Regulation of AMPK Activation by CD36 Links Fatty Acid Uptake to β-Oxidation

Abstract

Increases in muscle energy needs activate AMPK and induce sarcolemmal recruitment of the fatty acid (FA) translocase CD36. The resulting rises in FA uptake and FA oxidation are tightly correlated, suggesting coordinated regulation. We explored the possibility that membrane CD36 signaling might influence AMPK activation. We show, using several cell types, including myocytes, that CD36 expression suppresses AMPK, keeping it quiescent, while it mediates AMPK activation by FA. These dual effects reflect the presence of CD36 in a protein complex with the AMPK kinase LKB1 (liver kinase B1) and the src kinase Fyn. This complex promotes Fyn phosphorylation of LKB1 and its nuclear sequestration, hindering LKB1 activation of AMPK. FA interaction with CD36 dissociates Fyn from the protein complex, allowing LKB1 to remain cytosolic and activate AMPK. Consistent with this, CD36−/− mice have constitutively active muscle and heart AMPK and enhanced FA oxidation of endogenous triglyceride stores. The molecular mechanism described, whereby CD36 suppresses AMPK, with FA binding to CD36 releasing this suppression, couples AMPK activation to FA availability and would be important for the maintenance of cellular FA homeostasis. Its dysfunction might contribute to the reported association of CD36 variants with metabolic complications of obesity in humans.

Endothelial cell CD36 optimizes tissue fatty acid uptake

“…A recent report showed that a metabolite of branch chain amiof several PPAR and insulin signaling pathway genes such as Pparα and Glut1 were increased in hearts of EC-Cd36 -/-mice, while Fas and Ampk expression levels were decreased ( Figure 8C). Hearts from CM-Cd36 -/-mice, like those from germline Cd36 -/-mice, had higher Ampk mRNA levels (Supplemental Figure 8A) (10,23). This contrasted with lower Ampk levels in hearts from EC-Cd36 -/-mice ( Figure 8A), perhaps reflecting greater glucose uptake.…”

“…LCFA binding to the CD36 ectodomain is followed by FA transfer to the plasma membrane through an internal tunnel that runs the length of the protein, as shown by the crystal structure of the CD36-LCFA complex (8). CD36 also functions as a LCFA sensor, influencing activation of PPARs (9) and AMPK (10).…”

Cardiac metabolism — A promising therapeutic target for heart failure

“…AMPK activation by AMP in low energy states inhibits ACC and reduces malonyl CoA levels (thereby relieving inhibition of CPT1) and increases FA entry into the mitochondria to be oxidized by the β-oxidation machinery. AMPK also recruits CD36 to the sarcolemma, increasing cellular FA uptake (Samovski, et al, 2015).…”

Ca2+ Binding/Permeation via Calcium Channel, CaV1.1, Regulates the Intracellular Distribution of the Fatty Acid Transport Protein, CD36, and Fatty Acid Metabolism

“…Recently, CD36 was shown to negatively regulate AMPK (45), which phosphorylates and decreases ACC activity. Decreased AMPK and p-ACC raises the possibility that malonyl CoA, produced by ACC, plays a role in decreased FA oxidation in the muscle of EK mice.…”

“…Recently, Samovski et al (45) suggested that CD36 suppresses AMPK activation (assessed as p-AMPK/AMPK) but fatty acids relieve this inhibition. We assessed AMPK activation in muscle of EK and WT mice and found that AMPK activity is reduced in EK muscle (Fig.…”