Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ, and γ

Abstract

PPARα, β/δ, and γ regulate genes involved in the control of lipid metabolism and inflammation and are expressed in all major cell types of atherosclerotic lesions. In vitro studies have suggested that PPARs exert antiatherogenic effects by inhibiting the expression of proinflammatory genes and enhancing cholesterol efflux via activation of the liver X receptor-ABCA1 (LXR-ABCA1) pathway. To investigate the potential importance of these activities in vivo, we performed a systematic analysis of the effects of PPARα, β, and γ agonists on foam-cell formation and atherosclerosis in male LDL receptor-deficient (LDLR -/-) mice. Like the PPARγ agonist, a PPARα-specific agonist strongly inhibited atherosclerosis, whereas a PPARβ-specific agonist failed to inhibit lesion formation. In concert with their effects on atherosclerosis, PPARα and PPARγ agonists, but not the PPARβ agonist, inhibited the formation of macrophage foam cells in the peritoneal cavity. Unexpectedly, PPARα and PPARγ agonists inhibited foam-cell formation in vivo through distinct ABCA1-independent pathways. While inhibition of foam-cell formation by PPARα required LXRs, activation of PPARγ reduced cholesterol esterification, induced expression of ABCG1, and stimulated HDL-dependent cholesterol efflux in an LXR-independent manner. In concert, these findings reveal receptor-specific mechanisms by which PPARs influence macrophage cholesterol homeostasis. In the future, these mechanisms may be exploited pharmacologically to inhibit the development of atherosclerosis.

Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

“…In recent years our laboratory has established that fetal brown adipocytes constitute an ideal system for studying molecular mechanisms of insulin resistance and for testing novel approaches to overcome or bypass such resistance. One such approach is ligand activation of nuclear receptors, which can regulate glucose metabolism in multiple tissues including adipose tissue [3][4][5]. Accordingly, we decided to explore and compare the effect of nuclear receptor agonists on glucose uptake in brown adipocytes.…”

“…NR1HRs are activated by naturally produced oxysterols, including (22R)-hydroxycholesterol, (24,25S)-epoxycholesterol, and 27-hydroxycholesterol, as well as by synthetic compounds such as T0901317 and GW3965 [1,2]. Although NR1HR function has been elucidated in detail with respect to cholesterol and lipid metabolism, new findings have indicated that NR1HR is an important regulator of glucose metabolism in liver and adipose tissue [3][4][5]. Recent studies have reported low plasma glucose, improved glucose tolerance and increased glucose-induced insulin secretion by islets in genetic and dietary models of type 2 diabetes treated with synthetic NR1HR agonists [6][7][8].…”

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

“…Similarly, PPARα and PPARγ agonists have been shown to significantly reduce atherosclerotic lesions in mice. However, a synthetic PPARδ agonist has little effect on atherosclerosis in mice (Li et al, 2004), suggesting that PPARs may have diverse effects on the atherogenic processes. In macrophages, PPARα also induces the expression of NPC1 and NPC2, which control the transport of free cholesterol from the lysosome to the plasma membrane (Chinetti-Gbaguidi et al, 2005), thus leading to increased cholesterol efflux.…”

Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice

“…PPAR␥ is thought to promote cholesterol efflux through LXR-dependent and -independent pathways (22). The lack of PPAR␥ expression raised the question of its requirement for cholesterol efflux from foam cells.…”