AMPK activates LXRα and ABCA1 expression in human macrophages

Zou

et al. 2020

Preprint

Abbreviations:ABCA1: ATP-binding cassette subfamily A member 1 ABCG1: ATP-binding cassette subfamily G member 1 ABCG5: ATP-binding cassette subfamily G member 5 AMPK: adenosine monophosphate activated protein kinases CE: cholesterol ester CER: Cholesterol esterification rate LXRα: liver X receptor alpha pAMPK: phosphorylated-AMPK RCT: cholesterol reverse transport SR-BI: scavenger receptor class B type I TC: total cholesterol Abstract Cholesterol efflux from macrophages is the first step of cholesterol reverse transport (RCT), whose increase inhibits cholesterol accumulation and foam cell formation to suppress atherogenesis. Liver X receptor alpha (LXRα) and adenosine monophosphate activated protein kinases (AMPK) both have the pivotal role in cholesterol homeostasis. However the association between these two molecules in cell model of atherosclerosis is poorly understood.Hesperetin has been reported to possess several protective effects for cardiovascular diseases, while little is known about the role of hesperetin and its underlying mechanism on macrophage foam cell formation. In this study, we sought to investigate the potential effects of hesperetin in cholesterol efflux by using human macrophage derived foam cells, focusing on liver X receptor alpha (LXRα) and adenosine monophosphate activated protein kinases (AMPK) implication. Hesperetin treatment concentration-dependently reduced foam cell formation, intracellular cholesterol level and cholesterol esterification rate, and enhanced cholesterol efflux in THP-1 macrophages. Hesperetin upregulated the protein levels of LXRα and its targets including ABCA1, ABCG1 as well as SR-BI, and phosphorylated-AMPK.Meanwhile, hesperetin-induced upregulation of LXRα expression was enhanced by AMPK agonist and inhibited by AMPK inhibitor. Furthermore, hesperetin increased mRNA level of LXRα and its target genes, all which were depressed by AMPKα1/α2 small interfering RNA (siRNA) transfection. In conclusion, we founded for the first time that hesperetin could active AMPK. And this activation upregulated LXRα and its targets including ABCA1, ABCG1 and SR-BI, which significantly inhibited foam cell formation and promoted cholesterol efflux in THP-1 macrophages. Our results highlight the therapeutic potential of hespretin for the possible reduction in foam cell formation. This new mechanism could contribute the anti-atherogenic effects of hesperetin.

Section: Discussionsupporting

confidence: 93%

Hesperetin inhibits foam cell formation in macrophages via activating LXRα signal in an AMPK dependent manner

Zou

et al. 2020

Preprint

J Cellular Molecular Medi

“…Consistent with this, CTRP9 pre‐treatment of VSMCs significantly enhanced the degree of phosphorylation of AMPK in cholesterol‐loaded cells. Once activated, AMPK phosphorylates and regulates several downstream proteins including LOX1 , LXR , ABCA1 and ABCG1 . Our results demonstrated that CTRP9 increased LXR, ABCA1 and ABCG1 expression in VSMCs, while decreasing LOX1 levels.…”

Section: Discussionmentioning

confidence: 57%

C1q/TNF‐related protein 9 inhibits the cholesterol‐induced Vascular smooth muscle cell phenotype switch and cell dysfunction by activating AMP‐dependent kinase

Liu

Zhang

Lin

et al. 2017

Vascular smooth muscle cells (VSMCs) switch to macrophage‐like cells after cholesterol loading, and this change may play an important role in the progression of atherosclerosis. C1q/TNF‐related protein 9 (CTRP9) is a recently discovered adipokine that has been shown to have beneficial effects on glucose metabolism and vascular function, particularly in regard to cardiovascular disease. The question of whether CTRP9 can protect VSMCs from cholesterol damage has not been addressed. In this study, the impact of CTRP9 on cholesterol‐damaged VSMCs was observed. Our data show that in cholesterol‐treated VSMCs, CTRP9 significantly reversed the cholesterol‐induced increases in pro‐inflammatory factor secretion, monocyte adhesion, cholesterol uptake and expression of the macrophage marker CD68. Meanwhile, CTRP9 prevented the cholesterol‐induced activation of the TLR4–MyD88–p65 pathway and upregulated the expression of proteins important for cholesterol efflux. Mechanistically, as siRNA‐induced selective gene ablation of AMPKα1 abolished these effects of CTRP9, we concluded that CTRP9 achieves these protective effects in VSMCs through the AMP‐dependent kinase (AMPK) pathway.

BMC Complement Altern Med

“…Although the expression of genes involved in cholesterol biosynthesis, bile acid synthesis, and cholesterol efflux is regulated by LXR, our data show that CCGQ up-regulated some genes involved in these processes (CYP7A1 and ABCA1) and down-regulated others (HMGCR and SREBP2). In recent reports, AMPK activation increased ABCA1 mRNA and protein expression, increasing the cholesterol efflux capacity of macrophages [ 32 , 33 ]. Activation of AMPK by sulfated low molecular weight guluronate was linked to up-regulation of CYP7A1 in HepG2 cells [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Synergistic effect of phytochemicals on cholesterol metabolism and lipid accumulation in HepG2 cells

Leng

Yuan

et al. 2018

BackgroundCrocin (CRO), chlorogenic acid (CGA), geniposide (GEN), and quercetin (QUE) are all natural compounds with anti-obesity properties, in particular, hypolipidemic effects, which have been widely used for the treatment of obesity-related metabolic diseases. However, it is not yet known whether these compounds interact synergistically. Here, we investigated the effects and molecular mechanisms of CRO, CGA, GEN, QUE, and a combination of all four compounds (CCGQ), on lipid accumulation in human hepatoma (HepG2 cells).MethodsThe optimal concentration of CRO, CGA, GEN, QUE to stimulate HepG2 cells proliferation was determined using MTT assay. HepG2 cells were pretreated with 10 μmol/L simvastatin, 1 μmol/L CRO, 30 μmol/L CGA, 10 μmol/L GEN, 10 μmol/L QUE, and CCGQ (a combination of 1 μmol/L CRO, 30 μmol/L CGA, 10 μmol/L GEN, and 10 μmol/L QUE) for 24 or 48 h. Oil red O staining and extracellular TC and TG levels were detected. The RT-PCR was used to observe on cholesterol metabolism-related gene expression. Immunocytochemistry and western-blot assayed the 3-hydroxy-3-methylglutaryl-coenzyme (HMGCR) protein expression in HepG2 cells.ResultsCompared to those of control, we demonstrated that treating HepG2 cells for 48 h with CCGQ resulted in a strong synergistic effect, causing a marked decrease in lipid deposition in comparison to individual treatments, in both triglyceride and total cholesterol (CRO, 5.74- and 1.49-folds; CGA, 3.38- and 1.12-folds; GEN, 4.04- and 1.44-folds; QUE, 3.36- and 1.24-folds; simvastatin, 5.49- and 1.83-folds; and CCGQ, 7.75- and 2.20-folds), and Oil red O staining assays. In addition, CCGQ treatment increased ATP-binding cassette transporter (ABCA1), cholesterol 7α-hydroxylase (CYP7A1), and AMP-activated protein kinase 2α (AMPKα2) mRNA expression, while decreasing sterol regulatory element binding protein 2 (SREBP2), and liver X receptor alpha (LXRα) mRNA expression. Notably, CCGQ was more effective in decreasing HMGCR expression than the individual treatments.ConclusionThe CCGQ combination has potential, both as a complementary therapy for hyperlipemia, and in preventing further obesity-related complications.