Effect of SCP-x gene ablation on branched-chain fatty acid metabolism

Atshaves, Barbara P.; McIntosh, Avery L.; Landrock, Danilo; Payne, H. Ross; Mackie, John T.; Maeda, Nobuyo; Ball, Joseph A.; Schroeder, Friedhelm; Kier, Ann B.

doi:10.1152/ajpgi.00308.2006

Cited by 54 publications

(115 citation statements)

References 45 publications

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“…Effect of SUV lipid composition on the α-helical content of proSCP-2 and SCP-2 N-terminal peptides upon membrane interaction. Circular dichroism spectra were obtained as described in Experimental Procedures: (A and B) peptide [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Pro, (C and D) peptide Pro, (E and F) peptide Colocalization of Cy5-SCP-2 and Cy5-proSCP-2 with a plasma membrane marker in L cells. L cells were incubated in the presence of Cy5-SCP-2 (A-D) or Cy5-proSCP-2 (E-H) and the plasma membrane marker, AlexaFluor 488-cholera toxin B (AF488-CTB), and examined by laser scanning confocal microscopy (LSCM) as described in Experimental Procedures.…”

Section: Discussionmentioning

confidence: 99%

Structure and Function of the Sterol Carrier Protein-2 N-Terminal Presequence

et al. 2008

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Although sterol carrier protein-2 (SCP-2) is encoded as a precursor protein (proSCP-2), little is known regarding the structure and function of the 20-amino acid N-terminal presequence. As shown herein, the presequence contains significant secondary structure and alters SCP-2: (i) secondary structure (CD), (ii) tertiary structure (aqueous exposure of Trp shown by UV absorbance, fluorescence, fluorescence quenching), (iii) ligand binding site [Trp response to ligands, peptide cross-linked by photoactivatable free cholesterol (FCBP)], (iv) selectivity for interaction with anionic phospholipid-rich membranes, (v) interaction with a peroxisomal import protein [FRET studies of Pex5p(C) binding], the N-terminal presequence increased SCP-2's affinity for Pex5p(C) by 10-fold, and (vi) intracellular targeting in living and fixed cells (confocal microscopy). Nearly 5-fold more SCP-2 than proSCP-2 colocalized with plasma membrane lipid rafts/caveolae (AF488-CTB), 2.8-fold more SCP-2 than proSCP-2 colocalized with a mitochondrial marker (Mitotracker), but nearly 2-fold less SCP-2 than proSCP-2 colocalized with peroxisomes (AF488-antibody to PMP70). These data indicate the importance of the N-terminal presequence in regulating SCP-2 structure, cholesterol localization within the ligand binding site, membrane association, and, potentially, intracellular targeting.Keywords sterol carrier protein-2; presequence; cholesterol; peroxin; peroxisome Sterol carrier protein-2 (SCP-2) 1 is a ubiquitous, soluble protein present at highest level in tissues involved in cholesterol uptake (intestine), oxidation (liver, steroidogenic cells), and/or elimination (liver) (reviewed in ref 1). SCP-2 exhibits high (nanomolar K d values) affinity for

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Section: Discussionmentioning

confidence: 99%

Structure and Function of the Sterol Carrier Protein-2 N-Terminal Presequence

et al. 2008

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“…Conversely, in control-fed SCP-2/SCP-x null mice hepatic cholesteryl-esters and triacylglycerols, but not cholesterol, decreased by 50% (45). Control-fed SCP-x null mice also displayed a smaller, more complex pattern of reduced hepatic cholesteryl-esters and triacylglycerols (46).…”

Section: Effect Of Scp-2 Overexpression and Cholesterol-rich Diet On mentioning

confidence: 88%

“…Similarly, control-fed SCP-2/SCP-x null or SCP-x null mice also exhibited little alteration in whole body phenotype (45,46). Second, SCP-2 overexpression induced hepatic lipid accumulation (especially in the form of cholesteryl esters, cholesterol, and triacylglyceride) with the pattern of lipid accumulation dependent on sex and exacerbated by cholesterol-rich diet.…”

