Deletion of fatty acid transport protein 2 (FATP2) in the mouse liver changes the metabolic landscape by increasing the expression of PPARα-regulated genes

Abstract

Fatty acid transport protein 2 (FATP2) is highly expressed in the liver, small intestine, and kidney, where it functions in both the transport of exogenous long-chain fatty acids and the activation of very-long-chain fatty acids. Here, using a murine model, we investigated the phenotypic impacts of deleting FATP2, followed by a transcriptomic analysis using unbiased RNA-Seq to identify concomitant changes in the liver transcriptome. WT and FATP2-null (Fatp2−/−) mice (5 weeks) were maintained on a standard chow diet for 6 weeks. The Fatp2−/− mice had reduced weight gain, lowered serum triglyceride, and increased serum cholesterol levels and attenuated dietary fatty acid absorption. Transcriptomic analysis of the liver revealed 258 differentially expressed genes in male Fatp2−/− mice and a total of 91 in female Fatp2−/− mice. These genes mapped to the following gene ontology categories: fatty acid degradation, peroxisome biogenesis, fatty acid synthesis, and retinol and arachidonic acid metabolism. Targeted RT-quantitative PCR verified the altered expression of selected genes. Of note, most of the genes with increased expression were known to be regulated by peroxisome proliferator–activated receptor α (PPARα), suggesting that FATP2 activity is linked to a PPARα-specific proximal ligand. Targeted metabolomic experiments in the Fatp2−/− liver revealed increases of total C16:0, C16:1, and C18:1 fatty acids; increases in lipoxin A4 and prostaglandin J2; and a decrease in 20-hydroxyeicosatetraenoic acid. We conclude that the expression of FATP2 in the liver broadly affects the metabolic landscape through PPARα, indicating that FATP2 provides an important role in liver lipid metabolism through its transport or activation activities.

Fatty acid transport protein-2 regulates glycemic control and diabetic kidney disease progression

“…In contrast to this report, we observed no significant effect of FATP2 deletion on hepatosteatosis, perhaps reflecting the relatively modest liver disease in Slc27a2 +/+ Lepr db/db eNOS -/mice, differences in genetic background, and/or differences between acute shRNA knockdown versus chronic gene deletion. On the other hand, Slc27a2 -/mice on normal chow demonstrated increased liver fatty acid content and lipid droplets (46), which is consistent with our data (Supplemental Figure 11B). Of other possible extrarenal FATP2 effects, a recent report demonstrates that FATP2-dependent arachidonic acid uptake activates a subset of neutrophils involved in cancer pathophysiology (47).…”

Involvement of FATP2-mediated tubular lipid metabolic reprogramming in renal fibrogenesis

“…Recently, study has shown that SLC27A2 ablation can restore FAO-related key enzymes activity caused by kidney damage, and protect TECs from lipotoxicity 28 . Deleting FATP2 in the mouse liver also found it changes the metabolic landscape by increasing the expression of PPARα 27 . Interestingly, PPAR signaling pathway can be downregulated by TGF-β in almost all fibrotic tissues [46][47][48] .…”

Exercise Attenuates the Transition from Fatty Liver to Steatohepatitis and Reduces Tumor Formation in Mice

“…However, when mice were fed a lipogenic methionine choline-deficient diet for 4 weeks, FATP2 and 5 were marginally decreased, although increases in FATP 1 and FATP4 were noted [29]. Apart from any dietary stimulus, the genetic deletion of FATP2 in the liver provokes commensurate increases in CD36 and FATP1 expression, indicating compensatory mechanisms to coordinate and regulate the uptake of lipids [27]. Although we did not investigate the complete profile of fatty acid uptake systems in our CD-HFD model, we deduce that the negative correlation between exercise and hepatic lipid accumulation was independent of the changes in FATP2, FATP5, and CD36.…”

“…The upregulation of CD36 is consistent with the increase in plasma and hepatic FFA levels ( Figure 4 and Figure 5 ) and is a feature observed in other experimental models [ 25 , 26 ]. This increased CD36 expression promotes the accumulation of unsaturated FAs, which are a driving force for steatotic triglyceride formation [ 27 ].…”

“…In NAFLD, proinflammatory TNFα released by Kupffer cells and steatotic hepatocytes mediates liver injury in part by activating NFkB signaling pathways in stellate cells [ 27 , 30 ]. Exercise reduced the TNFα release elicited by CD-HFD ( Figure 6 A).…”