Hepatic Overexpression of Murine Abcb11 Increases Hepatobiliary Lipid Secretion and Reduces Hepatic Steatosis

Figge, A.; Lammert, Frank; Paigen, Beverly; Henkel, Anne S.; Matern, Siegfried; Korstanje, Ron; Shneider, Benjamin L.; Chen, Fanglin; Stoltenberg, Erik; Spatz, Kathryn; Hoda, Farzana; Cohen, David E.; Green, Richard M.

doi:10.1074/jbc.m307363200

Cited by 90 publications

(69 citation statements)

References 42 publications

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“…increased bile salt pool hydrophobicity due to elevated concentrations of taurodeoxycholate; they are also resistant to hepatic steatosis on high-fat and high-cholesterol diets supplemented with CA (57). While diminished hepatic cholesterol deposition in mice overexpressing Abcb11 is similar to that in L-ΔID animals, other features, such as increased BA pool hydrophobicity and increased biliary cholesterol excretion, are opposite of what is seen in L-ΔID mice.…”

Section: Figurementioning

confidence: 67%

Hepatic nuclear corepressor 1 regulates cholesterol absorption through a TRβ1-governed pathway

Astapova¹,

Ramadoss²,

Costa-e-Sousa³

et al. 2014

J. Clin. Invest.

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Transcriptional coregulators are important components of nuclear receptor (NR) signaling machinery and provide additional mechanisms for modulation of NR activity. Expression of a mutated nuclear corepressor 1 (NCoR1) that lacks 2 NR interacting domains (NCoRΔID) in the liver leads to elevated expression of genes regulated by thyroid hormone receptor (TR) and liver X receptor (LXR), both of which control hepatic cholesterol metabolism. Here, we demonstrate that expression of NCoRΔID in mouse liver improves dietary cholesterol tolerance in an LXRα-independent manner. NCoRΔID-associated cholesterol tolerance was primarily due to diminished intestinal cholesterol absorption as the result of changes in the composition and hydrophobicity of the bile salt pool. Alterations of the bile salt pool were mediated by increased expression of genes encoding the bile acid metabolism enzymes CYP27A1 and CYP3A11 as well as canalicular bile salt pump ABCB11. We have determined that these genes are regulated by thyroid hormone and that TRβ1 is recruited to their regulatory regions. Together, these data indicate that interactions between NCoR1 and TR control a specific pathway involved in regulation of cholesterol metabolism and clearance. IntroductionCholesterol metabolism in the liver is critical for normal systemic regulation of serum cholesterol levels and eventual cardiac risk. Both the thyroid hormone receptor (TR) and liver X receptor (LXR) regulate multiple cholesterol clearance pathways and have been targeted as potential therapeutic avenues to improve cholesterol metabolism in humans (1-4). Thyroid hormone (TH) and its liver-specific analogs have been shown to lower serum cholesterol levels through increased expression of the LDL-R and/or HDL receptor SR-B1 in the liver (2, 5, 6), stimulate cholesterol elimination via conversion to bile acids (3, 5, 7-9), enhance biliary cholesterol excretion through ATP-binding cassette transporter G5 and G8 (ABCG5/G8), and decrease cholesterol absorption (10-12). The effects of TH on the cholesterol metabolism in the liver are mediated by the TRβ1 isoform (7, 13).LXRα and LXRβ are activated by oxysterols and act as intracellular cholesterol sensors (14). LXRα is the major isoform in the liver that plays a predominant role in maintaining hepatic cholesterol homeostasis. Global or liver-specific KO of Lxra leads to a dramatic hepatic cholesterol accumulation in mice fed diets with high cholesterol content (15-17). LXRα controls cholesterol clearance through regulation of intestinal cholesterol absorption and biliary cholesterol secretion as well as cholesterol conversion into bile acids (15,(17)(18)(19). Thus, TRβ1 and LXRα regulate both distinct and overlapping pathways to control cholesterol metabolism in the liver. Based on this, we hypothesized that targeting common nuclear receptor (NR) coregulators could amplify beneficial effects of both pathways on cholesterol metabolism.Previous work from our laboratory and others has demonstrated that the NR corepressor, nuclear corepressor 1 (N...

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Section: Figurementioning

confidence: 67%

Hepatic nuclear corepressor 1 regulates cholesterol absorption through a TRβ1-governed pathway

Astapova¹,

Ramadoss²,

Costa-e-Sousa³

et al. 2014

J. Clin. Invest.

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“…The situation in patients with PFIC2 may differ to some extent from the knockout animals since analysis of four PFIC2 patients showed no significant upregulation of MDR1 mRNA [46]. Overexpression of Bsep in the liver transgenic animals leads to an increased biliary bile salt output concomitant with an increase in bile flow rate and biliary lipid secretion [26]. Fecal loss of bile salts is normal in these animals.…”

Section: Mice With Genetically Altered Bsep Expressionmentioning

confidence: 98%

The bile salt export pump

Stieger

Meier

2006

Pflugers Arch - Eur J Physiol

209

137

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“…Total bile acid pool size and composition were measured by HPLC as previously described ( 32 ). Samples were spiked with glycocholic acid as an internal standard to control for extraction effi ciency.…”

Section: Hplc Assaymentioning

confidence: 99%

A chronic high-cholesterol diet paradoxically suppresses hepatic CYP7A1 expression in FVB/NJ mice

Henkel

Anderson

Dewey

et al. 2011

Journal of Lipid Research

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Hepatic Overexpression of Murine Abcb11 Increases Hepatobiliary Lipid Secretion and Reduces Hepatic Steatosis

Cited by 90 publications

References 42 publications

Hepatic nuclear corepressor 1 regulates cholesterol absorption through a TRβ1-governed pathway

Hepatic nuclear corepressor 1 regulates cholesterol absorption through a TRβ1-governed pathway

The bile salt export pump

A chronic high-cholesterol diet paradoxically suppresses hepatic CYP7A1 expression in FVB/NJ mice

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