3. Niemann Pick C1-Like1

The discovery of Niemann Pick C1-like1 (NPC1L1) is an interesting story. The search for an explanation as to how cholesterol in the body is so finely regulated has been intensive. The finely tuned regulation of cholesterol was perhaps best illustrated by the report of the elderly gentleman who ate 25 eggs a day for many years but his cholesterol remained at just above 6 mmol/L [18]. Altman and Davis in their search for molecules that might inhibit cholesterol absorption discovered by chance a compound which is now known as Ezetimibe [19]. They discovered a putative gene, the Niemann Pick C1-like1 (NPC1-L1). Elegant studies in mice demonstrated that knocking out this gene reduced cholesterol absorption by the same amount as happened when the wild mice were fed with Ezetimibe. They showed that there was no further reduction in cholesterol absorption in the knockout mice when fed Ezetimibe. The group went on to show that lack of NPC1L1 in apoE^{−/−} mice results in a significant reduction in cholesterol absorption and plasma cholesterol levels and caused a nearly complete protection from the development of atherosclerosis, under both cholesterol-fed and non-cholesterol-fed conditions [20, 21]. Weinglass et al. [14] have shown that Ezetimibe binds to a site distinct to the site where cholesterol binds, preventing conformational changes in NPC1L1 that is necessary for translocation of cholesterol across the membrane. Statins, which inhibit HMGCoA reductase and cholesterol synthesis, have been shown to increase cholesterol absorption. It has also been shown that low absorbers of cholesterol respond better to statins than high absorbers [22]. Ezetimibe potentiates the effect of statins, increasing their effectiveness by another 15-20% in relation to cholesterol lowering. Tremblay et al. [23] reported an increase in NPC1L1 by 19% on atorvastatin thus describing a mechanism whereby cholesterol absorption is increased in patients on statins. The mechanism of action of NPC1L1 has recently been further elucidated. It has been shown that cholesterol promotes the formation and endocytosis of NPC1L1 which appears to be an early step in cholesterol uptake. Zhang et al. [24] have discovered that it is the N-terminal domain of NPC1L1 that binds cholesterol. It is interesting that this domain does not bind to plant sterols; thus it now seems that plasma membrane-bound NPC21L1 binds exogenous cholesterol and this binding facilitates the formation of NPC1L1-flotiln-cholestrerol microdomains that are then internalized into cells through the clathrin AP2 pathway. In animal studies we have demonstrated an increase in cholesterol absorption in diabetes [25]; we asked the question as to whether diabetes might be associated with an increase in cholesterol absorption through stimulation of NPC1-L1. We demonstrated in animal models of diabetes that NPC1L1 was upregulated [26] and in diabetic patients, and we demonstrated an increase in NPC1L1 mRNA [27] suggesting a mechanism for an increase in cholesterol absorption. In the Psammomys Obesus, a model of type 2 diabetes, the animals exhibiting weight gain, hyperinsulinaemia, and hypercholesterolaemia, NPC1-L1 protein and gene expression were both significantly reduced in the intestine, and the authors found a lower capacity to absorb cholesterol compared to controls [28]. This may suggest interspecies variation but it is a surprising finding considering that this animal model of diabetes has been shown to have increased production of intestinal lipoprotein-containing apo B48 [29]. Ezetimibe has been shown to bind to the brush border and to NPCILI-expressing cells, [30]. There is a sterol regulatory element in the promoter and a sterol-sensing domain of NPCILI which appears to regulate cholesterol absorption in response to cholesterol intake. Huff et al. [31] have shown that NPC1L1 is suppressed in mice given a cholesterol-rich diet and increased in the cholesterol-depleted porcine intestine. The nuclear receptor, peroxisome proliferator-activated receptor (PPAR) delta/beta, appears to control the expression of NPC1L1. Activation by a synthetic agonist of PPAR delta has been shown to reduce cholesterol absorption and reduce expression of NPC1L1 without altering ABC G5/8 [32]. Tremblay et al. [23] have shown that Atorvastatin increases Niemann Pick C1L1 in the intestine and decreased ABC G 5/8 which leads to an increase in cholesterol absorption. These findings were accompanied by an increase in the transcription factors, sterol regulatory binding protein (SREBP) 2 and hepatic nuclear factor (HNF)-4. There may be other transporters of cholesterol, for example, scavenger receptor class B type 1 (SR-B1) [33] which is located both in the apical and basolateral membranes of the enterocyte. They may also play a role in cholesterol absorption. (For review see Iqbal and Hussein [9])..



The 2012 Full Text will come later as this thread is developed.  Building upon Elements to Atherosclerosis.