Atorvastatin increases intestinal expression of NPC1L1 in hyperlipidemic men

Abstract

The relationship between elevated plasma levels of LDLcholesterol (LDL-C) and the risk of atherosclerosis has been very well established ( 1-3 ). Clinical trials have shown that reduction of LDL-C constitutes a primary strategy for the prevention and regression of coronary heart disease ( 4 ). Plasma cholesterol levels are regulated by feedback mechanisms including exogenous cholesterol absorption through the gastrointestinal tract and endogenous cholesterol synthesis by various tissues. Several studies have shown that the amount of dietary cholesterol absorbed also infl uences endogenous cholesterol synthesis ( 5-7 ). The newly identifi ed Niemann-Pick C1-like 1 (NPC1L1) protein expressed at the apical membrane of enterocytes has been shown to play a crucial role in the absorption of cholesterol and plant sterol ( 8 ). Several physiological determinants and pharmacological agents modulate cholesterol homeostasis, including genetic factors, body weight, ezetimibe therapy, and 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoAR) inhibitors (statins) therapy, the rate-limiting step in the cholesterol biosynthesis pathway ( 9 ). For instance, obese subjects show an increase in cholesterol synthesis with an associated decrease in cholesterol absorption ( 10, 11 ). Ezetimibe therapy has been shown to reduce intestinal cholesterol absorption while reciprocally elevating synthesis ( 12 ). These fi ndings suggest the presence of a reciprocal relationship between cholesterol absorption and synthesis, as a change in one vector results in a compensatory and opposing change in the other. Although recent data suggest that statin therapy is associated

Glucagon receptor antagonism induces increased cholesterol absorption

“…This, however, does not negate the published fi ndings of glucagon on the Srebp-2 pathway, including LDLR ( 46 ), PCSK9 ( 50 ), and cholesterol synthesis ( 29 ). The induction of GRA on GLP-2 is so dramatic that it might have masked the activation on the Srebp-2 pathway caused by blockade of GCGR, inasmuch as intestinal cholesterol absorption and hepatic cholesterol synthesis are reversely affected by each other ( 51,52 ). Another set of observations obtained in the present studies of GRA treatment that we posit to be fruitful for further examinations concerns bile acids.…”

Effects of CETP inhibition on triglyceride-rich lipoprotein composition and apoB-48 metabolism

“…This alteration in apoB-48 metabolism may be another mechanism by which CETP inhibition contributes to the reduction of CHD risk in humans. of ABCG5 and ABCG8, without changing signifi cantly the expression of apoB-48 ( 44 ). There is, however, a great deal of individual variability in these studies, and the precise effect that statin therapy has on apoB-48 metabolism may depend on the underlying lipoprotein disorder.…”

Disturbed Chylomicron Metabolism in Type 2 Diabetes - A Preventable Cause of Atherosclerosis?

“…Ezetimibe potentiates the effect of statins, increasing their effectiveness by another 15 -20% in relation to cholesterol lowering. Trembly et al [69] this year reported an increase in NPC1L1 by 19% in the small intestine in subjects on atorvastatin thus describing a mechanism whereby cholesterol absorption is increased in patients on statins. In animal studies we have demonstrated an increase in cholesterol absorption in diabetes [70] We asked the question as to whether diabetes might be associated with an increase in cholesterol absorption through stimulation of NPC1-L1.…”