Role of dipeptidyl peptidase IV (DPP4) in the development of dyslipidemia: DPP4 contributes to the steroid metabolism pathway.

Aims: We previously reported that dipeptidyl peptidase IV (DPP4)-deficient rats were susceptible to dyslipidemia induced by streptozotocin (STZ). Hence, it is suggested that DPP4 is important for lipid metabolism.

Main Methods: In this study, to verify the role of DPP4 in the development of dyslipidemia, we carried out a microarray analysis of the livers of STZ-treated wild-type and DPP4-deficient rats and showed that the expression levels of genes involved in metabolic processes (steroid metabolic processes and cellular lipid metabolic processes) were significantly altered by STZ treatment.

Key Findings: In the wild-type rats, the expression of hydroxysteroid (17-beta) dehydrogenase 2 (Hsd7b2), which catalyzes sex steroid synthesis from cholesterol, was significantly increased by about 15-fold after STZ treatment; however, it did not change in the DPP4-deficient rats. In the STZ untreated group of DPP4-deficient rats, the expression levels of cytochrome P450, subfamily 51 (Cyp51) and sterol-C4-methyl oxidase-like (Sc4mol), which catalyze intermediate steps in cholesterol synthesis, were significantly elevated compared to those of other groups. Similar results were demonstrated in HuH7-cells after DPP4 overexpression or the addition of human sera containing DPP4.

Significance: DPP4 is crucial for regulating the expression of factors related to steroid metabolism such as Cyp51, Sc4mol, and Hsd17b2, and DPP4 deficiency or inhibition may cause dyslipidemia.