied non-oncogenic liver proliferation and metabolism in the absence of Myc signaling. We employed basic metabolic benchmarks of liver function including measurements of triglyceride levels, oxidative phosphorylation, and TCA cycle and electron transport chain function. At the molecular level, RNAseq was performed on isolated hepatocytes and the mitochondrial proteome was evaluated by both differential and unbiased mass spectrometry. At the time of active Myc excision, myc-/- mice had a significantly lower liver: body weight ratios relative to myc+/+ controls. However, this was reversed in older mice and was associated with the hepatic accumulation of neutral lipids, cholesterol and increased fatty acid β-oxidation in myc-/- mice. RNAseq on hepatocytes and Ingenuity Pathway analyses showed differences in 105 transcripts (q PH may provide an insufficiently sustained proliferative challenge to allow adequate evaluation of Myc9s potential role in liver regeneration. We therefore utilized a mouse model of hereditary tyrosinemia in which knockout of the gene encoding fumarylacetoacetate hydrolase (FAH) leads to hepatocellular death that can be rescued by the infusion of fah+/+ hepatocytes, which expand and eventually replace the fah-/- recipient hepatocytes. FAH-deficient animals could be rescued equally well by both myc+/+ and myc-/- hepatocytes. However, livers from the latter group showed excessive neutral lipid accumulation and fibrosis, reminiscent of non-alcoholic steatohepatitis (NASH). Taken together, our results provide unequivocal evidence that Myc is dispensable for long-term hepatic regeneration but is necessary to maintain proper lipid and steroid metabolism. In Myc9s absence the excessive accumulation of these intermediates predisposes to the development of a relatively mild pathology mimicking non-alcoholic fatty liver disease, which under the duress of chronic proliferation, progresses to a more severe NASH-like picture of end-stage liver disease. Our studies thus reveal a heretofore unappreciated role for Myc in hepatic metabolic homeostasis. Citation Format: Lia R. Edmunds, Lokendra Sharma, Peter Anthony Otero, Sonia D9Souza, James M. Dolezal, Xuemei Zeng, Ying Ding, Fei Ding, Megan E. Beck, Lisa E. Kratz, Jerry Vockley, Eric Goetzman, Donald Scott, Nathan Yates, Andrew W. Duncan, Edward V. Prochownik. Novel hepatic phenotypes caused by conditional c-Myc deletion. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B25.