Alexandre Fredenrich

Peroxisome proliferator-activated receptor δ controls muscle development and oxidative capability

Peroxisome proliferator‐activated receptors (PPARs) are nuclear receptors exerting several functions in development and metabolism. The physiological functions of PPARδ remain elusive. By using a CRE‐Lox recombination approach, we generated an animal model for muscle‐specific PPARδ overexpression to investigate the role of PPARδ in this tissue. Muscle‐ specific PPARδ overexpression results in a profound change in fiber composition due to hyperplasia and/or shift to more oxidative fiber and, as a consequence, leads to the increase of both enzymatic activities and genes implicated in oxidative metabolism. These changes in muscle are accompanied by a reduction of body fat mass, mainly due to a large reduction of adipose cell size. Furthermore, we demonstrate that endurance exercise promotes an accumulation of PPARδ protein in muscle of wild‐type animals. Collectively, these results suggest that PPARδ plays an important role in muscle development and adaptive response to environmental changes, such as training exercise. They strongly support the idea that activation of PPARδ could be beneficial in prevention of metabolic disorders, such as obesity or type 2 diabetes.

Plasma remnant-like particle lipid and apolipoprotein levels in normolipidemic and hyperlipidemic subjects

Remnant-like particle (RLP) lipid and apolipoprotein (apo) levels were determined in the plasma of normolipidemic and hyperlipidemic subjects, in order to investigate the relationship between RLP levels and the concentration of other plasma lipoprotein parameters. Plasma RLP fractions were isolated with the use of an immunoaffinity gel (RLP-Cholesterol Jimro II, Japan Immunoresearch Lab.), containing specific anti-apoB-100 and anti-apoA-I antibodies. Four groups of human subjects were selected, who had either matching or significantly different levels of plasma triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C): (1) normolipidemic control (NC) subjects (n = 10), (2) patients with elevated levels of LDL-C (type IIa, LDL-C (mean +/- S.E.), 4.65 +/- 0.09 mmol/l, n = 10), (3) hypertriglyceridemic (HTG) patients with elevated LDL-C (type IIb, TG: 3.86 +/- 0.36; LDL-C: 4.67 +/- 0.21 mmol/l, n = 10), and (4) HTG patients with normal LDL-C (type IV, TG: 3.71 +/- 0.39 mmol/l, n = 10). NC subjects (RLP-C: 0.22 +/- 0.01; RLP-TG: 0.24 +/- 0.03 mmol/l) had RLP apoB, apoC-III and apoE levels of 3.2 +/- 0.3, 1.8 +/- 0.3, and 1.4 +/- 0.1 mg/dl, representing 3.2 +/- 0.4, 14.5 +/- 1.4 and 32.1 +/- 2.1% of total plasma levels, respectively. RLP lipid and apolipoprotein concentrations were significantly higher in HTG groups (type IIb and IV) compared to NTG groups (NC and type IIa) (e.g. RLP-C: 0.50 +/- 0.07 and 0.58 +/- 0.11 vs. 0.22 +/- 0.01 and 0.21 +/- 0.01 mmol/l, respectively (P < 0.01); RLP apoB: 8.4 +/- 1.6 and 8.2 +/- 0.9 vs. 3.2 +/- 0.3 and 3.4 +/- 0.2 mg/dl, respectively (P < 0.01)). No significant difference in RLP levels was observed between groups having different LDL levels, and thus no correlation existed between RLP-C and LDL-C levels (r = 0.24, n.s.). RLP-C and RLP apoB levels were, however, correlated with VLDL-C and VLDL apoB (r = 0.86, P < 0.001 and r = 0.70, P < 0.001, respectively). These results demonstrate that elevated levels of both RLP lipids and apolipoproteins are characteristic of patients with increased levels of plasma triglyceride, and not patients with increased levels of LDL.

