Efficient reabsorption of transintestinally excreted cholesterol is a strong determinant for cholesterol disposal in mice

Peppel, Ivo P van de; Bertolini, Anna; Dijk, Theo H. van; Groen, Albert K.; Jonker, Johan W.; Verkade, Henkjan J.

doi:10.1194/jlr.m094607

Cited by 19 publications

(28 citation statements)

References 54 publications

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“…Anti-steatotic effects of ASBT pharmacological inhibition have been a consistent finding in high fat diet-fed mouse models, including the CSAA diet-fed mice in this study (10,11), and we previously observed inhibitory effects of ASBT genetic inactivation on intestinal cholesterol and fat absorption (29,34,35). In our current study, ASBTi treatment lowered fatty acid absorption and intestinal fat absorption positively correlated with hepatic triglyceride levels in the CSAA diet-fed mice.…”

Section: Discussionsupporting

confidence: 87%

“…Inhibiting the ASBT in mice has been shown to increase the proportion of cholic acid (CA) plus its bacterial dehydroxylation product deoxycholic acid (DCA) and to reduce the proportion of 6-hydroxylated bile acid species, including alpha-muricholic acid (αMCA), beta-muricholic acid (βMCA), and the bacterial product omega-muricholic acid (ωMCA) (10,11,29). To determine if the CDAA diet alters the effect of ASBT inhibition on bile acid composition, the fecal bile acid profiles were determined using quantitative three-day fecal collections performed for individually-housed mice (Figure 2).…”

Section: Asbt Inhibitor Treatment Reduces Bodyweight Gain In Csaa Andmentioning

confidence: 99%

“…We previously reported that genetic ASBT knockout in mice reduces intestinal fat and cholesterol absorption (29,34,35). In order to determine if the ASBTi treatment had similar effects in the CSAA and CDAA diet-fed mice, we measured fat absorption using the sucrose polybehenate method (20).…”

Section: Asbt Inhibitor Treatment Reduces Intestinal Fat Absorption Imentioning

confidence: 99%

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Attenuation of the Hepatoprotective Effects of Ileal Apical Sodium Dependent Bile Acid Transporter (ASBT) Inhibition in Choline-Deficient L-Amino Acid-Defined (CDAA) Diet-Fed Mice

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) is a major growing worldwide health problem. We previously reported that interruption of the enterohepatic circulation of bile acids using a non-absorbable apical sodium-dependent bile acid transporter inhibitor (ASBTi; SC-435) reduced the development of NAFLD in high fat diet fed mice. However, the ability of ASBTi treatment to impact the progression of NAFLD to non-alcoholic steatohepatitis (NASH) and fibrosis in a diet-induced mouse model remains untested. In the current study, we assessed whether ASBTi treatment is hepatoprotective in the choline-deficient, L-amino acid-defined (CDAA) diet model of NASH-induced fibrosis. Methods: Male C57Bl/6 mice were fed with: (A) choline-sufficient L-amino acid-defined diet (CSAA) (31 kcal% fat), (B) CSAA diet plus ASBTi (SC-435; 60 ppm), (C) CDAA diet, or (D) CDAA diet plus ASBTi. Body weight and food intake were monitored. After 22 weeks on diet, liver histology, cholesterol and triglyceride levels, and gene expression were measured. Fecal bile acid and fat excretion were measured, and intestinal fat absorption was determined using the sucrose polybehenate method. Results: ASBTi treatment reduced bodyweight gain in mice fed either the CSAA or CDAA diet, and prevented the increase in liver to body weight ratio observed in CDAA-fed mice. ASBTi significantly reduced hepatic total cholesterol levels in both CSAA and CDAA-fed mice. ASBTi-associated significant reductions in hepatic triglyceride levels and histological scoring for NAFLD activity were observed in CSAA but not CDAAfed mice. These changes correlated with measurements of intestinal fat absorption, which was significantly reduced in ASBTi-treated mice fed the CSAA (85 vs. 94%, P < 0.001) but not CDAA diet (93 vs. 93%). As scored by Ishak staging of Sirius red stained liver sections, no hepatic fibrosis was evident in the CSAA diet mice. The CDAA diet-fed mice developed hepatic fibrosis, which was increased by the ASBTi. Rao et al. Hepatoprotective Mechanisms of ASBT Inhibition Conclusions: ASBT inhibition reduced intestinal fat absorption, bodyweight gain and hepatic steatosis in CSAA diet-fed mice. The effects of the ASBTi on steatosis and fat absorption were attenuated in the context of dietary choline-deficiency. Inhibition of intestinal absorption of fatty acids may be involved in the therapeutic effects of ASBTi treatment.

