| Title | Regulation of intestinal fat absorption as a novel therapeutic strategy to enhance excretion of toxic hydrophobic compounds from the body |
|---|---|
| Period | 05 / 2000 - unknown |
| Status | Completed |
| Research number | OND1272140 |
| The gastrointestinal tract is quantitatively the most important pathway for the excretion from the human body of endogenous and exogenous hydrophobic compounds, such as bilirubin, protoporphyrin, and hydrophobic drugs. The hydrophobic compounds enter the gastrointestinal lumen either via secretion into bile and/or via transintestinal secretion. Biliary secretion is actively studied in our laboratory. Most hydrophobic compounds are partly reabsorbed from the intestinal lumen, which limits the efficacy of their removal from the body. Under various pathophysiological conditions, hydrophobic compounds accumulate in the body, leading to deleterious, frequently irreversible effects in specific organs (liver, central nervous system). Clinical examples are the toxic accumulation of unconjugated bilirubin (prematurity, Crigler Najjar's disease) or of protoporphyrin (erythropoietic protoporphyria, EPP), for which the therapeutic possibilities are limited. Recently, anti-obesity strategies have been developed which involve the regulation of intestinal lipid absorption. lt is now proposed to test the following hypothesis: Regulation of intestinal fat absorption allows to increase the excretion of hydrophobic compounds from the body, by impairing their reabsorption from the intestinal lumen and by directly enhancing their transintestinal secretion. Specifically, the mechanisms involved in the transintestinal secretion of hydrophobic compounds will be characterized, including the contributions of putatively involved carrier proteins (mdr1a, mdr1b). In animal models of protoporphyrin or bilirubin accumulation (fch mice, model for EPP, and Gunn rats, model for Crigler Najjar's disease, respectively), lipid absorption will be regulated by various strategies (lipase inhibition, permanent bile diversion, alteration of luminal viscosity). The effects on intestinal reabsorption of hydrophobic compounds and on their steady-state levels in target organs (blood, liver, central nervous system) will be determined. In addition to the animal studies, the therapeutic potency of regulated lipid absorption will be tested in patients with Crigler Najjar's disease. If regulation of lipid absorption indeed allows to enhance the excretion of accumulated hydrophobic compounds from the body, it could imply a significant novel treatment strategy for unconjugated hyperbilirubinemia and for EPP. The proposed project involves mechanistic studies on the transintestinal secretion of hydrophobic compounds under physiological conditions and on the potency of induced intestinal lipid malabsorption to increase their disposal from the body under pathophysiological conditions (animals models, Crigler Najjar's disease). Physiology: Initial animal studies will be aimed to quantitate the relative contribution of biliary secretion and transintestinal secretion to the appearance of model compounds (protoporhyrin, unconjugated bilirubin) in the intestinal lumen. For these studies, a rat model will be applied which allows the controlled, permanent interruption of the enterohepatic circulation and the continuous collection of bile under unanaesthetized, unstressed conditions (Gastroenterology 1985; 88:403-11). The same model will be used to quantitate the absorption of the model compounds from the intestinal lumen. The contribution to biliary and transintestinal secretion of putatively involved carrier proteins will then be determined in mice in which these proteins are genetically inactivated [mdr1a -/-, mdr1b -/-, mdr1a,1b -/- (available through collaboration with Dr. A.H. Schinkel, Netherlands Cancer Institute, Amsterdam), mdr2 -/- (presently available in our group)] and in animal models in which P-glycoprotein expression is upregulated (for example, by cyclosporin A or rifampin). If mdr1a or mdr1b would appear to be involved in the transintestinal secretion of hydrophobic compounds, the generation of a transgenic mouse model will be commenced, in which specifically the intestinal expression of the carrier proteins is upregulated, using a I-FABP promoter (collaboration with Dr. R.P.J. Oude Elferink and Dr. P.J. Bosma, Academic Medical Center, Amsterdam; 4-6 months stay in their laboratory). In this animal model, it would be investigated whether manipulation of intestinal mdr1a and/or mdr1b expression could potentiate the capacity of intestinal, non-absorbed lipids to increase the disposal from the body of hydrophobic compounds. Pathophysiology: The potency of regulated lipid absorption to decrease pathophysiological accumulations of hydrophobic compounds will be investigated in mice in which biliary protoporphyrin secretion is inhibited (mdr2 -/- mice), in mice with protoporphyrin accumulates due to impaired heme synthesis (fch mice, model for EPP) and in Gunn rats (model for Crigier Najjar's disease type 1). Different strategies to induce fecal lipid excretion will be investigated, and the contributions of biliary and transintestinal secretion will be quantitaled. Patients: The patient study will be performed in collaboration with Dr. M. Sinaasappel (Sophia Children's Hospital / Academic Hospital Rotterdam) who treats and surveils most Crigler Najjar type I patients in the Netherlands. The actual design of the patient study will depend on the results from the animal studies. lt is envisioned that actual patient inclusion will start during the second year of the project. |
| Secretariat | Department of Pediatrics (RUG) |
|---|---|
| Financier | Royal Netherlands Academy of Arts and Sciences - KNAW (KNAW) |
| Researcher | Dr. C.M.A. Bijleveld |
|---|---|
| Researcher | Dr. H. van Goor |
| Researcher | Prof.dr. P.L.M. Jansen |
| Researcher | Prof.dr. F. Kuipers |
| Researcher | Prof.dr. A.J. Moshage |
| Researcher | Prof.dr. M. Müller |
| Researcher | Dr. F. Stellaard |
| Project leader | Prof.dr. P.J.J. Sauer |
| Project leader | Prof.dr. H.J. Verkade |
| A70000 | Public health and health care |
|---|---|
| D21300 | Biochemistry |
| D21700 | Physiology |
| D23220 | Internal medicine |
| D23362 | Pediatrics |
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