The Peroxisome Proliferator-Activated Receptor β/δ Agonist, GW501516, Regulates the Expression of Genes Involved in Lipid Catabolism and Energy Uncoupling in Skeletal Muscle Cells

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2003-12, Vol.17 (12), p.2477-2493
• Main Authors: Dressel, Uwe, Allen, Tamara L, Pippal, Jyotsna B, Rohde, Paul R, Lau, Patrick, Muscat, George E. O
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Cell Line; Cholesterol - metabolism; DNA Primers; Energy Metabolism - physiology; Gene Expression Regulation - drug effects; Lipid Metabolism; Mice; Muscle, Skeletal - drug effects; Muscle, Skeletal - physiology; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - genetics; Recombinant Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Thiazoles - pharmacology; Transcription Factors - agonists; Transcription Factors - genetics; Transfection
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2003-0151

Lipid homeostasis is controlled by the peroxisome proliferator-activated receptors (PPARα, -β/δ, and -γ) that function as fatty acid-dependent DNA-binding proteins that regulate lipid metabolism. In vitro and in vivo genetic and pharmacological studies have demonstrated PPARα regulates lipid catabolism. In contrast, PPARγ regulates the conflicting process of lipid storage. However, relatively little is known about PPARβ/δ in the context of target tissues, target genes, lipid homeostasis, and functional overlap with PPARα and -γ. PPARβ/δ, a very low-density lipoprotein sensor, is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for approximately 40% of total body weight. Skeletal muscle is a metabolically active tissue, and a primary site of glucose metabolism, fatty acid oxidation, and cholesterol efflux. Consequently, it has a significant role in insulin sensitivity, the blood-lipid profile, and lipid homeostasis. Surprisingly, the role of PPARβ/δ in skeletal muscle has not been investigated. We utilize selective PPARα, -β/δ, -γ, and liver X receptor agonists in skeletal muscle cells to understand the functional role of PPARβ/δ, and the complementary and/or contrasting roles of PPARs in this major mass peripheral tissue. Activation of PPARβ/δ by GW501516 in skeletal muscle cells induces the expression of genes involved in preferential lipid utilization, β-oxidation, cholesterol efflux, and energy uncoupling. Furthermore, we show that treatment of muscle cells with GW501516 increases apolipoprotein-A1 specific efflux of intracellular cholesterol, thus identifying this tissue as an important target of PPARβ/δ agonists. Interestingly, fenofibrate induces genes involved in fructose uptake, and glycogen formation. In contrast, rosiglitazone-mediated activation of PPARγ induces gene expression associated with glucose uptake, fatty acid synthesis, and lipid storage. Furthermore, we show that the PPAR-dependent reporter in the muscle carnitine palmitoyl-transferase-1 promoter is directly regulated by PPARβ/δ, and not PPARα in skeletal muscle cells in a PPARγ coactivator-1-dependent manner. This study demonstrates that PPARs have distinct roles in skeletal muscle cells with respect to the regulation of lipid, carbohydrate, and energy homeostasis. Moreover, we surmise that PPARβ/δ agonists would increase fatty acid catabolism, cholesterol efflux, and energy expenditure in muscle, and speculate selective activators of PPARβ/δ may