Fig. 6

Obesity, autophagy flux, miRNAs and endothelial function. Autophagy flux consists of a series of steps including initiation, elongation, fusion of the autophagosome with the lysosome and degradation. Autophagy induction is controlled by mTOR and AMPK, which tightly regulate the ULK complex: ULK1, ATG13 and FIP200. By modulating miRNA levels, obesity regulates autophagy induction. During obesity, increased levels of miR-155, miR-199a-5b and miR-101 are expressed and all directly target mTOR. miR-148b and miR-451, also increased during obesity, target AMPK. miR-199a, miR-28a, miR-106b and miR-17-5p target ULK1, while miR-20a and miR-20b target FIP200. Beclin1, which also plays an important role in autophagy initiation, is targeted by miR-506-3p, miR-216a, miR-129-5p and miR-376b. These four miRNAs are known to be increased during obesity. Autophagosome elongation involves ATG5, ATG7, ATG 12, ATG-16L1, LC3 and p62. ATG 5 can be suppressed by miR-181a and miR-374a; ATG7 by miR-210, miR-188-3p and miR-137; ATG 12 by miR-30d and miR-630 and ATG 16-L1 by miR-20a and miR-96. All these miRNAs are increased during obesity. LC3-II is post-transcriptionally controlled by miR-204, which is known to be induced during obesity. P62 is controlled by miR-17, miR-20, miR-93 and miR-106, which are all also increased during obesity. The fusion and degradation step is controlled by UVRAG, LAMP-1/2, RAB7, VAMP8 and STX17. All of these membrane fusion factors are tightly regulated by miRNAs. UVRAG is suppressed by miR-374, miR-630, miR-125, and miR-351; Lamp1 is inhibited by miR-23a and miR-320a, while LAMP2 is inhibited by miR-487-5p; Rab7, VAMP8 and STX17 are regulated by miR-30c, miR-96, and miR-124, respectively. All of these miRNAS are induced by obesity. In summary, the modulation that takes place in miRNA levels during obesity leads to autophagy flux disruption-induced endothelial dysfunction. ULK1: unc-51-like kinase 1; FIP200: focal adhesion kinase family interacting protein of 200 kDa; mTOR: mammalian target of rapamycin; ATG: autophagy-related protein; LC3: Microtubule-associated protein 1A/1B-light chain 3; p62: sequestrome 1; UVRAG: UV resistance-associated gene; VAMP8: vesicle-associated membrane protein; STX17: Syntaxin; LAMP: Lysosome-associated membrane proteins; Rab7: Ras-related protein