Dipeptidyl peptidase-4: a key player in chronic liver disease

Abstract

Dipeptidyl peptidase-4 (DPP-4) is a membrane-associated peptidase, also known as CD26. DPP-4 has widespread organ distribution throughout the body and exerts pleiotropic effects via its peptidase activity. A representative target peptide is glucagon-like peptide-1, and inactivation of glucagon-like peptide-1 results in the development of glucose intolerance/diabetes mellitus and hepatic steatosis. In addition to its peptidase activity, DPP-4 is known to be associated with immune stimulation, binding to and degradation of extracellular matrix, resistance to anti-cancer agents, and lipid accumulation. The liver expresses DPP-4 to a high degree, and recent accumulating data suggest that DPP-4 is involved in the development of various chronic liver diseases such as hepatitis C virus infection, non-alcoholic fatty liver disease, and hepatocellular carcinoma. Furthermore, DPP-4 occurs in hepatic stem cells and plays a crucial role in hepatic regeneration. In this review, we described the tissue distribution and various biological effects of DPP-4. Then, we discussed the impact of DPP-4 in chronic liver disease and the possible therapeutic effects of a DPP-4 inhibitor.

Keywords: Alogliptin; Cancer; Incretin; Insulin resistance; Linagliptin; Sitagliptin; Steatohepatitis; Teneligliptin; Vildagliptin; Viral hepatitis.

Figure 1

Pleiotropic effects of dipeptidyl peptidase-4. Dipeptidyl peptidase-4 (DPP-4) exerts various effects on metabolism and chemokine through peptidase activity. In addition, DPP-4 is involved in immune stimulation, binding to and degradation of extracellular matrix, and resistant to anti-cancer agents. DPP-4 also directly affects lipid accumulation. GLP: Glucagon-like peptide; ECM: Extracellular matrix; MMPs: Metalloproteinases; IL: Interleukin; IFN: Interferon; PPAR: Peroxisome proliferator-activated receptor; SREBP: Sterol regulatory element binding protein.