Enhancement by LDL of transfer of L-4F and oxidized lipids to HDL in C57BL/6J mice and human plasma

Meriwether, David; Imaizumi, Satoshi; Grijalva, Víctor; Hough, Greg; Vakili, Ladan; Anantharamaiah, G.M.; Farias‐Eisner, Robin; Navab, Mohamad; Fogelman, Alan M.; Reddy, Srinivasa T.; Shechter, Ishaiahu

doi:10.1194/jlr.m016741

Cited by 17 publications

(22 citation statements)

References 53 publications

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“…We have previously shown that circulating 4F has a high affinity for HDL and other lipoproteins (44), as well as for cholesterol (50). Thus, we next hypothesized that the transintestinal transport of 4F might partially depend on the transintestinal efflux of cholesterol.…”

Section: D-k-v-a-e-k-f-k-e-a-f-nhmentioning

confidence: 99%

“…TICE is also greatest in the proximal small bowel (25,28). We had previously reported that 4F binds with high affinity to lipoproteins including VLDL and HDL (44), as well as to cholesterol alone (50). Lipoproteins including LDL and VLDL (48) and possibly HDL (49) deliver cholesterol from the circulation to the basolateral side of small intestinal enterocytes, and TICE is itself an active and saturable pathway (25).…”

Section: Primary Enterocyte Cholesterol Efflux Studymentioning

confidence: 99%

“…4F has also been shown to improve HDL function (40,41), reduce systemic inflammation (42), reduce oxidative stress (43), and increase the clearance of oxidized lipid species from the circulation (44). Given these effects, and given the nature and location of atherosclerosis itself, our laboratory had long assumed that the circulation was the site of action for 4F (45).…”

Section: D-k-v-a-e-k-f-k-e-a-f-nhmentioning

confidence: 99%

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

Meriwether

Sulaiman

Wagner

et al. 2016

Journal of Lipid Research

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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.

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Section: D-k-v-a-e-k-f-k-e-a-f-nhmentioning

confidence: 99%

Section: Primary Enterocyte Cholesterol Efflux Studymentioning

confidence: 99%

Section: D-k-v-a-e-k-f-k-e-a-f-nhmentioning

confidence: 99%

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

Meriwether

Sulaiman

Wagner

et al. 2016

Journal of Lipid Research

Self Cite

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show abstract

“…Mice were fasted overnight with free access to water and were anesthetized with a mixture of ketamine (100-150 mg/kg) and by guest, on May 9, 2018 www.jlr.org …”

Section: Collection and Analysis Of Metabolites Of Arachidonic And LImentioning

confidence: 99%

“…The HDL particles formed in the small intestine enter the circulation directly; the HDL in lymph is predominantly derived from the plasma compartment ( 23 ). We recently reported that in the presence of the 4F peptide metabolites of arachidonic acid, such as free 15-HETE, are rapidly transferred in plasma from LDL to HDL and increase the association of 4F with HDL ( 24 ). Future studies are required to determine if 4F transfers oxidized metabolites of arachidonic and linoleic acids in enterocytes to intestinal HDL particles, which are then directly secreted into the circulation.…”

mentioning

confidence: 99%