AMPK activation enhances the anti-atherogenic effects of high density lipoproteins in apoE−/− mice

Abstract

HDL plays crucial roles at multiple stages of the pathogenesis of atherosclerosis. AMP-activated protein kinase (AMPK) is a therapeutic candidate for the treatment of cardiovascular disease. However, the effect of AMPK activation on HDL functionality has not been established in vivo. We assessed the effects of pharmacological AMPK activation using A-769662, AICAR, metformin, and IMM-H007 on the atheroprotective functions of HDL in apoE-deficient (apoE−/−) mice fed with a high-fat diet. After administration, there were no changes in serum lipid levels among the groups. However, mice treated with AMPK activators showed significantly enhanced reverse cholesterol transport in vivo and in vitro. AMPK activation also increased the expression of ABCA1 and ABCG1 in macrophages and scavenger receptor class B type I and LCAT in the liver. HDL from AMPK activation mice exhibited lower HDL inflammatory index and myeloperoxidase activity and higher paraoxonase 1 activity than HDL from untreated mice, implying superior antioxidant and anti-inflammatory capacities. Pharmacological AMPK activation also induced polarization of macrophages to the M2 state and reduced plasma lipid peroxidation, inflammatory cytokine production, and atherosclerotic plaque formation in apoE−/− mice. These observations suggest that pharmacological AMPK activation enhances the anti-atherogenic properties of HDL in vivo. This likely represents a key mechanism by which AMPK activation attenuates atherosclerosis.

Micro‐environment and intracellular metabolism modulation of adipose tissue macrophage polarization in relation to chronic inflammatory diseases

“…Although increased chronic inflammation in preadipocytes of EAT is related to VD deficiency that promoted CAD development in swine, whether the increased inflammation in EAT is caused by the cross‐talk between preadipocytes and macrophages in humans remains to be further clarified . In addition, the activation of AMPK, a crucial target for metabolic reprogramming, has been shown to be significantly increased in HDL‐stimulated macrophages that induced macrophage polarization to the M2 phenotype, thus improving the anti‐atherogenic function of HDL in apoE −/− mice . As noted earlier, miR‐33 directs the M1 polarization of macrophages that aggravates AS, while miR‐33 antagonism is atheroprotective, at least in part, by promoting M2 macrophage polarization via upregulating FAO, which reduces AS plaque inflammation, indicating a causal role of metabolic and phenotype shifts in ATMs in AS development.…”

“…Promoting intracellular cholesterol efflux by increasing HDL in macrophages has been found to induce the polarization of macrophages to the M2 phenotype, thus improving inflammation, oxidative damage, and AS in apoE knockout mice. 63 HDL also inhibits the phenotype and function of M1 by decreasing the M1-specific markers and inflammatory genes TNF-α, IL-6, and MCP-1 via redistribution of membrane caveolin-1 and phosphorylation of ERK1/2 in human macrophages. 64 However, HDLmediated cholesterol efflux was impaired under the obese state in humans, 65 which was related to elevated monocytes, indicating a pro-inflammatory state in these subjects.…”

“…Seminal works have demonstrated that HDL is a key player of cholesterol metabolism and anti‐inflammation that is important for the metabolic environment of AT. Promoting intracellular cholesterol efflux by increasing HDL in macrophages has been found to induce the polarization of macrophages to the M2 phenotype, thus improving inflammation, oxidative damage, and AS in apoE knockout mice . HDL also inhibits the phenotype and function of M1 by decreasing the M1‐specific markers and inflammatory genes TNF‐α, IL‐6, and MCP‐1 via redistribution of membrane caveolin‐1 and phosphorylation of ERK1/2 in human macrophages .…”

Berberine alleviates oxidized low‐density lipoprotein‐induced macrophage activation by downregulating galectin‐3 via the NF‐κB and AMPK signaling pathways

“…AMPK activation improves macrophage cholesterol homeostasis in mice (Fullerton et al, ), inhibits PMA‐induced monocyte‐to‐macrophage differentiation (Vasamsetti et al, ), and attenuates atherosclerosis by enhancing the anti‐atherogenic effects of high‐density lipoproteins (Ma, Wang, Yang, An, & Zhu, ) and reducing atheroma‐inducing macrophages formation in ApoE (−/−) mice (Wang, Ma, Zhao, & Zhu, ). In the present study, phosphate AMPK protein was downregulated on ox‐LDL‐induced macrophages, which was rescued by BBR.…”

Aspirin Improves Nonalcoholic Fatty Liver Disease and Atherosclerosis through Regulation of the PPARδ-AMPK-PGC-1αPathway in Dyslipidemic Conditions

“…Tert-butyl-4-(2-hydroxyethyl)-4-(pyrrolidin-1-yl)-piperidine-1-carboxylate (PYPEP), which is another PPARδ agonist, inhibited atherosclerosis in human apolipoprotein B100 and cholesteryl ester transfer protein doubletransgenic mice by improving the serum lipoprotein profiles [34]. Furthermore, the anti-NAFLD effects of dioscin and chicory (Cichorium intybus L.) polysaccharides were dependent to AMPK [35,36], and in ApoE knock-out mice, AMPK activation by agonists decreased the formation of atheromata-inducing macrophages, but it increased the antiatherogenic effects of HDL-cholesterol [37,38]. A disease-prone polymorphism of the PGC-1α gene was reported to elevate the risk of NAFLD in obese children [39], and lowered protein expression of PGC-1α was corelated with the development of atherosclerosis [40].…”