Cafestol: a multi-faced compound kinetics and metabolic effects of cafestol in mice

Cafestol and kahweol are two diterpenes present in unfiltered coffees such as Scandinavian-style boiled coffee, French press coffee and espresso. The health effects of cafestol and kahweol can be positive but also potentially harmful. On the one hand cafestol shows chemo-preventive properties, which might contribute to a reduction of the risk for certain cancers, especially colorectal cancer. On the other hand cafestol is known as the most potent cholesterol-raising compound present in the human diet and also causes a temporally rise in plasma ASAT and ALAT enzymes. This apparently ‘two-faced’ behavior of cafestol was the starting point of this thesis. It was demonstrated that in mice cafestol is extensively metabolized by the liver. Metabolism was found to be associated with Nrf2 activation, causing an induction of biotransformation enzymes and cellular antioxidant defense. This mechanism might explain the proposed anti-carcinogenic effects of cafestol. Furthermore, distribution studies indicated that in mice cafestol accumulates almost exclusively in liver and intestine, and suggested that cafestol undergoes enterohepatic cycling. Further studies showed that cafestol prevents the development of diet-induced obesity, its metabolic complications, and the development of hepatic steatosis in mice. Modulation of the dietary fat content was also used to study the hepatic and intestinal response to cafestol at a transcriptomic level. We showed that dietary fat content is an important determinant of the effects of cafestol. This has been evaluated for several processes already known to be influenced by cafestol, such as bile acid metabolism and Nrf2-mediated biotransformation. Furthermore it was shown that cafestol activated Nrf2-mediated biotransformation both in liver and small intestine. It is concluded that cafestol behaves as a hormetic compound. It elicits a combination of mechanisms which together determine the balance between positive and negative health outcomes. Although for some mechanisms, i.e. the induction of biotransformation enzymes and acute liver toxicity, a connection seems plausible, several questions remain regarding their interrelations. This thesis has generated new mechanistic insights in the multi-faced behavior of cafestol. More studies, including in humans, are needed to study its dose-effect relations and interactions with dietary compounds. For the time being it is advisable to keep cafestol under scrutiny.