The Enzymes, Regulation, and Genetics of Bile Acid Synthesis

Russell, David W.

doi:10.1146/annurev.biochem.72.121801.161712

Cited by 1,692 publications

(1,564 citation statements)

References 213 publications

(189 reference statements)

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“…By reversing this observation, a ligand-assisted targeting mechanism was proposed, where the PTS1 motif is pushed away from the SCP2 fold in response to ligand binding, thereby exposing the PTS1 residue uptake for the interaction with the Pex5p receptor. However, at variance with this model none of our experiments indicate that the PTS1 is affected by the presence of a lipid ligand (Figures 3E,F, 4E, and 6C, Supporting Information Figures 4,6,and 7). The 15 N relaxation data clearly show that the targeting signal is disordered and highly flexible, independent of the core lipid binding domain or its ligand binding state.…”

Section: The Conformation Of Termini Is Independent Of the Lipid Bindmentioning

confidence: 62%

Conformational Plasticity of the Lipid Transfer Protein SCP2

Filipp

Sattler

2007

Biochemistry

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The nonspecific lipid transfer protein sterol carrier protein 2 (SCP2) is involved in organellar fatty acid metabolism. A hydrophobic cavity in the structure of SCP2 accommodates a wide variety of apolar ligands such as cholesterol derivatives or fatty acyl-coenzyme A (CoA) conjugates. The properties of this nonspecific lipid binding pocket are explored using NMR chemical shift perturbations, paramagnetic relaxation enhancement, amide hydrogen exchange, and 15 N relaxation measurements. A common binding cavity shared by different physiological ligands is identified. NMR relaxation measurements reveal that residues in the three C-terminal α-helices within the lipid binding region exhibit mobility at fast (picosecond to nanosecond) and slow (microsecond to millisecond) time scales. Ligand binding is associated with a considerable loss of peptide backbone mobility. The observed conformational dynamics in SCP2 may play a role for the access of hydrophobic ligands to an occluded binding pocket. The C-terminal peroxisomal targeting signal of SCP2 is specifically recognized by the Pex5p receptor protein, which conducts cargo proteins toward the peroxisomal organelle. Neither the C-terminal targeting signal nor the N-terminal precursor sequence interferes with lipid binding by SCP2. The α-helices involved in lipid binding also mediate a secondary interaction interface with the Pex5p receptor. Silencing of conformational dynamics of the peptide backbone in these helices upon either lipid or Pex5p binding might communicate the loading state of the cargo protein to the targeting receptor. Graphical Abstract HHS Public AccessAuthor manuscript Biochemistry. Author manuscript; available in PMC 2016 September 08. Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptLipid transfer proteins are auxiliary shuttles ensuring the appropriate localization of lipids in cellular subcompartments. Sterol carrier protein 2 (SCP2 1 ) has been reported to interact with a wide variety of lipids associated with peroxisomal metabolism, including acyl-CoA conjugates as high-affinity ligands (1-3). Disruption of the scp2 gene in mice suggests bile acids (soluble derivatives of cholesterol) and branched-chain fatty acid CoAs as physiological ligands to be functionally associated with SCP2 (4-6). Enzymes involved in both cholesterol secretion and fatty acid oxidation include the peroxisomal thiolase, acylCoA hydrogenase, and enoyl-CoA hydratase (7,8), all of which are expressed as fusion proteins with a sterol carrier protein domain fold (9). The transfer of fatty acyl-CoA substrates by SCP2 may have evolved to assist enzymes involved in branched chain fatty acid α-oxidation or very long chain fatty acid β-oxidation in the peroxisome (8). In this context SCP2 may play a role in substrate and/or product binding during peroxisomal bile acid synthesis and fatty acid oxidation.Some molecular insight into the ligand binding site of the sterol carrier protein fold has been obtained from structural high-resolution studies of SC...

