Impact of L-FABP and glucose on polyunsaturated fatty acid induction of PPARα-regulated β-oxidative enzymes

Abstract

. Impact of L-FABP and glucose on polyunsaturated fatty acid induction of PPAR␣-regulated ␤-oxidative enzymes. Am J Physiol Gastrointest Liver Physiol 304: G241-G256, 2013. First published December 13, 2012; doi:10.1152/ajpgi.00334.2012.-Liver fatty acid binding protein (L-FABP) is the major soluble protein that binds very-long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) in hepatocytes. However, nothing is known about L-FABP's role in n-3 PUFA-mediated peroxisome proliferator activated receptor-␣ (PPAR␣) transcription of proteins involved in long-chain fatty acid (LCFA) ␤-oxidation. This issue was addressed in cultured primary hepatocytes from wild-type, L-FABP-null, and PPAR␣-null mice with these major findings: 1) PUFA-mediated increase in the expression of PPAR␣-regulated LCFA ␤-oxidative enzymes, LCFA/LCFA-CoA binding proteins (L-FABP, ACBP), and PPAR␣ itself was L-FABP dependent; 2) PPAR␣ transcription, robustly potentiated by high glucose but not maltose, a sugar not taken up, correlated with higher protein levels of these LCFA ␤-oxidative enzymes and with increased LCFA ␤-oxidation; and 3) high glucose altered the potency of n-3 relative to n-6 PUFA. This was not due to a direct effect of glucose on PPAR␣ transcriptional activity nor indirectly through de novo fatty acid synthesis from glucose. Synergism was also not due to glucose impacting other signaling pathways, since it was observed only in hepatocytes expressing both L-FABP and PPAR␣. Ablation of L-FABP or PPAR␣ as well as treatment with MK886 (PPAR␣ inhibitor) abolished/ reduced PUFA-mediated PPAR␣ transcription of these genes, especially at high glucose. Finally, the PUFA-enhanced L-FABP distribution into nuclei with high glucose augmentation of the L-FABP/ PPAR␣ interaction reveals not only the importance of L-FABP for PUFA induction of PPAR␣ target genes in fatty acid ␤-oxidation but also the significance of a high glucose enhancement effect in diabetes. polyunsaturated; fatty acid; oxidation; glucose; liver fatty acid binding protein; peroxisome proliferator activated receptor-␣; hepatocyte THE SEVERAL FORMS OF DIABETES mellitus and associated complications are the sixth leading cause of death in the US, and incidence is rising (22,101,123,132). Nearly 80% of people with diabetes die of cardiovascular disease (CVD), particularly coronary heart disease (20, 102). Thus benefits of any lipid intervention may be greatest in these individuals (97,102,114). Although dietary improvements, exercise, and statins have significantly decreased the incidence and severity of CVD, residual CVD risk remains especially high (62-82%) among individuals with diabetes mellitus, even with optimum statin therapy (102,113). This difference is thought to be due primarily to a residual dyslipidemia in this population, particularly hypertriglyceridemia (113).The liver is key in maintaining homeostasis of long-chain fatty acid (LCFA) and glucose metabolism (14, 105). Hepatic peroxisome proliferator activated receptor-␣ (PPAR␣) is the major transcription factor con...

Structural Basis for Ligand Regulation of the Fatty Acid-binding Protein 5, Peroxisome Proliferator-activated Receptor β/δ (FABP5-PPARβ/δ) Signaling Pathway

“…Increasingly, however, FABPs are emerging as specific mediators of precise signaling pathways. For instance, FABP1 facilitates the polyunsaturated fatty acid and fibrate-induced transactivation of PPAR␣, via direct interaction with the nuclear receptor's ligand binding domain (15)(16)(17). A similar role has been observed with FABP4, whereby its ligand-mediated dimerization state governs nuclear import and subsequent ligand delivery to PPAR␥ (18,19).…”

Recent insights into the biological functions of liver fatty acid binding protein 1

“…Restoration of hepatic FABP1 by receiving a fi sh oil diet was associated with lowered serum triglycerides and VLDL cholesterol levels and elevated serum high density lipoprotein cholesterol levels, as well as downregulated expression of TNF-␣ and IL-6, in livers of diabetic rats ( 94 ). FABP1 ablation significantly impacted hepatic fatty acid ␤ -oxidative genes mediated by PPAR ␣ activation of the dietary n-3 PUFAs (rich fi sh oil), an even more prominent effect in the context of high glucose ( 95 ). Higher dose alcohol consumption is associated with impaired peroxisomal ␤ -oxidation and FABP1 responses to PPAR ␣ in rats, and the severity of fatty liver correlated inversely with the level of FABP1.…”

Hepatic ATGL mediates PPAR-α signaling and fatty acid channeling through an L-FABP independent mechanism

“…Several studies have shown that L-FABP mediates the effects of exogenous FAs, especially polyunsaturated FAs, on PPAR-␣ gene expression and activity ( 17,42,43 ). L-FABP physically interacts with PPAR-␣ and it is thought that this interaction facilitates transfer of FA ligands ( 18 ).…”