Abstract
Peroxisome proliferator-activated receptor (PPAR) delta is an important regulator of fatty acid (FA) metabolism. Angiopoietin-like 4 (Angptl4), a multifunctional protein, is one of the major targets of PPAR delta in skeletal muscle cells. Here we investigated the regulation of Angptl4 and its role in mediating PPAR delta functions using human, rat and mouse myotubes. Expression of Angptl4 was upregulated during myotubes differentiation and by oleic acid, insulin and PPAR delta agonist GW501516. Treatment with GW501516 or Angptl4 overexpression inhibited both lipoprotein lipase (LPL) activity and LPL-dependent uptake of FAs whereas uptake of BSA-bound FAs was not affected by either treatment. Activation of retinoic X receptor (RXR), PPAR delta functional partner, using bexarotene upregulated Angptl4 expression and inhibited LPL activity in a PPAR delta dependent fashion. Silencing of Angptl4 blocked the effect of GW501516 and bexarotene on LPL activity. Treatment with GW501516 but not Angptl4 overexpression significantly increased palmitate oxidation. Furthermore, Angptl4 overexpression did not affect the capacity of GW501516 to increase palmitate oxidation. Basal and insulin stimulated glucose uptake, glycogen synthesis and glucose oxidation were not significantly modulated by Angptl4 overexpression. Our findings suggest that FAs-PPARdelta/RXR-Angptl4 axis controls the LPL-dependent uptake of FAs in myotubes, whereas the effect of PPAR delta activation on beta-oxidation is independent of Angptl4.
Highlights
Skeletal muscle is the main site for burning excess calories when exercised it plays a key role in the prevention and management of metabolic diseases such as type 2 diabetes
Because PPARd exerts its function by forming an obligatory heterodimer with retinoic X receptor (RXR) we evaluated whether RXR activation by bexarotene has similar effect compared with that of GW501516 on Angiopoietin-like 4 (Angptl4) expression and lipoprotein lipase (LPL) activity
In the present study we have demonstrated that activation of PPARd/RXR strongly upregulates Angptl4 causing the inhibition of LPL activity and LPL-dependent fatty acid (FA) uptake in myotubes
Summary
Skeletal muscle is the main site for burning excess calories when exercised it plays a key role in the prevention and management of metabolic diseases such as type 2 diabetes. As well as other tissues, obtain FAs either via lipoprotein lipase (LPL, EC 3.1.1.34)-mediated hydrolysis of lipoprotein triglycerides or from unesterified FAs bound to albumin [2]. It is difficult to discern which is the major pathway for FA uptake, the LPL-mediated uptake has the advantage of being tightly regulated in a tissue specific manner independent of albumin-bound FAs. Stored FAs are released from adipose tissue by intracellular lipolysis and are rapidly taken up by the liver, esterified to triglycerides, packed in lipoproteins and secreted as VLDL. .90% of circulating FAs are contained within VLDL and chylomicron particles and delivered to skeletal muscle and heart (oxidation) or adipose tissue (storage) by LPL-catalyzed lipolysis [2]. LPL is produced in parenchymal cells of these tissues, and it is transported and bound by glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) to the luminal side of the capillary endothelium where it exerts its main function [3,4]
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