The CD36-PPARγ Pathway in Metabolic Disorders

Abstract

Uncovering the biological role of nuclear receptor peroxisome proliferator-activated receptors (PPARs) has greatly advanced our knowledge of the transcriptional control of glucose and energy metabolism. As such, pharmacological activation of PPARγ has emerged as an efficient approach for treating metabolic disorders with the current use of thiazolidinediones to improve insulin resistance in diabetic patients. The recent identification of growth hormone releasing peptides (GHRP) as potent inducers of PPARγ through activation of the scavenger receptor CD36 has defined a novel alternative to regulate essential aspects of lipid and energy metabolism. Recent advances on the emerging role of CD36 and GHRP hexarelin in regulating PPARγ downstream actions with benefits on atherosclerosis, hepatic cholesterol biosynthesis and fat mitochondrial biogenesis are summarized here. The response of PPARγ coactivator PGC-1 is also discussed in these effects. The identification of the GHRP-CD36-PPARγ pathway in controlling various tissue metabolic functions provides an interesting option for metabolic disorders.

Keywords: GHRP; PGC-1; PPAR nuclear receptors; atherosclerosis; energy metabolism; fatty acid oxidation; hexarelin; insulin resistance; scavenger receptor.

Figure 1

Overview of the growth hormone releasing peptide (GHRP)-peroxisome proliferator-activated receptor-gamma (PPARγ) pathway in lipid and energy metabolism. The interaction of hexarelin with the scavenger receptor CD36 promotes the transcriptional activation of nuclear receptor PPARγ and target gene profiling involved in metabolism. In macrophages, hexarelin and other GHRPs induce a molecular cascade involving nuclear liver X receptor LXRα and expression of apolipoprotein E (apoE) and sterol transporters ABCA1 and ABCG1. Such activation of the PPARγ-LXRα-ABC metabolic pathway increases cholesterol efflux, resulting in enhanced HDL reverse cholesterol transport and regression of atherosclerosis. In hepatocytes, CD36 activation by hexarelin reduces de novo cholesterol synthesis. Activation of the LKB-AMPK pathway resulted in the inhibition of the rate-limiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) enzyme. Also, induction of Insig1/2 expression through PPARγ/PGC-1α activation led to HMGR degradation and SREBP-2 retention in the endoplasmic reticulum (ER), thereby blunting the homeostatic response to sterol depletion. In adipocytes, CD36 activation with hexarelin promotes mitochondrial activity and biogenesis through enhanced PPARγ and co-activator PGC-1α transcriptional activity. Induction of key genes involved in fatty acid utilization and energy production in mitochondria results in an increased fatty acid β-oxidation and thermogenic-like profile indicative of a browning effect of white fat (adapted from Refs [82,83]).