Towards novel strategies to improve lipid homeostasis. Targeting the intestine

PhD ceremony: Ms. M.Y.M. van der Wulp, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Disertation: Towards novel strategies to improve lipid homeostasis. Targeting the intestine

Promotor(s): prof. H.J. Verkade, prof. A.K. Groen, prof. E.H.H.M. Rings

Faculty: Medical Sciences

Hypercholesterolemia (excess cholesterol in blood), an important risk factor for cardiovascular diseases, is highly prevalent. It is the result of high dietary intake and resistance of the cholesterol molecule against breakdown. The only way to dispose of cholesterol is direct excretion with faeces or conversion to bile salts (BS) in the liver. Besides mediating excretion of the sterol nucleus, BS also fulfil biological functions. BS are important for efficient absorption of cholesterol, fat and fat-soluble vitamins. BS are metabolized by intestinal bacteria into more lipophilic forms, that can damage cell walls and have been associated with (early stages of) intestinal carcinomas. Recently it has become clear that transport of cholesterol via the blood towards the intestinal lumen, called “TransIntestinal Cholesterol Excretion” (TICE), can play a major role in cholesterol excretion. Stimulation of TICE could become an attractive therapeutic target. We studied the influence of different interventions in the intestine on cholesterol- and BS homeostasis.

Our studies show that acceleration of intestinal transit with the widely used laxative polyethylene glycol (PEG) in rats did not influence cholesterol uptake or excretion. On the other hand, PEG decreased intestinal microbial conversion of BS in the intestinal lumen. In mice we found that a high fat diet with extremely low amounts of polyunsaturated fatty acids stimulated TICE and doubled cholesterol excretion compared with a standard high fat diet. Finally, we found that specific mice, that spontaneously secrete extremely hydrophilic BS, barely absorb cholesterol and excrete high amounts in their faeces via TICE.

In summary, simple interventions can have health-promoting effects on cholesterol and BS homeostasis. Future studies can establish the effects of intake of for example non-absorbable fats (to prevent the negative effects of saturated fats) and hydrophilic BS on TICE, and determine the possible protective effect of PEG on BS homeostasis.