Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux

Abstract

Increasing evidence, both direct and indirect, indicates that the small intestine (SI) may be an important modulator of atherosclerosis. As a result, the SI offers promising therapeutic targets for the prevention and treatment of this disease.The SI is linked to atherosclerosis in at least four respects. First, intestinal inflammation in the form of inflammatory bowel disease (IBD) has been linked to an increased prevalence of early stage vascular disease in patients without the classical cardiovascular risk factors (1-3). Second, our own recent research has established a link between aberrant levels of lipid signals in the SI and both dyslipidemia and atherosclerosis. Intestinally derived unsaturated lysophosphatidic acids (LPAs) and eicosanoids can both induce dyslipidemia as well as systemic inflammation in LDL receptor null (LDLR / ) mice (4, 5). Dietary LPA can also induce atherogenesis (6), and the levels of unsaturated LPAs in the SI correlate with the extent of atherosclerosis in LDLR / mice fed a Western diet (WD) (7). Third, the SI is an important source of apoAI (8), and at least in mice 30% of the steady-state plasma HDLcholesterol pool is derived from the SI (9). Moreover, while HDL can interrupt atherogenesis by preventing oxidative Abstract The site and mechanism of action of the apoA-I mimetic peptide 4F are incompletely understood. Transintestinal cholesterol efflux (TICE) is a process involved in the clearance of excess cholesterol from the body. While TICE is responsible for at least 30% of the clearance of neutral sterols from the circulation into the intestinal lumen, few pharmacological agents have been identified that modulate this pathway. We show first that circulating 4F selectively targets the small intestine (SI) and that it is predominantly transported into the intestinal lumen. This transport of 4F into the SI lumen is transintestinal in nature, and it is modulated by TICE. We also show that circulating 4F increases reverse cholesterol transport from macrophages and cholesterol efflux from lipoproteins via the TICE pathway. We identify the cause of this modulation of TICE either as 4F being a cholesterol acceptor with respect to enterocytes, from which 4F enhances cholesterol efflux, or as 4F being an intestinal chaperone with respect to TICE. Our results assign a novel role for 4F as a modulator of the TICE pathway and suggest that the anti-inflammatory functions of 4F may be a partial consequence of the codependent intestinal transport of both 4F and cholesterol.

Apolipoprotein A-I mimetics mitigate intestinal inflammation in a COX2-dependent inflammatory disease model

“…We determined the effect of 4F on plasma paraoxonase-1 (PON1) activity as a measure of HDL and on plasma total cholesterol (TC) (Supplemental Figure 17) (41). 4F significantly reduced TC, consistent with our prior reports that 4F can enhance the trans-intestinal efflux of cholesterol (17). 4F also significantly improved PON1 activity.…”

“…4F and transgenic 6F (Tg6F; extract from tomatoes expressing the 6F peptide) are protective in numerous animal models of inflammatory diseases, including atherosclerosis (16). We previously reported that circulating 4F selectively targets the small intestine, where it is transported into the intestinal lumen, reabsorbed by the intestinal mucosa, and mediates the trans-intestinal efflux of cholesterol (17). We also demonstrated that both orally and subcutaneously administered 4F reduce the levels of proinflammatory fatty acid metabolites in enterocytes of low-density lipoprotein receptor-null (LDLR-null) mice on Western diet (18).…”

ApoA-I mimetic administration, but not increased apoA-I-containing HDL, inhibits tumour growth in a mouse model of inherited breast cancer

“…The presence of 4F in HDL allowed the transfer of oxidized lipids (majorly oxidized phospholipids) from LDL to HDL and their pre-β HDL-facilitated elimination1931. Nevertheless, it has also been demonstrated that 4F preferentially targets the small intestine, and is predominantly transported into the intestinal lumen via a trans-intestinal pathway32. Although we cannot rule out the direct effect of D-4F within mammary glands, our results strongly indicate that the D-4F-mediated effects on oxLDL formation counteract the pro-carcinogenic signalling of these modified lipoproteins.…”

Oral Apolipoprotein A‐I Mimetic D‐4F Lowers HDL‐Inflammatory Index in High‐Risk Patients: A First‐in‐Human Multiple‐Dose, Randomized Controlled Trial

“…Meriwether et al 40 recently showed i.v. administration of both D-4F and L-4F in mice selectively targeted the small intestine and the peptides were transported into the intestinal lumen.…”