Linking nutritional regulation of Angptl4, Gpihbp1, and Lmf1 to lipoprotein lipase activity in rodent adipose tissue

Abstract

BackgroundLipoprotein lipase (LPL) hydrolyzes triglycerides in lipoproteins and makes fatty acids available for tissue metabolism. The activity of the enzyme is modulated in a tissue specific manner by interaction with other proteins. We have studied how feeding/fasting and some related perturbations affect the expression, in rat adipose tissue, of three such proteins, LMF1, an ER protein necessary for folding of LPL into its active dimeric form, the endogenous LPL inhibitor ANGPTL4, and GPIHBP1, that transfers LPL across the endothelium.ResultsThe system underwent moderate circadian oscillations, for LPL in phase with food intake, for ANGPTL4 and GPIHBP1 in the opposite direction. Studies with cycloheximide showed that whereas LPL protein turns over rapidly, ANGPTL4 protein turns over more slowly. Studies with the transcription blocker Actinomycin D showed that transcripts for ANGPTL4 and GPIHBP1, but not LMF1 or LPL, turn over rapidly. When food was withdrawn the expression of ANGPTL4 and GPIHBP1 increased rapidly, and LPL activity decreased. On re-feeding and after injection of insulin the expression of ANGPTL4 and GPIHBP1 decreased rapidly, and LPL activity increased. In ANGPTL4−/− mice adipose tissue LPL activity did not show these responses. In old, obese rats that showed signs of insulin resistance, the responses of ANGPTL4 and GPIHBP1 mRNA and of LPL activity were severely blunted (at 26 weeks of age) or almost abolished (at 52 weeks of age).ConclusionsThis study demonstrates directly that ANGPTL4 is necessary for rapid modulation of LPL activity in adipose tissue. ANGPTL4 message levels responded very rapidly to changes in the nutritional state. LPL activity always changed in the opposite direction. This did not happen in Angptl4−/− mice. GPIHBP1 message levels also changed rapidly and in the same direction as ANGPTL4, i.e. increased on fasting when LPL activity decreased. This was unexpected because GPIHBP1 is known to stabilize LPL. The plasticity of the LPL system is severely blunted or completely lost in insulin resistant rats.

Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

“…In white adipose tissue LPL activity is decreased by fasting, which has been demonstrated unequivocally to be mediated by up-regulation of Angptl4 (25). In brown adipose tissue LPL activity is increased by exposure to cold; such exposure is associated with a decrease in Angptl4 mRNA (26), hinting at a potential role of ANGPTL4.…”

Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets

“…The expression of angptl4 is up-regulated by per-oxisome proliferator-activated receptors, which in turn are activated by free fatty acids and other ligands (27,28). Angptl4 is a strong candidate for the tissue-specific, post-translational regulation of LPL activity that is necessary for directing uptake of blood lipids according to the needs of different tissues of the body (2,29) and for protecting tissues against deleterious effects of lipid overload (27,28).…”

Angiopoietin-like 4 Modifies the Interactions between Lipoprotein Lipase and Its Endothelial Cell Transporter GPIHBP1

“…LPL deficiency in humans results in severe hypertriglyceridemia and can cause eruptive xanthoma, lipemia retinalis, and pancreatitis (1). Moreover, LPL activity levels are altered in human obese and diabetic patients as well as in rodent models of metabolic disease, suggesting that LPL might play a role in the development of insulin resistance and diabetes (2)(3)(4)(5). LPL is regulated at multiple levels, including transcriptionally, translationally, and post-translationally (6 -8).…”