Ezetimibe reduces cholesterol content and NF-kappaB activation in liver but not in intestinal tissue in guinea pigs.
BACKGROUND
Statins (HMG CoA reductase inhibitors), in addition to reducing circulating cholesterol and incidence of coronary heart disease, also have pleiotropic, anti-inflammatory effects. Patients with chronic liver diseases, non-alcoholic fatty liver disease (NAFLD) or hepatitis C are often excluded from statin therapy because of adverse effects in a small cohort of patients despite increased cardiovascular risk cholesterol. Ezetimibe, which inhibits cholesterol absorption by inhibition of Niemann-Pick C1 like 1 (NPC1L1) protein in the brush border of intestinal cells, has been suggested as a new therapeutic option in these patients.


METHODS
Effects of ezetimibe on lipoprotein metabolism, hepatic and intestinal lipid content in guinea pigs, an animal model with a lipoprotein profile and pattern similar to humans were investigated. In order to investigate a possible effect of ezetimibe on cholesterol induced inflammation NF-kappaB activation as an indicator for inflammatory processes in liver and gut tissue was measured.


RESULTS
Lipid enriched diet led to accumulation of lipids in hepatic tissue which caused strong hepatic NF-kappaB activation. Ezetimibe reduced lipid diet induced increase of circulating cholesterol by about 77% and prevent hepatic NF-kappaB activation almost completely. In contrast in intestinal cells Ezetimibe, though lowering diet induced cholesterol accumulation, increased triglyceride content and subsequent NF-kappaB activation.


CONCLUSIONS
In summary these data show, that ezetimibe effectively reduced diet induced circulating cholesterol levels, hepatic lipid accumulation and inflammatory response in our guinea pig model. However this drug elicited a local inflammatory response in intestinal tissue. Whether these diverse effects of ezetimibe on inflammatory parameters such as NF-kappaB have clinical relevance remains to be determined.
Medical Central Laboratories, Carinagasse 41, A-6800 Feldkirch, Austria.|Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany.
Peter
P
Fraunberger
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Elisabeth
E
Gröne
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Hermann-Josef
HJ
Gröne
Vorarlberger Institute of Vascular Investigation and Treatment (VIVIT), Dornbirn, Austria.
Heinz
H
Drexel
Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany.
Autar K
AK
Walli
Cholesterol; Ezetimibe; Guinea pigs; Inflammation; Intestine; Liver