Relevance of Autophagy Induction by Gastrointestinal Hormones: Focus on the Incretin-Based Drug Target and Glucagon

Kanasaki, Keizo; Kawakita, Emi; Koya, Daisuke

DPP-4, a member of the serine peptidase/prolyl oligopeptidase gene family, was first found as a T cell differentiation antigen (CD26) and also as cell surface aminopeptidase. DPP-4 displays numerous biological functions, such as protease activity, interaction with adenosine deaminase and the extracellular matrix proteins, co-receptor activity mediating viral entry, and regulation of intracellular signals (Kameoka et al., 1993; Kahne et al., 1999; Lambeir et al., 2003; Lopez-Otin and Matrisian, 2007; Lu et al., 2013) . Some preclinical studies have shown a potential link between DPP-4 inhibition and autophagy induction. In leptin-deficient ob/ob mice, sitagliptin at 50 mg/kg daily for 4 weeks ameliorated weight gain, metabolic disorders, and steatosis in the liver as well as insulin sensitivity. In this study, sitagliptin increased AMPK phosphorylation and decreased mTOR phosphorylation associated with the restoration of ATG5 and Beclin 1 messenger RNA expression that was suppressed in ob/ob mice. In addition, the relative level of LC3-II/LC3-I was significantly diminished in ob/ob mice and was restored to the basal level by sitagliptin (Zheng et al., 2018) . Another report showed that autophagic responses were significantly diminished in OLETF rats after experimental myocardial infarction associated with a deficiency in AMPK/ULK-1 activation, Akt/mTOR/S6 signaling, and increased Beclin-1-Bcl-2 interaction, which are key molecular events for suppressing autophagy. Intervention with the DPP-4 inhibitor vildagliptin inhibited the Beclin-1-Bcl-2 interaction and enhanced both LC3-II protein and autophagosomes in the noninfarcted region in OLETF rats without normalization of either AMPK/ULK-1 or mTOR/S6 signaling. Such effects of vildagliptin on heart autophagy are associated with an 80% survival rate in OLETF rats; chloroquine, an autophagy inhibitor, diminished these beneficial effects of vildagliptin (Murase et al., 2015) .