Combining β-adrenergic and peroxisome proliferator–activated receptor γ stimulation improves lipoprotein composition in healthy moderately obese subjects

Abstract

Current pharmacological regimens for hypertriglyceridemia and low high-density lipoprotein (HDL) are limited to the peroxisome proliferator-activated receptor (PPAR) alpha activating fibrates, niacin, and statins. This pilot study examined the impact of simultaneous stimulation of cyclic adenosine monophosphate with a beta-adrenergic agonist and PPARgamma with pioglitazone (PIO) on lipoprotein composition in moderately obese, healthy subjects. Subjects were treated with PIO (45 mg) to stimulate PPARgamma or a combination of ephedrine (25 mg TID), a beta-agonist, with caffeine (200 mg TID), a phosphodiesterase inhibitor (ephedrine plus caffeine), or both for 16 weeks. Lipoproteins were separated by gradient ultracentrifugation into very low-density lipoprotein (VLDL), intermediate-density lipoprotein, low-density lipoprotein (LDL), and 3 HDL (L, M, and D) subfractions. Apolipoproteins were measured by high-performance liquid chromatography. PIO alone reduced the core triglyceride (TG) content relative to cholesterol ester (CE) in VLDL (-40%), IDL (-25%), and HDL-M (-38%). Ephedrine plus caffeine alone reduced LDL CE (-13%), phospholipids (-9%), and apolipoprotein (apo) B (-13%); increased HDL-M LpA-I (HDL containing apoA-I without apoA-II, 28%), CE/TG (23%), and CE/apoA-I (8%) while reducing apoA-II (-10%); and increased HDL-L LpA-I (29%). Combination therapy reduced total plasma TG (-28%), LDL cholesterol (LDL-C, -10%), apoB (-16%), apoB/apoA-I ratio (-21%) while increasing HDL cholesterol (HDL-C, 21%), total plasma apoA-I (12%), LpA-I (43%), and apoC-I (26%). It also reduced VLDL total mass (-34%) and apoC-III (-39%), LDL CE (-13%), apoB (-13%), and total mass (-11%). Combination therapy increased HDL-L CE/TG (32%), apoC-I (30%), apoA-I (56%), and LpA-I (70%), as well as HDL-M CE (35%), phospholipids (24%), total mass (19%), apoC-I (25%), apoA-I (18%), and LpA-I (56%). In conclusion, simultaneous beta-adrenergic and PPARgamma activation produced beneficial effects on VLDL, LDL, HDL-L, and HDL-M. Perhaps the most important impact of combination therapy was dramatic increases in LpA-I and apoC-I in HDL-L and HDL-M, which were much greater than the sum of the monotherapies. Because LpA-I appears to be the most efficient mediator of reverse-cholesterol transport and a major negative risk factor for cardiovascular disease, this combination therapy may provide very effective treatment of atherosclerosis.

The Effect of β-Adrenergic and Peroxisome Proliferator–Activated Receptor-γ Stimulation on Target Genes Related to Lipid Metabolism in Human Subcutaneous Adipose Tissue

“…For example, lipoprotein lipase (LPL) was upregulated after cAMP (17) and PPAR-␥ (18,19) activation. Combined therapy with ephedrine plus caffeine/pioglitazone (ECPio) significantly reduced plasma triglycerides (triglycerides), VLDL, and LDL levels while it increased HDL total mass (20). Our and several previous results demonstrated that PPAR-␥ activation increases body weight and the expression of several genes involved in mitochondrial biogenesis and lipid metabolism in subcutaneous fat obtained from subjects with type 2 diabetes (18,20 -22).…”

“…The characteristics of the study population were previously reported (20). Subjects were healthy and not taking thiazolidinediones, ␤-blockers, orlistat, sibutramine, ephedrine, phenylpropanolamine (Dexatrim), corticosteroids, statins, fibrates, cholesterol-binding drugs, or herbal supplements containing ephedrine and/or caffeine; abusing alcohol; or using other illicit drugs.…”

Rosiglitazone reverses salbutamol‐induced β2‐adrenoceptor tolerance in airway smooth muscle

“…PPARg-mediated signal transduction pathways in adipose tissue (Sell et al, 2004;Hughes et al, 2006;Bogacka et al, 2007). However, to our knowledge, no data on the synergistic effects of PPARg and b2-adrenoceptor agonists on airway smooth muscle in vivo and in vitro have been reported before the present study.…”

“…Noteworthy, we showed the presence of PPARγ both in control and desensitized airway smooth muscle tissues, a condition that may offer a pharmacodynamic basis for the use of PPAR targeting strategies in combination with β 2 ‐adrenoceptor agonists. Several lines of evidence suggest the existence of cross‐talk between the sympathetic nervous system and PPARγ‐mediated signal transduction pathways in adipose tissue (Sell et al ., 2004; Hughes et al ., 2006; Bogacka et al ., 2007). However, to our knowledge, no data on the synergistic effects of PPARγ and β 2 ‐adrenoceptor agonists on airway smooth muscle in vivo and in vitro have been reported before the present study.…”

PPARγ Dependence of Cyclosporine–Isoprenaline Renovascular Interaction: Roles of Nitric Oxide Synthase and Heme Oxygenase

“…28 Paradoxically, simultaneous activation of PPARg and b-adrenergic receptors exhibits synergistic favorable effects on lipoprotein composition. 29 The hemodynamic responses elicited by PPARg are also modulated by b 2 -adrenergic signaling. 30 Moreover, procaterol (a synthetic b 2 -adrenergic agonist) modulates eosinophil function by increasing PPARg expression.…”