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. 2015 Aug 15:580:41-9.
doi: 10.1016/j.abb.2015.06.009. Epub 2015 Jun 24.

Loss of L-FABP, SCP-2/SCP-x, or both induces hepatic lipid accumulation in female mice

Gregory G Martin  1 , Barbara P Atshaves  2 , Kerstin K Landrock  3 , Danilo Landrock  3 , Friedhelm Schroeder  1 , Ann B Kier  4
Affiliations

Loss of L-FABP, SCP-2/SCP-x, or both induces hepatic lipid accumulation in female mice

Gregory G Martin et al. Arch Biochem Biophys. .

Abstract

Although roles for both sterol carrier protein-2/sterol carrier protein-x (SCP-2/SCP-x) and liver fatty acid binding protein (L-FABP) have been proposed in hepatic lipid accumulation, individually ablating these genes has been complicated by concomitant alterations in the other gene product(s). For example, ablating SCP2/SCP-x induces upregulation of L-FABP in female mice. Therefore, the impact of ablating SCP-2/SCP-x (DKO) or L-FABP (LKO) individually or both together (TKO) was examined in female mice. Loss of SCP-2/SCP-x (DKO, TKO) more so than loss of L-FABP alone (LKO) increased hepatic total lipid and total cholesterol content, especially cholesteryl ester. Hepatic accumulation of nonesterified long chain fatty acids (LCFA) and phospholipids occurred only in DKO and TKO mice. Loss of SCP-2/SCP-x (DKO, TKO) increased serum total lipid primarily by increasing triglycerides. Altered hepatic level of proteins involved in cholesterol uptake, efflux, and/or secretion was observed, but did not compensate for the loss of L-FABP, SCP-2/SCP-x or both. However, synergistic responses were not seen with the combinatorial knock out animals-suggesting that inhibiting SCP-2/SCP-x is more correlative with hepatic dysfunction than L-FABP. The DKO- and TKO-induced hepatic accumulation of cholesterol and long chain fatty acids shared significant phenotypic similarities with non-alcoholic fatty liver disease (NAFLD).

Keywords: Gene ablation; L-FABP; SCP-2; SCP-x.

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Figures

Figure 1
Figure 1. Hepatic levels of key proteins involved in cholesterol uptake, transport, and efflux are altered in L-FABP/SCP-2/SCP-x gene-ablated female mice
Aliquots of liver homogenate proteins were examined by SDS-PAGE and subsequent western blot analysis to determine levels of SRB1 (panel A), LDLR (panel B), ABCA1 (panel C), ABCG1 (panel D), APO AI (panel E), APO AII (panel F), APO B100 (panel G), and APO B48 (panel H). Insets show representative western blots of the respective protein (lower blot) and the gel-loading control protein (GAPDH or COX4, upper blot). Relative concentration values (WT = 1) represent means ± SEM (n = 8). Statistically different values (P < 0.05, ANOVA) within a panel are denoted by a different lower-case letter (a, b, c, d).
Figure 2
Figure 2. Effect of ablating SCP-2/SCP-x, L-FABP, or both on expression of key soluble intracellular proteins involved in cholesterol binding, transport, and metabolism in female mice
Aliquots of liver homogenate proteins were examined by SDS-PAGE and subsequent western blot analysis as described in Methods to determine levels of SCP-2 (panel A), SCP-x (panel B), L-FABP (panel C), ACBP (panel D), ACAT-2 (panel E), and PPARα (panel F). Insets show representative western blots of the respective protein (lower blot) and the gel-loading control protein (GAPDH or COX4, upper blot). SCP-2, SCP-x, and L-FABP were quantified (ng protein/μg liver homogenate protein) as described in Methods. Relative concentration values for ACBP, ACAT-2, and PPARα protein are shown with WT = 1. Values represent means ± SEM (n = 8). Statistically different values (P < 0.05, ANOVA) within a panel are denoted by a different lower-case letter (a, b, c).
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