AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases

Abstract

This article is available online at http://www.jlr.org termed as metabolic syndrome (MetS) ( 1 ), characterized by a clustering of major risk factors for developing cardiovascular disease. Obesity, representing derangement in energy balances, is tightly linked with the development of type-2 diabetes through its ability to engender insulin resistance, leading to glucose intolerance and development of type-2 diabetes and dyslipidemia. Thus, insulin resistance The pathophysiology of diabetes and obesity is a very complex process involving many pathways. Deregulation of these pathways gives rise to metabolic abnormalities

ETC-1002 regulates immune response, leukocyte homing, and adipose tissue inflammation via LKB1-dependent activation of macrophage AMPK

“…Benefi cial effects of ETC-1002 on lipid and glucose metabolism have been demonstrated in multiple animal models and have been linked to ETC-1002-mediated activation of AMP-activated protein kinase (AMPK) (12)(13)(14)(15). AMPK represents an attractive therapeutic target, as it plays a fundamental role in maintaining cellular energy homeostasis via coordinating glucose and lipid metabolism as well as downregulating proinfl ammatory signaling pathways (16)(17)(18). In clinical studies, ETC-1002 has not only demonstrated improved lipid profi les but also revealed signifi cantly attenuated levels of hsCRP ( 19 ), an independent risk factor for CAD and a well-established clinical biomarker of infl ammation ( 20,21 ).…”

“…Liver kinase B1 is an essential serine-threonine kinase that directly phosphorylates and activates AMPK ( 16,18,38,39 ). Previously, we have demonstrated that in HepG2 cells, …”

“…In the present study, siRNA interference targeting endogenous levels of LKB1 was utilized to confi rm the mechanistic link between ETC-1002-mediated AMPK activation and its anti-infl ammatory effects. LKB1 is a well-established, physiologically relevant kinase that phosphorylates and activates AMPK ( 16,18,38,39 ). AMPK activation by agonists, such as AICAR, metformin, or phenformin, or in response to stress was absent in LKB1-deficient cells, identifying LKB1 as an obligatory AMPK-activating kinase ( 38,46 ).…”

Adenosine Monophosphate–Activated Kinase and Its Key Role in Catabolism: Structure, Regulation, Biological Activity, and Pharmacological Activation

“…In most cells, including skeletal and cardiac muscle, liver, and adipose tissue, AMPK stimulates fatty acid oxidation, mitochondrial biogenesis, glucose transporter type 4 (GLUT4) translocation, and glucose uptake, while inhibiting protein synthesis, gluconeogenesis, and fatty acid and cholesterol synthesis (Steinberg and Kemp, 2009;Srivastava et al, 2012;Ruderman et al, 2013). Insulin secretion from pancreatic b-cells can be inhibited by AMPK (Steinberg and Kemp, 2009), and it has been shown that AMPK can increase food intake via activating signaling in the hypothalamus (Minokoshi et al, 2004).…”

Senna alata leaf extract restores insulin sensitivity in high-fat diet-induced obese mice

“…In mice fed with high-fat diet (HFD), absence of AMPKα2 in skeletal muscle subunit led to a development of glucose intolerance and insulin resistance [6]. AMPK is thus considered a therapeutic target in the prevention and treatment of T2DM [7][8][9]. Activation of AMPK in the liver and muscle is expected to elicit beneficial metabolic effects with the potential to improve the defects associated with T2DM and the metabolic syndrome [8].…”