Effect of human native low-density and high-density lipoproteins on prostaglandin production by mouse macrophage cell line P388D1: Possible implications in pathogenesis of atherosclerosis☆

Macrophages have been shown to play a key-role in the development of atherosclerotic lesions. Monocyte attraction and activation in the arterial wall lead to foam cell formation, cholesterol accumulation and secretion of inflammation mediators. Among macrophage secretions, prostacyclin and thromboxane are prostaglandins involved in the regulation of coagulation and vascular permeability. In this study, we have evaluated the effects of human native low-density and high-density lipoproteins on macrophage prostaglandin production (P388D1 mouse cell line). Lipoprotein fractions were purified from venous blood of healthy volunteers by sequential ultracentrifugation. After lipoprotein incubation with cells, supernatants were extracted and prostaglandins quantified by high-performance liquid chromatography. Our technique allows the determination of the main classes of prostaglandins. In the presence of low-density lipoproteins, time-course study showed an increase in total prostaglandin production within 10 min (50 times basal secretion level). This increase was dose-dependent. A steady-state was obtained at 20 mg protein LDL/1. Stimulation of thromboxane B2 and prostacyclin was predominant, with a main effect on the proaggregant thromboxane. Production of the proinflammatory PGF2 alpha and the immunoregulatory PGE2 was lower. In the presence of high-density lipoproteins, P388D1 cells also increased their total prostaglandin secretion at 30 min, in a dose-dependent manner. This increase was directly related to a stimulation of prostacyclin, with no significant effect on thromboxane. Our results demonstrate that normal low-density lipoproteins can stimulate macrophage prostaglandin secretions, with putative deleterious effects on the arterial wall, in particular thrombus formation. On the other hand, high-density lipoproteins, by mainly stimulating prostacyclin, could theoretically have a beneficial influence.

Roles of peroxisome proliferator-activated receptor delta in skeletal muscle function and adaptation.

Purpose of the reviewPeroxisome proliferator-activated receptors mediate the transcriptional effects of fatty acids and fatty acid metabolites and regulate many physiological functions including development and metabolism. The roles of peroxisome proliferator-activated receptor α and γ isotypes have been well established, while the functions of the third member of the family, peroxisome proliferator-activated receptor δ, remained unclear until very recently. This review focuses on the physiological functions of the nuclear receptor and especially on its roles in the control of fatty acid metabolism. Recent findingsWe review very recent data demonstrating that peroxisome proliferator-activated receptor δ plays a central role in the regulation of fatty acid oxidation in several tissues, such as skeletal muscle and adipose tissue, and also that the nuclear receptor is involved in cholesterol metabolism. SummaryUse of potent and specific peroxisome proliferator-activated receptor δ agonists and appropriate transgenic animal models revealed the importance of this nuclear receptor in regulation of fatty acid catabolism in skeletal muscle and other tissues. It also indicated the potential of peroxisome proliferator-activated receptor δ as a therapeutic target in pathologies such as metabolic syndrome. However, the effects of peroxisome proliferator-activated receptor δ activation in atherosclerosis and the control of cell proliferation remain to be established.

Effects of low density and high density lipoproteins isolated from non-insulin dependent diabetic patients on prostaglandin secretion by mouse macrophage cell line P388D1

We have previously shown that low-density (LDL) and high-density (HDL) lipoprotein from healthy subjects can promote in vitro prostaglandin (PG) release by murine macrophages. In this pilot study, we have measured PG production induced by lipoproteins of six diabetic patients with poor metabolic control, compared to five healthy controls. Plasma lipoprotein levels were similar in both groups. Lipoprotein fractions were purified by sequential ultracentrifugation. After lipoprotein incubation with cells, supernatants were extracted and PG quantified by HPLC. In presence of LDL, in control subjects, there was an increase in total PG production, mainly due to thromboxane B2 (TxB2). In diabetic patients, the secretion pattern was similar. In presence of HDL, in control subjects, total PG secretion was also increased, but it was balanced between TxB2 and prostacyclin. In diabetic patients, at low HDL concentration (10 mg/l) the secretion was mainly due to TxB2, while at higher HDL concentrations (100 mg/l). the secretion was balanced between TxB2 and prostacyclin. Comparison of means of areas under curve for the two groups studied showed that LDL increased all PG secretion in diabetic patients compared to controls (P < 0.05 for PGF2alpha), while HDL increased all PG secretion in controls compared to diabetic patients, except PGF2alpha. Our work suggests a key role of LDL in TxB2 secretion in diabetic patients, which is a major proaggregant and vasoconstrictive agent. There was also an increased secretion of all PG in diabetic patients.