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Section: Discussionsupporting

confidence: 87%

Section: Asbt Inhibitor Treatment Reduces Bodyweight Gain In Csaa Andmentioning

confidence: 99%

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Attenuation of the Hepatoprotective Effects of Ileal Apical Sodium Dependent Bile Acid Transporter (ASBT) Inhibition in Choline-Deficient L-Amino Acid-Defined (CDAA) Diet-Fed Mice

et al. 2020

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“…Interruption of the enterohepatic circulation of BAs by inhibition or genetic inactivation of the apical sodium-dependent BA transporter (ASBT, SLC10A2) in mice decreased intestinal lipid absorption. [9][10][11] Micellar solubilization is most important for hydrophobic lipids such as cholesterol, fat-soluble vitamins, and (long-chain) saturated fatty acids (SFAs). Studies using cholestatic and bile-deficient rat models showed more pronounced effects on absorption of long chain SFAs than on long chain PUFAs.…”

Section: Introductionmentioning

confidence: 99%

“…[12,13] ASBT deficiency, however, not only decreases total BA concentrations, but also shifts the BA composition towards a more hydrophobic profile containing more cholic acid (CA) and less muri-cholic acid (MCA). [9,11,14] Hydrophobic BAs have a lower CMC and are more efficient in micellar solubilization. [15,16] Therefore, it was hypothesized that the increase in biliary hydrophobicity relatively preserves lipid absorption in Asbt −/− mice.…”

Section: Introductionmentioning

confidence: 99%

The Beneficial Effects of Apical Sodium‐Dependent Bile Acid Transporter Inactivation Depend on Dietary Fat Composition

Peppel

Rao

Dommerholt

et al. 2020

Molecular Nutrition Food Res

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Scope The apical sodium‐dependent bile acid transporter (ASBT, SLC10A2) is important in the enterohepatic cycling of bile acids and thereby in the intestinal absorption of lipids. ASBT inhibition has been shown to improve aspects of the metabolic syndrome, but the underlying mechanisms have remained unclear. Here, the effect of ASBT inhibition on the uptake of specific fatty acids and its consequences for diet‐induced obesity and non‐alcoholic fatty liver disease (NAFLD) are investigated. Methods Intestinal fat absorption is determined in mice receiving an ASBT inhibitor and in Asbt−/− mice. Metabolic disease development is determined in Asbt−/− mice receiving a low‐fat control diet (LFD) or high‐fat diet (HFD) rich in saturated fatty acids (SFAs) or PUFAs. Results Both ASBT inhibition and Asbt gene inactivation reduce total fat absorption, particularly of SFAs. Asbt gene inactivation lowers bodyweight gain, improves insulin sensitivity, and decreases the NAFLD activity score upon feeding a HFD rich in SFAs, but not in PUFAs. Conclusions The beneficial metabolic effects of ASBT inactivation on diet‐induced obesity depend on decreased intestinal absorption of SFAs, and thus on the dietary fatty acid composition. These findings highlight the importance of dietary fatty acid composition in the therapeutic effects of ASBT inhibition.

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Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology

et al. 2021

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Bile salts play a pivotal role in lipid homeostasis, are sensed by specialized receptors, and have been implicated in various disorders affecting the gut or liver. They may play a role either as culprit or as potential panacea. Four very efficient transporters mediate most of the hepatic and intestinal bile salt uptake and efflux, and are each essential for the efficient enterohepatic circulation of bile salts. Starting from the intestinal lumen, conjugated bile salts cross the otherwise impermeable lipid bilayer of (primarily terminal ileal) enterocytes through the apical sodium–dependent bile acid transporter (gene SLC10A2 ) and leave the enterocyte through the basolateral heteromeric organic solute transporter, which consists of an alpha and beta subunit (encoded by SLC51A and SLC51B ). The Na + ‐taurocholate cotransporting polypeptide (gene SLC10A1 ) efficiently clears the portal circulation of bile salts, and the apical bile salt export pump (gene ABCB11 ) pumps the bile salts out of the hepatocyte into primary bile, against a very steep concentration gradient. Recently, individuals lacking either functional Na + ‐taurocholate cotransporting polypeptide or organic solute transporter have been described, completing the quartet of bile acid transport deficiencies, as apical sodium–dependent bile acid transporter and bile salt export pump deficiencies were already known for years. Novel pathophysiological insights have been obtained from knockout mice lacking functional expression of these genes and from pharmacological transporter inhibition in mice or humans. Conclusion : We provide a concise overview of the four main bile salt transport pathways and of their status as possible targets of interventions in cholestatic or metabolic disorders.

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Efficient reabsorption of transintestinally excreted cholesterol is a strong determinant for cholesterol disposal in mice

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Cited by 19 publications

References 54 publications

Attenuation of the Hepatoprotective Effects of Ileal Apical Sodium Dependent Bile Acid Transporter (ASBT) Inhibition in Choline-Deficient L-Amino Acid-Defined (CDAA) Diet-Fed Mice

Attenuation of the Hepatoprotective Effects of Ileal Apical Sodium Dependent Bile Acid Transporter (ASBT) Inhibition in Choline-Deficient L-Amino Acid-Defined (CDAA) Diet-Fed Mice

The Beneficial Effects of Apical Sodium‐Dependent Bile Acid Transporter Inactivation Depend on Dietary Fat Composition

Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology

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