RElevance of the sterol carrier protein 2 (Scp2) gene for bile acid synthesis andgallstone formation in genetically susceptible CS7BL/6 mice

Muench, Christian; Hafer, Andrea; Katzberg, Nadine; Scheibner, Juergen; Stange, Eduard F.; Seedorf, Udo; Fuchs, Michael

doi:10.1016/s0016-5085(00)86141-7

Cited by 10 publications

(7 citation statements)

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“…Similarly, SCP2 also facilitates cholesterol transfer from the plasma membrane to the endoplasmic reticulum [29,102] for esterification by ACAT2 [34,86], to mitochondria and peroxisomes for oxidation to steroids [13,14] or bile acids [30,54,81], and to bile canaliculi for biliary excretion [36,54,121]. Thus, it was important to determine the effect of sex and TKO on hepatic expression of cytosolic cholesterol binding/transfer proteins in HFD fed mice.…”

Section: Resultsmentioning

confidence: 99%

“…FABP1 binds bile acids [60,63,66,67] and enhances transfer/targeting of HDL-derived cholesterol (and cholesteryl ester after hydrolysis) to the bile canaliculus for biliary excretion [36,63,121]. SCP2 enhances cholesterol transfer to mitochondria and peroxisomes for oxidation to bile acids [30,54,81] and to the bile canaliculus for cholesterol biliary excretion [36,54,121]. Therefore, the impact of sex and TKO on hepatic expression of proteins involved in bile acid production and dynamics was determined in HFD fed mice.…”

Section: Resultsmentioning

confidence: 99%

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Ablating both Fabp1 and Scp2/Scpx (TKO) induces hepatic phospholipid and cholesterol accumulation in high fat-fed mice

Milligan

Martin

Landrock

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Although singly ablating Fabp1 or Scp2/Scpx genes may exacerbate the impact of high fat diet (HFD) on whole body phenotype and non-alcoholic fatty liver disease (NAFLD), concomitant upregulation of the non-ablated gene, preference for ad libitum fed HFD, and sex differences complicate interpretation. Therefore, these issues were addressed in male and female mice ablated in both genes (Fabp1/Scp2/Scpx null or TKO) and pair-fed HFD. Wild-type (WT) males gained more body weight as fat tissue mass (FTM) and exhibited higher hepatic lipid accumulation than WT females. The greater hepatic lipid accumulation in WT males was associated with higher hepatic expression of enzymes in glyceride synthesis, higher hepatic bile acids, and upregulation of transporters involved in hepatic reuptake of serum bile acids. While TKO had little effect on whole body phenotype and hepatic bile acid accumulation in either sex, TKO increased hepatic accumulation of lipids in both, specifically phospholipid and cholesteryl esters in males and females and free cholesterol in females. TKO-induced increases in glycerides were attributed not only to complete loss of FABP1, SCP2 and SCPx, but also in part to sex-dependent upregulation of hepatic lipogenic enzymes. These data with WT and TKO mice pair-fed HFD indicate that: i) Sex significantly impacted the ability of HFD to increase body weight, induce hepatic lipid accumulation and increase hepatic bile acids; and ii) TKO exacerbated the HFD ability to induce hepatic lipid accumulation, regardless of sex, but did not significantly alter whole body phenotype in either sex.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Ablating both Fabp1 and Scp2/Scpx (TKO) induces hepatic phospholipid and cholesterol accumulation in high fat-fed mice

Milligan

Martin

Landrock

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…In vivo studies with liver from wild-type mice, rats treated with antisense SCP-2 RNA, and mice wherein the SCP-2/SCP-x gene is ablated indicate that SCP-2 stimulates cholesterol esterification in liver [20], cholesterol hypersecretion into bile [21,22], delivery of newly synthesized cholesterol from the endoplasmic reticulum (ER) for secretion into bile [23], and oxidation of branched-side chain lipids not only in vitro [24][25][26] but also in mice [20,[27][28][29][30]. Specifically, SCP-x oxidizes the branched-side chain of cholesterol (to form bile acids) as well as the branched-chains of fatty acids (to detoxify) [24,[27][28][29]. In summary, while compelling evidence indicates important direct roles for SCP-2 in mediating cholesterol, phospholipid, and fatty acid metabolism, exciting recent data indicate that this protein may have additional physiological functions, especially in intracellular lipid signaling.…”

