Inhibition of ileal apical but not basolateral bile acid transport reduces atherosclerosis in apoE−/− mice

Lan, Tian; Haywood, Jamie; Dawson, Paul A.

doi:10.1016/j.atherosclerosis.2013.05.017

Cited by 28 publications

(23 citation statements)

References 42 publications

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“…Our observation that RSV does not affect OSTα protein expression has physiological significance. Lan et al [41] showed recently that inhibition of ASBT, but not OSTα, is required to achieve plasma cholesterol reduction when blocking intestinal bile acid reabsorption. NTCP degradation has been shown previously to occur via the ubiquitin-proteasome pathway [42].…”

Section: Discussionmentioning

confidence: 98%

Resveratrol promotes degradation of the human bile acid transporter ASBT (SLC10A2)

Chothe

Swaan

2014

Biochemical Journal

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The sodium/bile acid co-transporter ASBT [apical sodium-dependent bile acid transporter; SLC10A2 (solute carrier family 10 member 2)] plays a key role in the enterohepatic recycling of the bile acids and indirectly contributes to cholesterol homoeostasis. ASBT inhibitors reportedly lower plasma triglyceride levels and increase HDL (high-density lipoprotein) cholesterol levels. RSV (resveratrol), a major constituent of red wine, is known to lower LDL (low-density lipoprotein) cholesterol levels, but its mechanism of action is still unclear. In the present study, we investigated the possible involvement of ASBT in RSV-mediated cholesterol-lowering effects. We demonstrate that RSV inhibits ASBT protein expression and function via a SIRT1 (sirtuin 1)-independent mechanism. The effect was specific to ASBT since other transporters involved in cholesterol homoeostasis, NTCP (SLC10A1), OSTα (SLC51A) and ABCG1 (ATP-binding cassette G1), remained unaffected. ASBT inhibition by RSV was reversed by proteasome inhibitors (MG-132 and lactacystin) and the ubiquitin inhibitor LDN57444, suggesting involvement of the ubiquitin-proteasome pathway. Immunoprecipitation revealed high levels of ubiquitinated ASBT after RSV treatment. Phosphorylation at Ser335 and Thr339 was shown previously to play a role in proteosomal degradation of rat ASBT. However, mutation at corresponding residues in rat ASBT revealed that phosphorylation does not contribute to RSV-mediated degradation of ASBT. Combined, our data indicate that RSV promotes ASBT degradation via the ubiquitin-proteasome pathway without requiring phosphorylation. We conclude that regulation of ASBT expression by RSV may have clinical relevance with regard to the observed cholesterol-lowering effects of RSV.

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Section: Discussionmentioning

confidence: 98%

Resveratrol promotes degradation of the human bile acid transporter ASBT (SLC10A2)

Chothe

Swaan

2014

Biochemical Journal

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“…The effect of inactivation of the Asbt on development of hypercholesterolemia and atherosclerosis in female LDLr and apoE null mice maintained for 16 weeks on an atherogenic diet has been reported recently [29]. In that study, introducing the Asbt null allele into the LDLr null or apoE null backgrounds resulted in significant reductions in total plasma cholesterol, apoB-containing lipoprotein (VLDL plus LDL) cholesterol, and the plasma cholesterol exposure (area under the curve) over the 16-week dietary challenge.…”

Section: Effect Of Blocking Ileal Apical Brush Border Membrane Bile Amentioning

confidence: 99%

“…In agreement with the proposed role of the FXR-FGF15 pathway as a negative regulator of hepatic bile acid synthesis, there was a strong inverse correlation between the levels of mRNA expression for ileal FGF15 and hepatic Cyp7a1 in these models. However even more intriguing, there was a strong direct correlation between ileal FGF15 mRNA expression and total plasma cholesterol levels, and between ileal FGF15 mRNA expression and aortic cholesterol content, a measure of atherosclerosis [29]. The question of whether a similar relationship exists between plasma levels of FGF19 (human ortholog of mouse FGF15) and markers of atherosclerosis exists in humans has not yet been examined.…”

Section: Effect Of Blocking Ileal Apical Brush Border Membrane Bile Amentioning

confidence: 99%

Impact of Inhibiting Ileal Apical versus Basolateral Bile Acid Transport on Cholesterol Metabolism and Atherosclerosis in Mice

Dawson

2015

Dig Dis

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Background: Bile acid sequestrants have been used for many years to treat hypercholesterolemia by increasing hepatic conversion of cholesterol to bile acids, thereby inducing hepatic LDL receptor expression and clearance of apoB-containing particles. In order to further understand the underlying molecular mechanisms linking gut-liver signaling and cholesterol homeostasis, mouse models defective in ileal apical membrane bile acid transport (Asbt-null) and ileal basolateral membrane bile acid transport (Ostα-null) were studied under basal and hypercholesterolemic conditions. Key Messages: Hepatic conversion of cholesterol to bile acids is the major pathway for cholesterol catabolism and a major mechanism for cholesterol elimination. Blocking ileal apical membrane bile acid transport (Asbt-null mice) increases fecal bile acid excretion, hepatic Cyp7a1 expression, and the relative proportion of taurocholate in the bile acid pool, but decreases ileal FGF15 expression, bile acid pool size, and hepatic cholesterol content. In contrast, blocking ileal basolateral membrane bile acid transport (Ostα-null mice) increases ileal FGF15 expression, reduces hepatic Cyp7a1 expression, and increases the proportion of tauro-β-muricholic acid in the bile acid pool. In the hypercholesterolemic apoE-null background, plasma cholesterol levels and measurements of atherosclerosis were reduced in Asbt/apoE-null mice, but not in Ostα/apoE-null mice. Conclusions: Blocking the intestinal absorption of bile acids at the apical versus basolateral membrane differentially affects bile acid and cholesterol metabolism, including the development of hypercholesterolemia-associated atherosclerosis. The molecular mechanism likely involves an altered regulation of ileal FGF15 expression.

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“…More recently, Lan et al showed that mice lacking the intestine basolateral bile acid efflux transporter ostα had significantly reduced bile acid pool size but also lower hepatic CYP7A1 gene expression (10), which was resulted from bile acid retention in the intestine that leads to FGF15 induction. The same group also demonstrated that mice lacking the intestine apical sodium dependent bile acid transporter (ASBT) showed reduced intestine FGF15 expression, higher hepatic CYP7A1 expression and resistance to atherosclerosis development (11). These studies reiterated the importance of gut-liver signaling axis in the regulation of bile acid and lipid homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Bile acids as metabolic regulators

Chiang

2015

Current Opinion in Gastroenterology

238

183

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Summary Small molecule ligands that target to TGR5 and FXR have shown promise in treating various metabolic and inflammation-related human diseases. New insights into the mechanisms underlying the bariatric surgery and bile acid sequestrant treatment suggest that targeting the enterohepatic circulation to modulate gut-liver bile acid signaling, incretin production and microbiota represents a new strategy to treat obesity and type-2 diabetes.

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Inhibition of ileal apical but not basolateral bile acid transport reduces atherosclerosis in apoE−/− mice

Cited by 28 publications

References 42 publications

Resveratrol promotes degradation of the human bile acid transporter ASBT (SLC10A2)

Resveratrol promotes degradation of the human bile acid transporter ASBT (SLC10A2)

Impact of Inhibiting Ileal Apical versus Basolateral Bile Acid Transport on Cholesterol Metabolism and Atherosclerosis in Mice

Bile acids as metabolic regulators

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