PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis

Abstract

On June 1, 1889, 72 year old Charles-Edouard BrownSequard reported to the Societe de Biologie of Paris that he had injected himself with aqueous extracts of guinea pig and dog testes and within a short period of time experienced a remarkable enhancement in physical strength, intellectual capacity, and sexual potency (1). Brown-Sequard's self-experimentation was based on the then novel hypothesis that the testes were the source of a substance that was released into the circulation and exerted masculinizing effects on other tissues in the body. Subsequent investigation indicated that testicular extracts contain little or no active androgen, and Brown-Sequard's "rejuvination" is now considered to be a well-documented example of a placebo effect. Nevertheless, his concept of a chemical messenger was correct and greatly influenced studies of hormone-producing tissues and translational research. By 1891, Murray had successfully treated a hypothyroid patient with extracts made from the thyroid glands of sheep using Brown-Sequard's methods, representing the first example of successful hormone replacement therapy (1). Thereafter, steady progress was made in the identification and characterization of the classical steroid and thyroid hormones, which were subsequently shown to have their activity by binding to and activating so-called nuclear receptors that exerted their biological effects by regulating gene transcription. Nearly 100 years after Brown-Sequard's experiments, cDNAs encoding the glucocorticoid receptor, estrogen receptor, and thyroid hormone receptors were cloned, leading to the recognition of a superfamily of nuclear receptors that responded not only to steroid hormones but to other classes of lipid-derived mediators that function to regulate development and homeostasis (2). Here, we review recent findings that provide new insights into the roles of nuclear receptors in the control of lipid metabolism and atherosclerosis, focusing on liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs). Although drugs that regulate LXRs and PPARs may not have the rejuvenating properties sought by Brown-Sequard, they do hold promise for new approaches for the prevention of atherosclerosis, the leading cause of age-related morbidity and mortality in Western societies (3). PATHOGENESIS OF ATHEROSCLEROSISAtherosclerosis has its origins in pathogenic interactions between circulating lipoproteins, hemodynamic factors, the arterial wall, and the immune system. The earliest visible lesion is the "fatty streak," consisting predominantly of monocyte-derived macrophages engorged with lipoprotein-derived cholesterol (reviewed in 4).

PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale

“…Indeed, ChIP-QPCR analysis of rosiglitazone-treated adipocytes at the seven sites did not reveal substantial PPAR␥ enrichment over IgG (data not shown). These findings indicate that there is little or no additional binding of PPAR␥ upon exogenous ligand stimulation, which is consistent with reported in vitro data indicating that DNA binding by PPAR␥ is ligand-independent (Li and Glass 2004;Lehrke and Lazar 2005).…”

Regulation of adiponectin receptors in hepatocytes by the peroxisome proliferator-activated receptor-γ agonist rosiglitazone

“…As a result, we found a consensus glucocorticoid receptor (GR) binding element in this region (Fig. 4b), instead of a classical PPAR-responsive element [15][16][17]. It is significant that the human ADIPOR1 promoter did not contain such a GR element in the corresponding region.…”

“…The peroxisome proliferator-activated receptors (PPARs) belong to a subfamily of nuclear receptors composed of three isoforms, PPARG, PPARA and PPARD [15][16][17]. PPARs are nutrient sensors that regulate the homeostasis of metabolism.…”

“…Rosiglitazone, a representative TZD, is active in vivo as an anti-diabetic agent in the ob/ob mouse model, and has been used as an oral hypoglycaemic agent in the treatment of type 2 diabetes in humans for many years [20]. The insulin-sensitising activities of PPARG agonists are associated with their ability to decrease the circulating levels of free fatty acids via inhibition of adipocyte lipolysis, as well as regulation of proteins that modulate insulin sensitivity and lipid metabolism [15][16][17]. Interestingly, PPARG functionally interacts with adiponectin in the regulation of energy metabolism.…”

Long-term treatment with hyperbaric air improves hyperlipidemia of db/db mice

“…CPT-1 mRNA expression in the soleus muscle and liver was not altered by HBA exposure in db/+m mice. The mRNA expressions of the transcription factors PPARα and PGC-1α were examined since the former was reported to control lipid metabolism (21,22) and the latter was reported to increase β-oxidation in brown adipocytes (23) or in skeletal muscle with enhanced mitochondria function coordinated with exercise (24), even though PGC-1α usually has roles in glucose metabolism to attribute a gluconeogenesis and mitochondria biosynthesis (25). Moreover, it has been shown that PGC-1α can cooperate with PPARα to express the genes of mitochondrial fatty acid oxidation enzymes such as CPT-1 in a hepatoma cell line (26).…”