Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE−/− mice by SC-435

Bhat, Balkrishen; Rapp, Stéphen R.; Beaudry, Judith A.; Napawan, Nida; Butteiger, Dustie N; Hall, Kerri A.; Null, Christopher L.; Luo, Yi; Keller, Bradley T.

doi:10.1194/jlr.m200469-jlr200

Cited by 87 publications

(80 citation statements)

References 37 publications

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“…This point is nicely illustrated in a study comparing the development of hypercholesterolemia and atherosclerosis in apoE-null mice lacking either the ASBT or OST ␣ ( 100 ). Similar to the effects of bile acid sequestrants ( 101 ) or ASBT inhibitors ( 102,103 ), levels of plasma and hepatic cholesterol and markers of atherosclerosis development were reduced in apoE-null mice lacking the ASBT. However, these markers were not reduced in apoE-null mice lacking OST ␣ .…”

Section: Enterocyte Metabolism Of Bile Acidsmentioning

confidence: 57%

Intestinal transport and metabolism of bile acids

Dawson

Karpen

2015

Journal of Lipid Research

424

371

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Section: Enterocyte Metabolism Of Bile Acidsmentioning

confidence: 57%

Intestinal transport and metabolism of bile acids

Dawson

Karpen

2015

Journal of Lipid Research

424

371

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“…Several in vivo studies were performed with SC-435 treatment in Hartley guinea pigs, miniature pigs, New Zealand White rabbits and dogs. Concordantly, these studies found an increase of faecal bile acid excretion, decreased total and LDL-cholesterol plasma levels, and enhanced expression of the hepatic LDL receptor, secondary to the upregulation of hepatic cholesterol 7α-hydroxylase (CYP7A1) expression (Huff et al 2002;West et al 2002West et al , 2003Bhat et al 2003;Telford et al 2003;Li et al 2004).…”

Section: Pharmacological Inhibition Of the Asbtmentioning

confidence: 70%

The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

Geyer

Wilke

Petzinger

2006

Naunyn Schmied Arch Pharmacol

158

138

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The solute carrier family 10 (SLC10) comprises two sodium-dependent bile acid transporters, i.e. the Na + / taurocholate cotransporting polypeptide (NTCP; SLC10A1) and the apical sodium-dependent bile acid transporter (ASBT; SLC10A2). These carriers are essentially involved in the maintenance of the enterohepatic circulation of bile acids mediating the first step of active bile acid transport through the membrane barriers in the liver (NTCP) and intestine (ASBT). Recently, four new members of the SLC10 family were described and referred to as P3 (SLC10A3), P4 (SLC10A4), P5 (SLC10A5) and sodium-dependent organic anion transporter (SOAT; SLC10A6). Experimental data supporting carrier function of P3, P4, and P5 is currently not available. However, as demonstrated for SOAT, not all members of the SLC10 family are bile acid transporters. SOAT specifically transports steroid sulfates such as oestrone-3-sulfate and dehydroepiandrosterone sulfate in a sodium-dependent manner, and is considered to play an important role for the cellular delivery of these prohormones in testes, placenta, adrenal gland and probably other peripheral tissues. ASBT and SOAT are the most homologous members of the SLC10 family, with high sequence similarity (∼70%) and almost identical gene structures. Phylogenetic analyses of the SLC10 family revealed that ASBT and SOAT genes emerged from a common ancestor gene. Structure-activity relationships of NTCP, ASBT and SOAT are discussed at the amino acid sequence level.Based on the high structural homology between ASBT and SOAT, pharmacological inhibitors of the ASBT, which are currently being tested in clinical trials for cholesterollowering therapy, should be evaluated for their crossreactivity with SOAT.

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“…It is reasonable to speculate that a reduced ability to convert cholesterol to bile acids would lead to body cholesterol overload, with the subsequent development of atherosclerosis [Assmann et al 2006;Sudhop et al 2002;Rajaratnam et al 2000Rajaratnam et al , 1999Glucc et al1991]. Studies in animals have revealed that mice and rats [Guorong et al 2004;Bhat et al 2003;Post et al 2003;Lutton, 1990] do not develop experimental atherosclerosis, despite ingestion of a cholesterol-rich diet. They were able to react to the overload of cholesterol intake by excreting large amounts of bile acids.…”

Section: Introductionmentioning

confidence: 99%

“…statins), the development of atherosclerosis cannot be stopped in a significant number of patients. In addition to statins, low-density lipoprotein cholesterol (LDL-c) can be reduced by increasing the fecal bile acid waste and by compensatory hepatic upregulation of bile acid synthesis [Bhat et al 2003;Izzat et al 2000]. While a great deal of attention has been given to the factors that determine cholesterol homeostasis, cholesterol excretion via bile in patients with CAD has not been examined in depth.…”

Section: Introductionmentioning

confidence: 99%

The association of bile acid excretion and atherosclerotic coronary artery disease

Charach

Grosskopf

Rabinovich

et al. 2010

Therap Adv Gastroenterol

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Abstract:Background: Excess cholesterol is usually eliminated from the body by conversion to bile acids excreted in feces as bile salts. The excretion of large amounts of bile protects against atherosclerosis, while diminished excretion may lead to coronary artery disease (CAD). Objective: To investigate a relationship between CAD and bile acid excretion. Methods: Bile acid excretion was compared between 36 patients with proven CAD and 37 CAD-free individuals (controls). The groups were comparable for demographics and selected risk factors. All subjects received a 4-day standard diet that included $500 mg of cholesterol. Fecal bile acids from 24-hour stool collections were measured by gas liquid chromatography. Results: CAD patients excreted lower amounts of total bile acids (358±156 mg) than controls (617±293 mg; p < 0.01) and less deoxycholic acid (188.29±98.12 mg versus 325.96±198.57 mg; p < 0.0001) and less lithocholic acid (115.43±71.89 mg versus 197.27±126.87 mg; p < 0.01). Advanced age, male gender, left ventricular ejection fraction and total bile acid levels were significant independent factors that predicted CAD (p < 0.05). Mortality, CAD and cerebrovascular accident development rates were significantly lower for the controls at the 13-year follow up. Conclusion: CAD patients have significantly decreased bile acid excretion levels than non-CAD patients. An impaired ability to excrete cholesterol may be an additional risk factor for CAD development.

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Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE−/− mice by SC-435

Abstract: These results suggest that specific inhibition of ASBT is a novel therapeutic approach for treatment of hypercholesterolemia resulting in a decreased risk for atherosclerosis. -

Cited by 87 publications

References 37 publications

Intestinal transport and metabolism of bile acids

Intestinal transport and metabolism of bile acids

The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

The association of bile acid excretion and atherosclerotic coronary artery disease

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