The Impact of FABP1/SCP2/SCPx Ablation in Mice Challenged With High Phytanic Acid and High Fat Pair-Fed Diets

In vitro studies suggest that fatty acid bind protein 1 (Fabp1) and sterol carrier protein 2/sterol carrier protein x (Scp2/Scpx) gene products facilitate the uptake, metabolism and detoxification of dietary phytol in mammals. In fact, individually ablating FABP1 or SCP2/SCPx each impairs hepatic branched-chain fatty acid uptake and/or metabolism. Studies also suggest that singly ablating Fabp1 or Scp2/Scpx genes may exacerbate the impact of a high fat diet on whole body phenotype and non-alcoholic fatty liver disease (NAFLD). However, concomitant upregulation of FABP1 in SCP2/SCPx null mice complicates interpretation of each protein’s physiological role in studies where only one of these proteins has been ablated. Therefore, the impact of ablating both Fabp1 and Scp2/Scpx genes was explored in phytol and high fat diet fed mice. In the phytol study, triple gene ablation (TKO) increased hepatic total lipid accumulation, primarily phospholipid, by mechanisms involved in increasing hepatic levels of proteins in the phospholipid synthesis pathway while reducing expression of proteins in targeting fatty acids towards the triacylglycerol synthesis pathway. Concomitantly, TKO also reduced expression of proteins in targeting fatty acids towards the triacylglycerol synthesis pathway. In the high fat study, wild type (WT) male mice exhibited higher hepatic lipid accumulation than WT females and TKO increased hepatic lipid accumulation in both. The greater hepatic lipid accumulation in WT males was associated with high hepatic expression of enzymes in glyceride synthesis, higher hepatic bile acids and upregulation of transporters involved in hepatic reuptake of serum bile acids. The TKO-induced increases in hepatic glycerides were attributed to sex dependent upregulation of hepatic lipogenic enzymes. Overall, since individually ablating the Scp2/Scpx gene elicits the upregulation of the FABP1 protein, these findings with TKO mice help to resolve the contributions of Scp2/Scpx gene ablation on dietary phytol and high fat induced whole body and hepatic lipid phenotype independent of concomitant upregulation of FABP1