Section: Effect Of Scp-2 Overexpression and Cholesterol-rich Diet On mentioning

confidence: 93%

“…In summary, while the physiological function of one of the SCP-2/SCP-x gene products (SCP-x) in branched-chain lipid (phytol, cholesterol) metabolism has been resolved in both mice and man (9,45,46,52), that for the other gene product (SCP-2) remained to be established. Earlier studies performed in vitro and in transfected transformed cells overexpressing SCP-2 have suggested a role for SCP-2 in cholesterol uptake, trafficking, metabolism, and efflux (reviewed in Refs.…”

Section: Scp-2 Alters Cholesterol Metabolism 1443mentioning

confidence: 99%

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Overexpression of sterol carrier protein-2 differentially alters hepatic cholesterol accumulation in cholesterol-fed mice

Atshaves

McIntosh

Martin

et al. 2009

Journal of Lipid Research

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Although in vitro studies suggest a role for sterol carrier protein-2 (SCP-2) in cholesterol trafficking and metabolism, the physiological significance of these observations remains unclear. This issue was addressed by examining the response of mice overexpressing physiologically relevant levels of SCP-2 to a cholesterol-rich diet. While neither SCP-2 overexpression nor cholesterol-rich diet altered food consumption, increased weight gain, hepatic lipid, and bile acid accumulation were observed in wild-type mice fed the cholesterol-rich diet. SCP-2 overexpression further exacerbated hepatic lipid accumulation in cholesterol-fed females (cholesterol/cholesteryl esters) and males (cholesterol/ cholesteryl esters and triacyglycerol). Primarily in female mice, hepatic cholesterol accumulation induced by SCP-2 overexpression was associated with increased levels of LDLreceptor, HDL-receptor scavenger receptor-B1 (SR-B1) (as well as PDZK1 and/or membrane-associated protein 17 kDa), SCP-2, liver fatty acid binding protein (L-FABP), and 3a-hydroxysteroid dehydrogenase, without alteration of other proteins involved in cholesterol uptake (caveolin), esterification (ACAT2), efflux (ATP binding cassette A-1 receptor, ABCG5/8, and apolipoprotein A1), or oxidation/ transport of bile salts (cholesterol 7a-hydroxylase, sterol 27a-hydroxylase, Na 1 /taurocholate cotransporter, Oatp1a1, and Oatp1a4). The effects of SCP-2 overexpression and cholesterol-rich diet was downregulation of proteins involved in cholesterol transport (L-FABP and SR-B1), cholesterol synthesis (related to sterol regulatory element binding protein 2 and HMG-CoA reductase), and bile acid oxidation/ transport (via Oapt1a1, Oatp1a4, and SCP-x). Levels of serum and hepatic bile acids were decreased in cholesterol-fed SCP-2 overexpression mice, especially in females, while the total bile acid pool was minimally affected. Taken together, these findings support an important role for SCP-2 in hepatic cholesterol homeostasis. Due to the deleterious effects associated with cholesterol accumulation leading to atherosclerosis, levels of cholesterol in cells and tissues are carefully regulated (1, 2). Cholesterol is derived from both diet and endogenous synthesis, and in order to maintain cholesterol homeostasis, human liver excretes nearly 2 g of cholesterol per day into bile (3). Decreased cholesterol disposal results in hepatic cholesterol accumulation and elevated blood cholesterol, while excessive cholesterol secretion or disproportionate biliary constituents may lead to cholelithiasis and inflammatory gallbladder disease (3, 4). Cholesterol is removed from peripheral tissues to the liver for elimination by oxidation and/or biliary excretion via a process termed reverse cholesterol transport (RCT). Recent novel experiments have elucidated many molecular details of the RCT pathway, including those involving scavenger receptor-B1 (SR-B1)-mediated uptake of HDL-cholesteryl esters and ABC transporter- Abbreviations: 3a-HSD, 3a-hydroxysteroid dehydrogenase; ABCA-...

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“…24,25) It has been reported that phytol and phytanic acid activated the retinoid X receptor (RXR), 26) sterol carrier protein x (SCP-x), 27) and livertype fatty acid binding protein (L-FABP) in a dosedependent manner. 28,29) It is not clear at present whether Actin Fig.…”

Section: )mentioning

confidence: 99%