Uncoupling AMPK from autophagy: a foe that hinders the beneficial effects of metformin treatment on metabolic syndrome-associated atherosclerosis? Focus on “Glucose and palmitate uncouple AMPK from autophagy in human aortic endothelial cells”

Abstract

METABOLIC SYNDROME IS A CLUSTER of conditions including insulin resistance, dyslipidemia, hypertension, and central obesity, and it results in an increased risk of type 2 diabetes mellitus and cardiovascular diseases such as atherosclerosis. These conditions are rising year to year and are a leading cause of deaths worldwide. Therefore, potential therapeutic approaches to attenuate the pathogenesis of metabolic syndrome are urgently needed. Autophagy is a bulk intracellular degradation pathway that involves the formation of a double-membrane autophagosome, which enwraps and delivers cargo to the lysosome for their degradation. Autophagy is a catabolic process that is activated when cells lack nutrients and energy. Autophagy also serves as a cellular protective mechanism by removing damaged organelles including mitochondria and toxic protein aggregates under many pathophysiological conditions. Emerging evidence indicates that autophagy plays critical roles in cardiovascular diseases (5). Studies from cardiomyocyte-specific Atg5 knockout mice revealed that basal autophagy is essential in removing damaged organelles and proteins in cardiomyocytes to maintain their normal functions (8). Autophagy protects against ischemia-induced heart injury, but autophagy can also be detrimental in pressure overloadinduced heart failure and during reperfusion (5). Impaired autophagy is also associated with increased apoptosis, mitochondrial injury, intracellular Ca 2ϩ dysregulation, and cardiac contractile dysfunction. Furthermore, autophagy is also implicated in the regulation of atherosclerosis by regulating reactive oxygen species production, endoplasmic reticulum stress, inflammation, and oxidized lipoproteins in atherosclerotic plagues (5).Overnutrition due to excessive food consumption and its resultant obesity is a major cause of metabolic syndrome. Under metabolic syndrome conditions, it is well known that excessive nutrient intake leads to activation of the mammalian target of rapamycin (mTOR) and suppression of the AMPactivated protein kinase (AMPK), the key sensors of cellular nutrients and energy, respectively. mTOR and AMPK regulate autophagy on the Unc-51 like kinase 1 (ULK1, the yeast Atg1 homolog) complex, the most upstream component of the core autophagy machinery that is composed of ULK1, Atg13, FIP200, and Atg101 (7). Under excessive nutrient conditions, mTOR inhibits autophagy by directly phosphorylating ULK1 (S757), resulting in decreased ULK1 kinase activity (2, 4). Lack of cellular energy leads to the activation of AMPK, which phosphorylates ULK1 at different sites (S317, S467, S555, T574, S637, and S777) and activates ULK1 to promote autophagy (2, 4). Under this energy depletion condition, AMPK also suppresses mTOR by phosphorylating TSC2 and RAPTOR, two essential regulators of mTOR. Moreover, AMPK also regulates the function of the Beclin 1 complex by directly phosphorylating VPS34 and Beclin 1, which is essential for autophagosome formation by providing phosphatidylinositol 3-phosphate (PI3P) (3). The mult...

Metformin-induced activation of AMPK inhibits the proliferation and migration of human aortic smooth muscle cells through upregulation of p53 and IFI16

“…Previous studies have suggested that metformin exerts significant cardioprotective effects alongside its fundamental role as an antidiabetic agent ( 10 , 11 ). The mechanism of action of metformin in atherosclerosis is associated with AMPK ( 29 , 30 ). It has previously been reported that numerous cytokines, chemokines and growth factors regulate smooth muscle cell proliferation and the progression of atherosclerosis ( 31 , 32 ).…”

Endothelial Cell Autophagy in Atherosclerosis is Regulated by miR-30-Mediated Translational Control of ATG6

“…Upon injury, endothelial cell autophagy may occur to protect the cells from being damaged, while the failure or inhibition of autophagy results in endothelial cell apoptosis, leading to the break-down of the integrity of endothelium to facilitate the local lipid deposition into atherogenesis, plaque instability, and even acute coronary occlusion and sudden death [13,[18][19][20][21][22][23]. Nevertheless, our understanding of the mechanisms that control the autophagy of endothelial cells is still limited.…”

“…Autophagy-associated protein 6 (ATG6, or Beclin-1), ATG7 and p62 are several key autophagy-associated proteins that strongly induce autophagy in an independent or coordinated manner [27]. Autophagy has been shown to play a critical role in endothelial cells to prevent development of atherosclerosis [13,[18][19][20][21][22][23]. Nevertheless, the underlying mechanisms remain elusive.…”

Shear Stress in Autophagy and Its Possible Mechanisms in the Process of Atherosclerosis

“…Moreover, the autophagosome formation is dependent on the AMPK, due to direct phosphorylation of VPS34 and BECN1, and then regulates the activity of BECN1 complex (Kim et al, 2013). Taken together, when cellular energy is depleted, AMPK can regulate mTOR, ULK1, and VPS34-BECN1 complex and then guarantee the activation of autophagy (Ding, 2015). In VSMCs, TRPV1 induced by capsaicin can activate autophagy and then decrease the accumulation of lipid through decreased uptake of lipid and promote cholesterol efflux.…”