AMPK facilitates intestinal long-chain fatty acid uptake by manipulating CD36 expression and translocation.

Cellular long-chain fatty acids' (LCFAs) uptake is a crucial physiological process that regulates cellular energy homeostasis. AMPK has been shown to modulate LCFAs uptake in several kinds of cells, but whether it exerts an impact on intestinal LCFAs uptake is not quite clear. In the current study, we found that AMPK reinforced LCFAs uptake in intestinal epithelial cells (IECs). Moreover, intestinal epithelium-specific AMPK deletion impaired intestinal LCFAs absorption and protected mice from high-fat diet-induced obesity. Mechanistically, we discovered that AMPK deletion reduced the CD36 protein level by upregulating Parkin-mediated polyubiquitination of CD36 in IECs. Furthermore, our results revealed that AMPK affected PARK2 (gene name of Parkin) mRNA stability in a YTHDF2-dependent manner through FTO-dependent demethylation of N -methyladenosine (m A). Besides, AMPK promoted the translocation of CD36 to the plasma membrane in IECs, but the inhibition of AKT signaling suppressed this effect, which also halted the accelerated fatty acid uptake induced by AMPK. These results suggest that AMPK facilitates the intestinal LCFAs uptake by upregulating CD36 protein abundance and promoting its membrane translocation simultaneously. Such findings shed light on the role of AMPK in the regulation of intestinal LCFAs uptake.