Section: Introductionmentioning

confidence: 99%

Sterol carrier protein-2: New roles in regulating lipid rafts and signaling

Schroeder

Atshaves

McIntosh

et al. 2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Sterol carrier protein-2 (SCP-2) was independently discovered as a soluble protein that binds and transfers cholesterol as well as phospholipids (nonspecific lipid transfer protein, nsLTP) in vitro. Physiological functions of this protein are only now beginning to be resolved. The gene encoding SCP-2 also encodes sterol carrier protein-x (SCP-x) arising from an alternate transcription site. In vitro and in vivo SCP-x serves as a peroxisomal 3-ketoacyl-CoA thiolase in oxidation of branchedchain lipids (cholesterol to form bile acids; branched-chain fatty acid for detoxification). While peroxisomal SCP-2 facilitates branched-chain lipid oxidation, the role(s) of extraperoxisomal (up to 50% of total) are less clear. Studies using transfected fibroblasts overexpressing SCP-2 and hepatocytes from SCP-2/SCP-x gene-ablated mice reveal that SCP-2 selectively remodels the lipid composition, structure, and function of lipid rafts/caveolae. Studies of purified SCP-2 and in cells show that SCP-2 has high affinity for and selectively transfers many lipid species involved in intracellular signaling: fatty acids, fatty acyl CoAs, lysophosphatidic acid, phosphatidylinositols, and sphingolipids (sphingomyelin, ceramide, mono-di-and multi-hexosylceramides, gangliosides). SCP-2 selectively redistributes these signaling lipids between lipid rafts/caveolae and intracellular sites. These findings suggest SCP-2 serves not only in cholesterol and phospholipid transfer, but also in regulating multiple lipid signaling pathways in lipid raft/caveolae microdomains of the plasma membrane.

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“…SCP-2 is involved in the transport of cholesterol from the endoplasmic reticulum to bile [30]. Both SCP-2 [28,29,45,46] and SCP-x participate in different aspects of bile acid synthesis [47 -49]. In summary, altered cellular levels of SCP-2 are associated with a variety of abnormalities in the trafficking and intracellular utilization of cholesterol and other lipids.…”

Section: Introductionmentioning

confidence: 99%

Sterol carrier protein-2: structure reveals function

Stolowich

Petrescu²,

Huang³

et al. 2002

CMLS, Cell. Mol. Life Sci.

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The multiple actions of sterol carrier protein-2 (SCP-2) in intracellular lipid circulation and metabolism originate from its gene and protein structure. The SCP-x/pro-SCP-2 gene is a fusion gene with separate initiation sites coding for 15-kDa pro-SCP-2 (no enzyme activity) and 58-kDa SCP-x (a 3-ketoacyl CoA thiolase). Both proteins share identical cDNA and amino acid sequences for 13-kDa SCP-2 at their C-termini. Cellular 13-kDa SCP-2 derives from complete, posttranslational cleavage of the 15-kDa pro-SCP-2 and from partial posttranslational cleavage of 58-kDa SCP-x. Putative physiological functions of SCP-2 have been proposed on the basis of enhancement of intermembrane lipid transfer (e.g., cholesterol, phospholipid) and activation of enzymes involved in fatty acyl CoA transacylation (cholesterol esters, phosphatidic acid) in vitro, in transfected cells, and in genetically manipulated animals. At least four important SCP-2 structural domains have been identified and related to specific functions. First, the 46-kDa N-terminal presequence present in 58-kDa SCP-x is a 3-ketoacyl-CoA thiolase specific for branched-chain acyl CoAs. Second, the N-terminal 20 amino acid presequence in 15-kDa pro-SCP-2 dramatically modulates the secondary and tertiary structure of SCP-2 as well as potentiating its intracellular targeting coded by the C-terminal peroxisomal targeting sequence. Third, the N-terminal 32 amino acids form an amphipathic a-helical region, one face of which represents a membrane-binding domain. Positively charged amino acid residues in one face of the amphipathic helices allow SCP-2 to bind to membrane surfaces containing anionic phospholipids. Fourth, the hydrophobic faces of the N-terminal amphipathic a helices along with beta strands 4, 5, and helix D form a ligand-binding cavity able to accommodate multiple types of lipids (e. g., fatty acids, fatty acyl CoAs, cholesterol, phospholipids, isoprenoids). Two-dimensional 1H-15N heteronuclear single quantum coherence spectra of both apo-SCP-2 and of the 1:1 oleate-SCP-2 complex, obtained at pH 6.7, demonstrated the homogenous formation of holo-SCP-2. While comparison of the apo- and holoprotein amide fingerprints revealed about 60% of the resonances remaining essentially unchanged, 12 assigned amide residues underwent significant chemical-shift changes upon oleic acid binding. These residues were localized in three regions: the juncture of helices A and B, the mid-section of the beta sheet, and the interface formed by the region of beta strands 4, 5, and helix D. Circular dichroism also showed that these chemical-shift changes, upon oleic acid binding, did not alter the secondary structure of SCP-2. The nuclear magnetic resonance chemical shift difference data, along with mapping of the nearby hydrophobic residues, showed the oleic acid-binding site to be comprised of a pocket created by the face of the beta sheet, helices A and B on one end, and residues associated with beta strands 4, 5, and helix D at the other end of the binding cavity. Furthermore, the ...

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RElevance of the sterol carrier protein 2 (Scp2) gene for bile acid synthesis andgallstone formation in genetically susceptible CS7BL/6 mice

Cited by 10 publications

References 0 publications

Ablating both Fabp1 and Scp2/Scpx (TKO) induces hepatic phospholipid and cholesterol accumulation in high fat-fed mice

Ablating both Fabp1 and Scp2/Scpx (TKO) induces hepatic phospholipid and cholesterol accumulation in high fat-fed mice

Sterol carrier protein-2: New roles in regulating lipid rafts and signaling

Sterol carrier protein-2: structure reveals function

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