Regulation and function of AMPK in physiology and diseases

Abstract

5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that was originally identified as the key player in maintaining cellular energy homeostasis. Intensive research over the last decade has identified diverse molecular mechanisms and physiological conditions that regulate the AMPK activity. AMPK regulates diverse metabolic and physiological processes and is dysregulated in major chronic diseases, such as obesity, inflammation, diabetes and cancer. On the basis of its critical roles in physiology and pathology, AMPK is emerging as one of the most promising targets for both the prevention and treatment of these diseases. In this review, we discuss the current understanding of the molecular and physiological regulation of AMPK and its metabolic and physiological functions. In addition, we discuss the mechanisms underlying the versatile roles of AMPK in diabetes and cancer.

Figure 1

Molecular regulation of AMPK and LKB1. (a) Modification of the AMPK α1 (top) and α2 (bottom) subunits by phosphorylation/dephosphorylation, ubiquitination, sumoylation and oxidation/reduction. Pathways marked in red indicate α1- or α2-subunit-specific modifications. Numbers of modified amino acids are based on human proteins, and numbers in parenthesis are those reported in the original research (see text for details). (b) Modification of the AMPK β1 (top) and β2 (bottom) subunits by myristoylation, ubiquitination, sumoylation and glycogen binding. Pathways marked in red indicate β1- or β2-subunit-specific modifications (see text for details). (c) Modification of the AMPK γ-subunit by AMP, ADP or ATP binding. Binding of AMP to CBS1 induces allosteric activation, and binding of AMP or ADP to CBS3 induces T172 phosphorylation (see text for details). (d) Modification and regulation of LKB1 by phosphorylation, acetylation, ubiquitination, sumoylation and 4HNE adduction (see text for details). Arrow indicates activation, and bar-headed line indicates inhibition. α/γ-BD, α/γ-subunit-binding domain; AID, autoinhibitory domain; β-BD, β-subunit-binding domain; CBM, carbohydrate-binding module; CBS, cystathionine beta-synthase domain; NLS, nuclear localization signal.

Figure 2

Metabolic functions of AMPK. A schematic summarizing the mechanisms underlying AMPK-induced regulation of diverse metabolic pathways. Arrow indicates activation, and bar-headed line indicates inhibition (see text for details).

Figure 3

Physiological regulation of AMPK. A schematic summarizing the mechanisms underlying the regulation of AMPK activity under diverse physiological and pathological conditions. Arrow indicates activation, and bar-headed line indicates inhibition (see text for details).

Figure 4

Integrative role of AMPK in diabetes and cancer. This model describes the integrative role of AMPK in diabetes and cancer. AMPK exerts anti-inflammatory effects largely by regulating FA metabolism, NFκB and ER stress, indicating that AMPK activators can be used for both preventing and treating insulin resistance and diabetes. The anti-inflammatory effects of AMPK also prevent cancer by inhibiting the cancer initiation and promotion stages. However, AMPK activation can also promote malignant conversion, progression and metastasis by enabling metabolic adaptation of tumor cells. Arrow indicates activation, bar-headed line indicates inhibition (see text for details). N, normal cells; I, initiated cells.