Fat primes the liver for hepatocellular carcinoma development by inducing a Warburg metabolism

Hepatocellular carcinoma (HCC) is one of the most common and deadliest cancers worldwide, with an overall mortality rate of 93%. A major risk factor for HCC development is obesity with concomitant insulin resistance. Already today 30% of all HCC cases are related to obesity and insulin resistance. However, obesity and insulin resistance by their own are not sufficient to drive HCC development in mice. Surprisingly, the combination of fat-induced obesity with carbohydrate feeding is required to drive HCC. Yet, a mechanistic understanding of this observation is missing. Such an understanding is, however, of utmost importance to define novel therapeutic strategies that decrease the HCC risk of obese patients. Strikingly, we have discovered that fat rewires how the normal liver processes glucose, a major carbohydrate source in western diet. Thus, we hypothesize that fat induces a cancer-like glucose metabolism in the liver and thereby primes it for HCC development. Specifically, we will define 1) what are the metabolic commonalities between a fat-induced liver metabolism and HCC, 2) how does fat induce an altered glucose processing in normal, non-transformed liver cells and 3) how can cellular glucose metabolism be targeted to reduce the obesity related risk of HCC development. We will address these questions using mouse models, metabolic measurements and pharmacologic interventions. We expect that our results will contribute to therapeutic strategies against obesity induced HCC.