College of Animal Science, Zhejiang University, Hangzhou, P.R. China.
Key Laboratory of Animal Nutrition & Feed Sciences, Ministry of Agriculture, Zhejiang University, Hangzhou, P.R. China.
FASEB J. 2020 Apr;34(4):4852-4869. doi: 10.1096/fj.201901994R. Epub 2020 Feb 11.
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.
细胞长链脂肪酸 (LCFAs) 的摄取是调节细胞能量稳态的关键生理过程。AMPK 已被证明可调节多种细胞中的 LCFAs 摄取，但它是否对肠道 LCFAs 摄取有影响尚不清楚。在本研究中，我们发现 AMPK 增强了肠道上皮细胞 (IECs) 中的 LCFAs 摄取。此外，肠道上皮细胞特异性 AMPK 缺失会损害肠道 LCFAs 的吸收，并保护小鼠免受高脂肪饮食诱导的肥胖。在机制上，我们发现 AMPK 通过上调 Parkin 介导的 CD36 多泛素化，降低了 IECs 中的 CD36 蛋白水平。此外，我们的结果表明，AMPK 通过 FTO 依赖性去甲基化 N6-甲基腺苷（m6A），以 YTHDF2 依赖的方式影响 PARK2（Parkin 基因名称）mRNA 的稳定性。此外，AMPK 促进了 IECs 中 CD36 向质膜的易位，但 AKT 信号通路的抑制抑制了这种效应，也阻止了 AMPK 诱导的脂肪酸摄取加速。这些结果表明，AMPK 通过上调 CD36 蛋白丰度并促进其膜易位来促进肠道 LCFAs 的摄取。这些发现揭示了 AMPK 在调节肠道 LCFAs 摄取中的作用。
