Studies with sterol carrier protein 2 (SCP2) gene knockout mice identify liver fatty acid binding protein (FABP1) as intracellular cholesterol transporter contributing to biliary cholesterol hypersecretion and gallstone formation

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

doi:10.1016/s0016-5085(00)85843-6

Cited by 14 publications

(19 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 33,40], faster intracellular transport [27,40-43], and increased LCFA utilization by catabolic (mitochondrial and peroxisomal oxidation) [27,44] and anabolic (endoplasmic esterification) [45-47] lipid metabolic pathways. Recently, L-FABP has also been identified as a key liver protein involved in intracellular bile acid transport and secretion as well as in the regulation of cholesterol accumulation and metabolism in young (2-4 mo) mice in response to dietary cholesterol [28,30,48,49]. Genomic roles of L-FABP involve: enhanced fatty acid distribution to nuclei [12,13], interaction with PPARα in nuclei [rev.…”

Section: Discussionmentioning

confidence: 99%

Liver fatty acid binding protein gene ablation enhances age-dependent weight gain in male mice

et al. 2008

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Although studies performed in vitro and with transfected cells in culture suggest a role for liver fatty acid binding protein (L-FABP) in regulating fatty acid oxidation and fat deposition, the physiological significance of this possibility is not completely clear. To begin to address this question, the effect of L-FABP gene ablation on phenotype of standard rodent chow-fed male mice was examined with increasing age up to 18 mo. While young (2-3 mo) L-FABP null mice displayed no visually obvious phenotype, with increasing age > 9 mo the L-FABP null mice were visibly larger, exhibiting increased body weight due to increased fat and lean tissue mass. Liver lipid concentrations were unaffected by L-FABP gene ablation with the exception of triacylglycerol, which was decreased by 74% in the livers of 3 mo old mice. Likewise, serum lipid levels were not altered in L-FABP null mice with the exception of triacylglycerol, which was increased in the serum of 18 mo old mice. Increased body weight, fat tissue mass, and lean tissue mass in 18 mo old L-FABP null mice were accompanied by increased hepatic levels of low density lipoprotein (LDL) receptor, peroxisome proliferator-activated receptor (PPAR) α, and PPARα-regulated proteins such as fatty acid transport protein (FATP), fatty acid translocase (FAT/CD36), carnitine palmitoyl transferase I (CPT I), and lipoprotein lipase (LPL). A key enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase was down-regulated in L-FABP null mice. These findings were consistent with a proposed role for L-FABP as an important physiological regulator of PPARα.

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“…While SCP-x protein appears almost exclusively localized in peroxisomes, the fact that it is partially posttranslationally cleaved to SCP-2 complicates interpretations of exclusive actions for SCP-x (18,19). Likewise, studies with SCP-2/ SCP-x gene-ablated mice do not resolve the relative contributions of either protein (9,64) and are complicated by concomitant up-regulation of L-FABP (9,65,66). To more clearly resolve the potential roles of SCP-2 and SCP-x in branched-and straight-chain FA uptake, oxidation, and esterification, the effects of these SCP-2 gene products on phytanic (branched-chain) and palmitic (straight-chain) acid uptake and metabolism were examined in transfected L cell fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Sterol carrier protein-2/sterol carrier protein-x expression differentially alters fatty acid metabolism in L cell fibroblasts

Atshaves

Storey

Schroeder

2003

Journal of Lipid Research

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Sterol carrier protein-2 (SCP-2) and SCP-x are ubiquitous proteins found in all mammalian tissues. Although both proteins interact with fatty acids, their relative contributions to the uptake, oxidation, and esterification of straight-chain (palmitic) and branched-chain (phytanic) fatty acids in living cells has not been resolved. Therefore, the effects of each gene product on fatty acid metabolism was individually examined. Based on the following, SCP-2 and SCP-x did not enhance the uptake/translocation of fatty acids across the plasma membrane into the cell: i ) a 2-fold increase in phytanic and palmitic acid uptake was observed at long incubation times in SCP-2-and SCP-x-expressing cells, but no differences were observed at initial time points; ii ) uptake of 2-bromo-palmitate, a nonoxidizable, poorly metabolizable fatty acid analog, was unaffected by SCP-2 or SCP-x overexpression; and iii ) SCP-2 and SCP-x expression did not increase targeting of radiolabeled phytanic and palmitic acid to the unesterified fatty acid pool. Moreover, SCP-2 and SCP-x expression enhanced fatty acid uptake by stimulating the intracellular metabolism via fatty acid oxidation and esterification. In summary, these data showed for the first time that SCP-2 and SCP-x stimulate oxidation and esterification of branched-chain as well as straight-chain fatty acids in intact cells. 1)]. More recent studies indicate that SCP-2 also functions in the uptake and esterification of straight-chain (e.g., oleic acid) fatty acids (FAs) (2), while SCP-x participates in the oxidation of branchedchain (e.g., phytanic acid) FAs (3, 4). However, almost nothing is known about the function of SCP-x in FA uptake or esterification. Likewise, the relative roles of SCP-2 versus SCP-x in straight-chain or branched-chain FA oxidation remain unresolved. Despite the lack of conclusive evidence, several observations point to an important role for SCP-2 and SCP-x in functioning in these capacities, including FA binding affinities where SCP-2 binds straightchain FAs (5-11) and their metabolically active fatty acyl CoA derivatives (9, 12) to a high degree, as exhibited by K d s in the submicromolar and nM range, respectively. In addition, SCP-2 also binds branched-chain FAs such as phytanic or pristanic acid (9), as well as their respective acyl CoAs with high affinity (7, 9).The intracellular localization of SCP-x and SCP-2 also indicate a role in FA metabolism. The highest concentration of SCP-2 and SCP-x is in peroxisomes (13), where ␣ -oxidation of branched-chain FAs as well as the ␤ -oxidation of some straight chain FAs occurs (14-16). Additionally, it has been shown that half or more of total SCP-2 is extraperoxisomal (13, 17), where part of the SCP-2 may arise from the partial posttranslational cleavage of the SCP-x protein (18,19). Extraperoxisomal SCP-2 locations include: i ) plasma membrane in caveolae, wherein several FA translocase/transporter proteins reside (20); ii ) cytoplasm, where SCP-2 enhances diffusion of fluorescent fatty acid (21); ii...

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Studies with sterol carrier protein 2 (SCP2) gene knockout mice identify liver fatty acid binding protein (FABP1) as intracellular cholesterol transporter contributing to biliary cholesterol hypersecretion and gallstone formation

Cited by 14 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

Liver fatty acid binding protein gene ablation enhances age-dependent weight gain in male mice

Sterol carrier protein-2/sterol carrier protein-x expression differentially alters fatty acid metabolism in L cell fibroblasts

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