Establishing c-Myc's (Myc) role in liver regeneration has proven difficult particularly since the traditional model of partial hepatectomy may provoke an insufficiently demanding proliferative stress. We used a model of hereditary tyrosinemia whereby the affected parenchyma can be gradually replaced by transplanted hepatocytes, which replicate 50-100-fold, over several months. Prior to transplantation, livers from myc−/− (KO) mice were smaller in young animals and larger in older animals relative to myc+/+ (WT) counterparts. KO mice also consumed more oxygen, produced more CO2 and generated more heat. Although WT and KO hepatocytes showed few mitochondrial structural differences, the latter demonstrated defective electron transport chain function. RNAseq revealed differences in transcripts encoding ribosomal subunits, cytochrome p450 members and enzymes for triglyceride and sterol biosynthesis. KO hepatocytes also accumulated neutral lipids. WT and KO hepatocytes repopulated recipient tyrosinemic livers equally well although the latter were associated with a pro-inflammatory hepatic environment that correlated with worsening lipid accumulation, its extracellular deposition and parenchymal oxidative damage. Our results show Myc to be dispensable for sustained in vivo hepatocyte proliferation but necessary for maintaining normal lipid homeostasis. myc−/− livers resemble those encountered in non-alcoholic fatty liver disease and, under sustained proliferative stress, gradually acquire the features of non-alcoholic steatohepatitis.

Background: Reversible lysine acetylation regulates the fatty acid oxidation enzyme long-chain acyl-CoA dehydrogenase (LCAD). Results: Residues Lys-318 and Lys-322 are responsible for these effects. Conclusion: Acetylation of Lys-318/Lys-322 alters the conformation of the LCAD active site. Sirtuin 3 (SIRT3) deacetylates these lysines and restores function. Significance: Acetylation of LCAD Lys-318/Lys-322 can disrupt fatty acid oxidation and contribute to metabolic disease.

Background: Cells lacking c-Myc demonstrate metabolic abnormalities marked by reduced glycolysis, oxidative phosphorylation, and proliferation. Results: These cells preferentially utilize fatty acids as energy-generating substrates and reprogram other pathways to maximize acetyl-CoA and ATP production. Conclusion: Despite these compensatory changes, basal levels of acetyl-CoA and ATP remained low. Significance: Therapies that limit acetyl-CoA availability might represent novel ways of inhibiting tumor cell growth.