Dietary fructose and NASH/HCC progression

PROJECT SUMMARY “Dietary fructose and NASH/HCC progression” Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is emerging as a leading risk factor driving the development of hepatocellular carcinoma (HCC). Dietary fructose is a major risk factor for NAFLD and subsequent HCC progression. Fructose is primarily metabolized by ketohexokinase (KHK) and KHK-

deficient mice or pharmacologic inhibition is protective against NAFLD but the underlying mechanisms responsible are largely unexplored. We recently designed studies to investigate whether loss or inhibition of KHK impacts HIF-α protein stabilization by crossing HIF stabilization reporter (ODD-luc) mice with KHK-/- mice

discovered that intestinal HIF-stabilization (as measured by luciferase activity) is significantly and consistently reduced by KHK-deficiency. Interestingly, reduced HIF-α stability in KHK-/- mice is fully rescued by the small molecule inhibitor of pyruvate kinase M2 (PKM2) suggesting that fructose/KHK-dependent HIF-α stabilization

may be mediated by the PKM2 inhibitory metabolite, F1P. Consistent with the reduced HIF-α stabilization observed in KHK-deficient mice, intestinal expression of the HIF-2α-induced iron transporter, DMT1, is reduced in KHK-/- mice consistent with our observations that KHK-deficient mice exhibit spontaneous systemic iron

deficiency. Because plasma iron is essential for maximal neutropoiesis coupled with the fact that KHK-deficiency also results in markedly reduced neutrophil numbers and percentages, our overarching hypothesis is that fructose facilitates increased intestinal iron absorption via a KHK/F1P/HIF-2α axis, leading to pro-inflammatory

neutropoiesis that, in turn, contributes to the development of HCC. We will test this hypothesis using the following two specific aims: Aim 1. Determine whether dietary fructose promotes intestinal iron absorption in a KHK, F1P and HIF-2α-dependent manner. Aim 2. Determine whether dietary fructose promotes systemic inflammation

leading to pro-tumorigenic liver microenvironments due to increased iron-dependent neutropoiesis.