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Section: The Conformation Of Termini Is Independent Of the Lipid Bindmentioning

confidence: 62%

Conformational Plasticity of the Lipid Transfer Protein SCP2

Filipp

Sattler

2007

Biochemistry

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“…Only the short chain fatty acids are amenable to absorption without the aid of bile acids. The primary bile acids are actively re-absorbed in the distal ileum and recycled, but those that escape re-absorption are de-conjugated to deoxycholic acid and lithocholic acid by colonic bacteria -mostly the bacteroides species -and reabsorbed through the portal system [1] . Ursodeoxycholic acid makes up about 3% of the total bile acids and has anti-inflammatory properties that have been used in hepatitis and bile acid reflux conditions [2] .…”

Section: Introductionmentioning

confidence: 99%

Obesity diabetes and the role of bile acids in metabolism

Tomkin

Owens

2016

Journal of Translational Internal Medicine

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Bile acids have many activities over and above their primary function in aiding absorption of fat and fat soluble vitamins. Bile acids are synthesized from cholesterol, and thus are involved in cholesterol homeostasis. Bile acids stimulate glucagon-like peptide 1 (GLP1) production in the distal small bowel and colon, stimulating insulin secretion, and therefore, are involved in carbohydrate and fat metabolism. Bile acids through their insulin sensitising effect play a part in insulin resistance and type 2 diabetes. Bile acid metabolism is altered in obesity and diabetes. Both dietary restriction and weight loss due to bariatric surgery, alter the lipid carbohydrate and bile acid metabolism. Recent research suggests that the forkhead transcription factor FOXO is a central regulator of bile, lipid, and carbohydrate metabolism, but conflicting studies mean that our understanding of the complexity is not yet complete.

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“…These bile acids are produced by two major pathways, the neutral pathway and the acidic pathway. 1,2 The initial step of the neutral pathway is a hydroxylation at the 7a-position of cholesterol, a reaction catalyzed by the rate-limiting enzyme cholesterol 7a-hydroxylase (CYP7A1). The acidic pathway begins with the oxidation of the cholesterol side chain, in which the first step is catalyzed by sterol 27-hydroxylase (CYP27A1).…”

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confidence: 99%

Addition of Dexamethasone Alters the Bile Acid Composition by Inducing CYP8B1 in Primary Cultures of Human Hepatocytes

Mörk

Strom

Mode

et al. 2016

Journal of Clinical and Experimental Hepatology

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Background: Primary human hepatocytes offer the best human in vitro model for studies on human liver cell metabolism. Investigators use a variety of different media supplements and matrix biocoatings and the type of culture system used may influence the outcome. Objectives: To optimize in vitro conditions for primary human hepatocytes with regard to bile acid synthesis. Methods: Human hepatocytes were isolated and cultured on collagen type I or EHS matrigel in cell media with or without dexamethasone. The glucocorticoid receptor (GR) antagonist RU486 was used to elucidate the involvement of GR. Results: Hepatocytes cultured on EHS matrigel produced more bile acids and expressed higher levels of cholesterol 7a-hydroxylase (CYP7A1) than cells cultured on rat tail collagen. Supplementation with dexamethasone increased the formation of cholic acid (CA) and decreased chenodeoxycholic acid formation. In line with these results, the mRNA expression of sterol 12a-hydroxylase (CYP8B1) increased following dexamethasone treatment. Surprisingly, the mRNA expression of CYP7A1 and CYP27A1 was not increased to the same extent. By using the GR antagonist RU486, we concluded that CYP8B1 induction is mediated via a GR-independent pathway. An altered expression of retinoid-related orphan receptor (ROR) a and ROR a target gene Glucose-6-phosphatase (G6Pase) suggests that ROR a signaling may regulate CYP8B1 expression. Conclusion: Primary human hepatocytes have an increased bile acid synthesis rate when cultured on matrigel as compared to collagen. Exposure to glucocorticoid hormones stimulates the expression of CYP8B1, leading to an increased formation of CA and alteration of the bile acid composition. The effect is most likely mediated through a GR-independent pathway, possibly through ROR a. (J CLIN EXP HEPATOL 2016;6:87-93)

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The Enzymes, Regulation, and Genetics of Bile Acid Synthesis

Cited by 1,692 publications

References 213 publications

Conformational Plasticity of the Lipid Transfer Protein SCP2

Conformational Plasticity of the Lipid Transfer Protein SCP2

Obesity diabetes and the role of bile acids in metabolism

Addition of Dexamethasone Alters the Bile Acid Composition by Inducing CYP8B1 in Primary Cultures of Human Hepatocytes

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