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

Kanasaki, Keizo; Kawakita, Emi; Koya, Daisuke

The liver is the potential target organ for GLP-1-induced autophagy (He et al., 2016) . Among the organs, the level of GLP-1 in the liver is highest because of transport through the hepatic portal vein from the gut. Intervention of GLP-1 or its analogs could ameliorate several aspects of liver injury (D'Alessio et al., 2004; Cantini et al., 2016) and influence hepatic gluconeogenesis, glycogen synthesis, and glycolysis (Figure 2) . For the effects of GLP-1, its receptor GLP-1R is essential; the presence of GLP-1R is controversial in hepatocytes and the focus of intense discussion. Protein expression of GLP-1R has been reported in transformed human hepatocyte cell lines, Hep-G2, HuH7, and primary human hepatocytes (Gupta et al., 2010) . Even though there is confirmation of GLP-1R expression on hepatocytes, research has suggested that some effects of GLP-1 are indeed GLP-1R-independent events (Bullock et al., 1996 ; Flock et al., 2007; Aviv et al., 2009; Tomas et al., 2010 ). An alternative possible explanation could be based on the GLP-1 degradation products, such as GLP-1 9-36, GLP-1 28-36, or GLP-1 32-36. Studies have indicated that both GLP-1 28-36 and GLP-1 32-36 are cell-penetrating peptides that do not require a GLP-1R (Elahi et al., 2014) . GLP-1(32-36) amide, a novel pentapeptide cleavage product of GLP-1, modulates whole-body glucose metabolism in dogs (Elahi et al., 2014) . GLP1-derived nonapeptide GLP1(28-36) amide preserves pancreatic β cells from glucolipotoxicity (Liu et al., 2012) and activates PKA and Wnt signaling [reviewed in (Jin and Weng, 2016) ]. The beneficial effects of GLP-1 fragments were reported to include kidney protective effects in db/db mice with diabetes (Moellmann et al., 2018) . Whether such GLP-1 derived fragments are relevant for the GLP-1-induced liver autophagy induction is not known and required further investigation.